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

PubMed Central

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-1?, TNF?, immunoglobulin G (IgG), AQP4 mRNA and protein were measured in brain tissues. IL-1?, 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-1?, TNF?, 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-1? 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-1? and TNF?) 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.



Pharmacologic management of brain edema  

Microsoft Academic Search

Opinion statement  Cerebral edema is an intrinsic response to a variety of structural and metabolic insults. It is a major contributing factor\\u000a in the development of intracranial hypertension and brain herniation, underscoring the need for early identification through\\u000a an integration of clinical and neuroimaging findings, followed by timely institution of measures to reduce brain edema and\\u000a intracranial hypertension. The management of

Alexander Papangelou; John J. Lewin III; Marek A. Mirski; Robert D. Stevens



Purinergic Receptor Stimulation Reduces Cytotoxic Edema and Brain Infarcts in Mouse Induced by Photothrombosis by Energizing Glial Mitochondria  

PubMed Central

Treatments to improve the neurological outcome of edema and cerebral ischemic stroke are severely limited. Here, we present the first in vivo single cell images of cortical mouse astrocytes documenting the impact of single vessel photothrombosis on cytotoxic edema and cerebral infarcts. The volume of astrocytes expressing green fluorescent protein (GFP) increased by over 600% within 3 hours of ischemia. The subsequent growth of cerebral infarcts was easily followed as the loss of GFP fluorescence as astrocytes lysed. Cytotoxic edema and the magnitude of ischemic lesions were significantly reduced by treatment with the purinergic ligand 2-methylthioladenosine 5? diphosphate (2-MeSADP), an agonist with high specificity for the purinergic receptor type 1 isoform (P2Y1R). At 24 hours, cytotoxic edema in astrocytes was still apparent at the penumbra and preceded the cell lysis that defined the infarct. Delayed 2MeSADP treatment, 24 hours after the initial thrombosis, also significantly reduced cytotoxic edema and the continued growth of the brain infarction. Pharmacological and genetic evidence are presented indicating that 2MeSADP protection is mediated by enhanced astrocyte mitochondrial metabolism via increased inositol trisphosphate (IP3)-dependent Ca2+ release. We suggest that mitochondria play a critical role in astrocyte energy metabolism in the penumbra of ischemic lesions, where low ATP levels are widely accepted to be responsible for cytotoxic edema. Enhancement of this energy source could have similar protective benefits for a wide range of brain injuries.

Zheng, Wei; Watts, Lora Talley; Holstein, Deborah M.; Prajapati, Suresh I.; Keller, Charles; Grass, Eileen H.; Walter, Christi A.; Lechleiter, James D.



Osmotherapy in brain edema: a questionable therapy.  


Despite the fact that it has been used since the 1960s in diseases associated with brain edema and has been investigated in >150 publications on head injury, very little has been published on the outcome of osmotherapy. We can only speculate whether osmotherapy improves outcome, has no effect on outcome, or leads to worse outcome. Here we describe the action and potentially beneficial and adverse effects of the 2 most commonly used osmotic solutions, mannitol and hypertonic saline, and present some critical aspects of their use. There is a well-documented transient intracranial pressure (ICP)-reducing effect of osmotherapy, but an adverse rebound increase in ICP after its withdrawal has been discussed extensively in the literature and is an expected pathophysiological phenomenon. From side effects related to renal and pulmonary failure, electrolyte disturbances, and a rebound increase in ICP, osmotherapy can be negative for outcome, which may explain why we lack scientific support for its use. These drawbacks, and the fact that the most recent Cochrane meta-analyses of osmotherapy in brain edema and stroke could not find any beneficial effects on outcome, make routine use of osmotherapy in brain edema doubtful. Nevertheless, the use of osmotherapy as a temporary measure may be justified to acutely prevent brain stem compression until other measures, such as evacuation of space-occupying lesions or decompressive craniotomy, can be performed. This article is the Con part in a Pro-Con debate in the present journal on the general routine use of osmotherapy in brain edema. PMID:22955195

Grände, Per-Olof; Romner, Bertil



HEPES prevents edema in rat brain slices  

Microsoft Academic Search

Brain slices gain water when maintained in bicarbonate-buffered artificial cerebro-spinal fluid (ACSF) at 35°C. We previously showed that this edema is linked to glutamate receptor activation and oxidative stress. An additional factor that may contribute to swelling is acidosis, which arises from high CO2 tension in brain slices. To examine the role of acidosis in slice edema, we added N-2-hydroxyethylpiperazine-N?-2-ethanesulfonic

Duncan G. MacGregor; Mitchell Chesler; Margaret E. Rice



International brain edema symposia 1967-2011.  


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

Kuroiwa, Toshihiko



Brain edema in diseases of different etiology.  


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

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



Ethanol-induced hyponatremia augments brain edema after traumatic brain injury.  


Alcohol consumption augments brain edema by expression of brain aquaporin-4 after traumatic brain injury. However, how ethanol induces brain aquaporin-4 expression remains unclear. Aquaporin-4 can operate with some of ion channels and transporters. Therefore, we hypothesized that ethanol may affect electrolytes through regulating ion channels, leading to express aquaporin-4. To clarify the hypothesis, we examined role of AQP4 expression in ethanol-induced brain edema and changes of electrolyte levels after traumatic brain injury in the rat. In the rat traumatic brain injury model, ethanol administration reduced sodium ion concentration in blood significantly 24 hr after injury. An aquaporin-4 inhibitor recovered sodium ion concentration in blood to normal. We observed low sodium ion concentration in blood and the increase of brain aquaporin-4 in cadaver with traumatic brain injury. Therefore, ethanol increases brain edema by the increase of aquaporin-4 expression with hyponatremia after traumatic brain injury. PMID:22746038

Katada, Ryuichi; Watanabe, Satoshi; Ishizaka, Atsushi; Mizuo, Keisuke; Okazaki, Shunichiro; Matsumoto, Hiroshi



Effect of ifenprodil, a polyamine site NMDA receptor antagonist, on brain edema formation following asphyxial cardiac arrest in rats  

Microsoft Academic Search

Objective: Brain edema occurs in experimental and clinical cardiac arrest (CA) and is predictive of a poor neurological outcome. N-Methyl-d-aspartate (NMDA) receptors contribute to brain edema elicited by focal cerebral ischemia\\/reperfusion (I\\/R). Ifenprodil, a NMDA receptor antagonist, attenuates brain edema and injury size in rats after focal cerebral I\\/R. We assessed the hypothesis that ifenprodil reduces CA-elicited brain edema. Methods:

Feng Xiao; Sibile Pardue; Thomas Arnold; Donna Carden; J. Steven Alexander; Jared Monroe; Christopher D Sharp; Richard Turnage; Steven Conrad



Mild Intraischemic Hypothermia Reduces Postischemic Hyperperfusion, Delayed Postischemic Hypoperfusion, Blood-Brain Barrier Disruption, Brain Edema, and Neuronal Damage Volume After Temporary Focal Cerebral Ischemia in Rats  

Microsoft Academic Search

Summary: Mild to moderate hypothermia (30-33°C) reduces brain injury after brief (<2-h) periods of focal ischemia, but its effectiveness in prolonged temporary ischemia is not fully understood. Thirty-two Sprague-Dawley rats anesthetized with 1.5% isoflurane underwent 3 h of middle cerebral artery occlusion under hypothermic (33°C) or normothermic (37°C) conditions followed by 3 or 21 h of reperfusion under normothermic conditions

Hiroshi Karibe; Gregory J. Zarow; Steven H. Graham; Philip R. Weinstein



Enriched environment preconditioning induced brain ischemic tolerance without reducing infarct volume and edema: the possible role of enrichment-related physical activity increase.  


External stimuli, including environmental enrichment (EE) and physical activity, have been shown to significantly facilitate recovery from brain injury. However, whether EE can be used as a preconditioning method to induce cerebral ischemic tolerance has never been investigated. Furthermore, whether, and to what extent, such environmental stimuli regulate physical activity to promote neuroprotection is largely unclear. To examine the neuroprotective effects of pre-ischemic EE (PIEE) and to investigate the relationship between these effects and EE-induced physical activity, we tested neurobehavioral and morphological recovery of rats following transient focal cerebral ischemia. Our study showed that PIEE improved the recovery of motor function, spatial learning and memory without reduction in brain edema or infarct volume. We also found that PIEE robustly increased the level of physical activity of rats that positively correlated with the extent of neurobehavioral recovery. Our results suggest that PIEE may induce brain ischemic tolerance through, at least partially, increasing physical activity. PMID:23501217

Xie, Hongyu; Wu, Yi; Jia, Jie; Liu, Gang; Zhang, Feng; Zhang, Qi; Yu, Kewei; Hu, Yongshan; Bai, Yulong; Hu, Ruiping



Proton nuclear magnetic resonance studies on brain edema.  


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. PMID:6281400

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



Propofol Administration Modulates AQP-4 Expression and Brain Edema After Traumatic Brain Injury.  


The increased intracranial pressure caused by brain edema following traumatic brain injury (TBI) always leads to poor patient prognosis. Aquaporin-4 (AQP-4) plays an important role in edema formation and resolution, which may provide a novel therapeutic target for edema treatment. In this present study, we found that propofol treatment, within a short time, after TBI significantly reduced brain edema in a controlled cortical injury rat model and suppressed in vivo expression of AQP-4. The ameliorating effect of propofol was associated with attenuated expression of interleukin-1? (IL-1?) and tumor necrosis factor-? (TNF-?). In addition, the regulatory effect of propofol on AQP-4 expression was investigated in cultured astrocytes. Results showed that propofol could block the stimulatory effect of IL-1? and TNF-? on AQP-4 expression in cultured astrocytes. We also found that both NF?B and p38/MAPK pathways were involved in IL-1? and TNF-?-induced AQP-4 expression and that propofol functions as a dual inhibitor of NF?B and p38/MAPK pathways. In conclusion, treatment with propofol, within a short time, after TBI attenuates cerebral edema and reduces the expression of AQP-4. Propofol modulates acute AQP-4 expression by attenuating IL-1? and TNF-? expression and inhibiting IL-1? and TNF-? induced AQP-4 expression. PMID:23494261

Ding, Zhongyang; Zhang, Jiaming; Xu, Jinyu; Sheng, Guangjie; Huang, Guorong



Effect of VEGF Receptor Antagonist (VGA1155) on Brain Edema in the Rat Cold Injury Model  

Microsoft Academic Search

Vascular endothelial growth factor (VEGF) is a major mediator of angiogenesis and a strong vascular permeability factor. Blockade of VEGF may have a potential to treat brain edema after brain injury. In the rat cold injury model, the VEGF receptor antagonist VGA1155 significantly reduced the brain water content and the maximum effect was obtained when given at 30 minutes after




Xanthine oxidase-derived hydrogen peroxide contributes to ischemia reperfusion-induced edema in gerbil brains.  

PubMed Central

The contribution of toxic O2 metabolites to cerebral ischemia reperfusion injury has not been determined. We found that gerbils subjected to temporary unilateral carotid artery occlusion (ischemia) consistently developed neurologic deficits during ischemia with severities that correlated with increasing degrees of brain edema and brain H2O2 levels after reperfusion. In contrast, gerbils treated just before reperfusion (after ischemia) with dimethylthiourea (DMTU), but not urea, had decreased brain edema and brain H2O2 levels. In addition, gerbils fed a tungsten-rich diet for 4, 5, or 6 wk developed progressive decreases in brain xanthine oxidase (XO) and brain XO + xanthine dehydrogenase (XD) activities, brain edema, and brain H2O2 levels after temporary unilateral carotid artery occlusion and reperfusion. In contrast to tungsten-treated gerbils, allopurinol-treated gerbils did not have statistically significant decreases in brain XO or XO + XD levels, and reduced brain edema and brain H2O2 levels occurred only in gerbils developing mild but not severe neurologic deficits during ischemia. Finally, gerbils treated with DMTU or tungsten all survived, while greater than 60% of gerbils treated with urea, allopurinol, or saline died by 48 h after temporary unilateral carotid artery occlusion and reperfusion. Our findings indicate that H2O2 from XO contributes to reperfusion-induced edema in brains subjected to temporary ischemia. Images

Patt, A; Harken, A H; Burton, L K; Rodell, T C; Piermattei, D; Schorr, W J; Parker, N B; Berger, E M; Horesh, I R; Terada, L S



[Increased intracranial pressure and brain edema].  


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

Dietrich, W; Erbguth, F



Evaluation of brain edema using magnetic resonance proton relaxation times  

SciTech Connect

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.

Fu, Y.; Tanaka, K.; Nishimura, S. (Baba Memorial Hospital, Osaka (Japan))





... edema of the legs, especially in hot weather. Eating food with too much salt can make the problem worse. Edema can also be a side effect of taking certain medicines. Some health problems, such as congestive heart failure, liver disease and kidney disease, can cause edema. You cannot ...


Molecular mechanisms of brain tumor edema  

Microsoft Academic Search

Despite their diverse histological types, most brain tumours cause brain oedema, which is a significant cause of patient morbidity and mortality. Brain tumour oedema occurs when plasma-like fluid enters the brain extracellular space through impaired capillary endothelial tight junctions in tumours. Under-expression of the tight junction proteins occludin, claudin-1 and claudin-5 are key molecular abnormalities responsible for the increased permeability

M. C. Papadopoulos; S. Saadoun; D. K. Binder; G. T. Manley; S. Krishna; A. S. Verkman



The Effect of Dexmedetomidine on Brain Edema and Neurological Outcomes in Surgical Brain Injury in Rats  

PubMed Central

Background Surgical brain injury (SBI) is damage to functional brain tissue resulting from neurosurgical manipulations such as sharp dissection, electrocautery, retraction, and direct applied pressure. Brain edema is the major contributor to morbidity with inflammation, necrosis, oxidative stress and apoptosis likely playing smaller roles. Effective therapies for SBI may improve neurological outcomes and postoperative morbidities associated with brain surgery. Previous studies show an adrenergic correlation to blood-brain barrier control. The alpha-2 receptor agonist dexmedetomidine (DEX) has been shown to improve neurological outcomes in stroke models. We hypothesized that DEX may reduce brain edema and improve neurological outcomes in a rat model of SBI. Methods Male Sprague-Dawley rats (n=63) weighing 280–350g were randomly assigned to one of four intraperitoneal (IP) treatment groups: sham IP, vehicle IP, DEX 10 mg/kg, and DEX 30 mg/kg. Treatments were given 30 minutes before SBI. These treatment groups were repeated to observe the physiologic impact of DEX on mean arterial blood pressure (MAP), heart rate (HR), and blood glucose on SBI naïve animals. Rats were also assigned to four postinjury IV treatment groups: sham IV, vehicle IV, DEX 10/5, and DEX 30/15 (DEX group doses were 10 and 30 mg/kg/hr, with 5 and 15 mg/kg initial loading doses respectively). Initial loading doses began 20 minutes after SBI, followed by 2 hours of infusion. SBI animals were subjected to neurological testing 24 hours after brain injury by a blinded observer, promptly killed, and brain water content measured via the dry/wet weight method. Results All treatment groups showed a significant difference in ipsilateral frontal brain water content and neurological scores when compared with sham animals. However, there was no difference between DEX-treated and vehicle animals. Physiologic monitoring showed treatment with low or high doses of DEX significantly decreased MAP and HR, and briefly increased blood glucose compared with naïve or vehicle-treated animals. Conclusions DEX administration did not reduce brain edema or improve neurological function after SBI in this study. The statistical difference in brain water content and neurological scores when comparing sham treatment to vehicle and DEX treatments shows consistent reproduction of this model. Significant changes in MAP, HR, and blood glucose after DEX as compared to vehicle and sham treatments suggest appropriate delivery of drug.

Benggon, Michael; Chen, Han; Applegate, Richard; Martin, Robert; Zhang, John H.



Induced and sustained hypernatremia for the prevention and treatment of cerebral edema following brain injury.  


Cerebral edema develops in response to and as a result of a variety of neurologic insults such as ischemic stroke, traumatic brain injury, and tumor. It deforms brain tissue, resulting in localized mass effect and increase in intracranial pressure (ICP) that are associated with a high rate of morbidity and mortality. When administered in bolus form, hyperosmolar agents such as mannitol and hypertonic saline have been shown to reduce total brain water content and decrease ICP, and are currently the mainstays of pharmacological treatment. However, surprisingly, little is known about the increasingly common clinical practice of inducing a state of sustained hypernatremia. Herein, we review the available studies employing sustained hyperosmolar therapy to induce hypernatremia for the prevention and/or treatment of cerebral edema. Insufficient evidence exists to recommend pharmacologic induction of hypernatremia as a treatment for cerebral edema. The strategy of vigilant avoidance of hyponatremia is currently a safer, potentially more efficacious paradigm. PMID:23468135

Ryu, Justine H; Walcott, Brian P; Kahle, Kristopher T; Sheth, Sameer A; Peterson, Randall T; Nahed, Brian V; Coumans, Jean-Valery C E; Simard, J Marc



Expression of aquaporin-4 augments cytotoxic brain edema after traumatic brain injury during acute ethanol exposure.  


We previously reported that ethanol consumption affects morbidity and mortality after traumatic brain injury (TBI) by accelerating brain edema via oxidative stress after TBI. Aquaporin-4 (AQP4), a water channel, is involved in brain edema formation. In this study, we found that acute ethanol administration increased AQP4 expression after TBI, leading to severe brain edema in rats. Rats were pretreated with ethanol (3 g/kg) or dl-buthionine-(S,R)-sulfoximine (BSO; 100 mg/kg), an oxidative stressor, before TBI. Acetazolamide, an AQP4 inhibitor, was administered to ethanol-pretreated rats 3 or 12 hours after TBI. Brain edema was increased 24 hours after TBI in both the ethanol- and BSO-pretreated groups. Ethanol pretreatment induced lipid peroxidation 24 hours after TBI. Transcription factors, NF-?B and hypoxia-inducible factor-1?, were activated 3 and 24 hours after TBI in the BSO- and ethanol-pretreated groups, respectively. In the ethanol-pretreated group, AQP4 was accumulated, particularly in astrocyte end feet, 24 hours after TBI. Acetazolamide treatment improved the survival rate to 100% and decreased brain edema and AQP4 in ethanol-pretreated rats. These findings suggest that ethanol induces up-regulation of AQP4, leading to brain edema. The accumulation of AQP4 may play an important role in the augmentation of brain edema after TBI under ethanol consumption. PMID:22051773

Katada, Ryuichi; Nishitani, Yoko; Honmou, Osamu; Mizuo, Keisuke; Okazaki, Shunichiro; Tateda, Kenji; Watanabe, Satoshi; Matsumoto, Hiroshi



Quick detection of brain tumors and edemas: A bounding box method using symmetry  

Microsoft Academic Search

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,

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


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

NASA Astrophysics Data System (ADS)

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.

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



Tissue hyperosmolality and brain edema in cerebral contusion.  


Severe cerebral contusion is often associated with nonhemorrhagic mass effect that progresses rapidly within 12 to 48 hours posttrauma. The mechanisms underlying such a rapid progression of mass effect cannot be fully explained by classic concepts of vasogenic and cytotoxic brain edema. Data from previous clinical trials, including diffusion-weighted magnetic resonance imaging studies, have indicated that cells in the central (core) area of the contusion undergo shrinkage, disintegration, and homogenization, whereas cellular swelling is located predominately in the peripheral (rim) area during this period. The authors hypothesized that high osmolality within the contused brain tissue generates an osmotic potential across the central and peripheral areas or causes blood to accumulate a large amount of water. To elucidate the role of tissue osmolality in contusion edema, they investigated changes in tissue osmolality, specific gravity, and ion concentration in contused brain in both experimental and clinical settings. Their results demonstrated that cerebral contusion induced a rapid increase in tissue osmolality from a baseline level of 311.4 +/- 11.3 to 402.8 +/- 15.1 mOsm at 12 hours posttrauma (p < 0.0001). Specific gravity in tissue significantly decreased from 1.0425 +/- 0.0026 to 1.0308 +/- 0.0028 (p < 0.01), reflecting water accumulation in contused tissue. The total ionic concentration [Na+] + [K+] + [Cl-] did not change significantly at any time point. Inorganic ions do not primarily contribute to this elevation in osmolality, suggesting that the increase in colloid osmotic pressure through the metabolic production of osmoles or the release of idiogenic osmoles can be a main cause of contusion edema. PMID:17613236

Kawamata, Tatsuro; Mori, Tatsuro; Sato, Shoshi; Katayama, Yoichi



Proton-nuclear magnetic resonance relaxation times in brain edema  

SciTech Connect

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.

Kamman, R.L.; Go, K.G.; Berendsen, H.J. (Univ. of Groningen (Netherland))



Curcumin attenuates cerebral edema following traumatic brain injury in mice: a possible role for aquaporin-4?  

PubMed Central

Traumatic brain injury is a devastating neurological injury associated with significant morbidity and mortality. Medical therapies to limit cerebral edema, a cause of increased intracranial hypertension and poor clinical outcome, are largely ineffective, emphasizing the need for novel therapeutic approaches. In the present study, pre-treatment with curcumin (75, 150 mg/kg) or 30 minute post-treatment with 300 mg/kg significantly reduced brain water content and improved neurological outcome following a moderate controlled cortical impact in mice. The protective effect of curcumin was associated with a significant attenuation in the acute pericontusional expression of interleukin-1?, a pro-inflammatory cytokine, after injury. Curcumin also reversed the induction of aquaporin-4, an astrocytic water channel implicated in the development of cellular edema following head trauma. Notably, curcumin blocked IL-1?-induced aquaporin-4 expression in cultured astrocytes, an effect mediated, at least in part, by reduced activation of the p50 and p65 subunits of NF?B. Consistent with this notion, curcumin preferentially attenuated phosphorylated p65 immunoreactivity in pericontusional astrocytes and decreased the expression of glial fibrillary acidic protein, a reactive astrocyte marker. As a whole, these data suggest clinically-achievable concentrations of curcumin reduce glial activation and cerebral edema following neurotrauma, a finding which warrants further investigation.

Laird, Melissa D.; SR, Sangeetha; Swift, Andrew E.B.; Meiler, Steffen E.; Vender, John R.; Dhandapani, Krishnan M.



Increased cerebrospinal fluid glutamate and taurine concentrations are associated with traumatic brain edema formation in rats  

Microsoft Academic Search

Glutamate-mediated excitotoxicity results in cell swelling and contributes to brain edema formation. Since increased extracellular taurine reflects glutamate-induced cell swelling in vitro, elevated CSF taurine could therefore unmask glutamate-mediated cytotoxic edema formation under in vivo conditions. For this, the temporal profile of brain edema and changes in cisternal CSF glutamate and taurine levels were determined in 28 rats following focal

John F. Stover; Andreas W. Unterberg



Beneficial effect of agmatine on brain apoptosis, astrogliosis, and edema after rat transient cerebral ischemia  

PubMed Central

Background Although agmatine therapy in a mouse model of transient focal cerebral ischemia is highly protective against neurological injury, the mechanisms underlying the protective effects of agmatine are not fully elucidated. This study aimed to investigate the effects of agmatine on brain apoptosis, astrogliosis and edema in the rats with transient cerebral ischemia. Methods Following surgical induction of middle cerebral artery occlusion (MCAO) for 90 min, agmatine (100 mg/kg, i.p.) was injected 5 min after beginning of reperfusion and again once daily for the next 3 post-operative days. Four days after reperfusion, both motor and proprioception functions were assessed and then all rats were sacrificed for determination of brain infarct volume (2, 3, 5-triphenyltetrazolium chloride staining), apoptosis (TUNEL staining), edema (both cerebral water content and amounts of aquaporin-4 positive cells), gliosis (glial fibrillary acidic protein [GFAP]-positive cells), and neurotoxicity (inducible nitric oxide synthase [iNOS] expression). Results The results showed that agmatine treatment was found to accelerate recovery of motor (from 55 degrees to 62 degrees) and proprioception (from 54% maximal possible effect to 10% maximal possible effect) deficits and to prevent brain infarction (from 370 mm3 to 50 mm3), gliosis (from 80 GFAP-positive cells to 30 GFAP-positive cells), edema (cerebral water contents decreased from 82.5% to 79.4%; AQP4 positive cells decreased from 140 to 84 per section), apoptosis (neuronal apoptotic cells decreased from 100 to 20 per section), and neurotoxicity (iNOS expression cells decreased from 64 to 7 per section) during MCAO ischemic injury in rats. Conclusions The data suggest that agmatine may improve outcomes of transient cerebral ischemia in rats by reducing brain apoptosis, astrogliosis and edema.



[Changes in content of glycolipids, sphingosine and cytokines in the rat brain with experimental edema].  


The study of the content of cerebrosides, gangliosides and their hydrolytic degradation product--sphingosine in the rat brain with experimental edema was carried out. In parallel, the cytokine profile of pro- and anti-inflammatory cytokines in the blood of rats with experimental cerebral edema was studied. The experiments indicated that a decrease of the total fraction of glycolipids and an increase of sphingosine content in the brain of rats with brain swelling were observed. The development of brain edema was accompanied by the increase in proinflammatory and decrease in anti-inflammatory cytokine content. PMID:22946303

Zakharian, G V


The permissive nature of blood brain barrier (BBB) opening in edema formation following traumatic brain injury.  


The contribution of blood brain barrier opening to traumatic brain edema is not known. This study compares the course of traumatic BBB disruption and edema formation, with the hypothesis that they are not obligately related. Sprague-Dawley rats were divided into three groups: Group A (n = 47)--Impact Acceleration (IAM); Group B (n = 104)--lateral cortical impact (CCI); Group C (n = 26)--IAM + hypoxia & hypotension (THH). BBB integrity was assessed using i.v. markers (Evan's Blue, or gadolinium-DTPA). Edema formation was evaluated with gravimetry, and T1-weighted MRI. In IAM, BBB opened immediately but closed rapidly, and remained closed for at least the next 36 hours whilst 24-hour hemispheric water content (HWC) rose by 0.9% (p < 0.01). In CCI, BBB opened in both hemispheres for up to 4 hours; four hour HWC in the uninjured hemisphere was indistinguishable from Sham, where HWC in the injured hemisphere rose by approximately 1.5% (p < 0.005). We distinguished two THH animals based on Apparent Diffusion Coefficient (ADC) recovery: in ADC-recovery animals 4 hour cortical water content (CWC) was 80.4 +/- 0.6%, cf 81.4 +/- 1.3% in ADC-non-recovery (p < 0.05). In all animals the BBB was open, however two populations of permeability were seen which likely related to flow-limited extravasation of gadolinium. In IAM edema forms despite only brief BBB opening. Although there is diffuse BBB opening with lateral contusion, edema only forms in the injured hemisphere. In THH, edema formation in the face of a widely permeable barrier is driven by ADC changes or cell swelling. Edema formation clearly does not correspond with BBB opening and an open BBB is clearly not required for edema formation. However we hypothesize that a permeable BBB permissively worsens the process, by acting as a low resistance pathway for ion and water movement. These findings are consistent with our general hypothesis that edema formation after TBI is mainly cytotoxic. PMID:11449990

Beaumont, A; Marmarou, A; Hayasaki, K; Barzo, P; Fatouros, P; Corwin, F; Marmarou, C; Dunbar, J



Inhibition of Rho kinase by Hydroxyfasudil Attenuates Brain Edema after Subarachnoid Hemorrhage in Rats  

PubMed Central

The blood-brain barrier (BBB) disruption and brain edema are important pathophysiologies of early brain injury after subarachnoid hemorrhage (SAH). This study is to evaluate whether Rho kinase (Rock) enhances BBB permeability via disruption of tight junction proteins during early brain injury. Adult male rats were assigned to five groups; sham-operated, SAH treated with saline, a Rock inhibitor hydroxyfasudil (HF) (10mg/kg) treatment at 0.5 hours after SAH, HF treatment at 0.5 and 6 hours (10mg/kg, each) after SAH, and another Rock inhibitor Y27632 (10mg/kg) treatment at 0.5 hrs after SAH. The perforation model of SAH was performed and neurological score and brain water content were evaluated 24 and 72 hours after surgery. Evans blue extravasation, Rock activity assay, and Western blotting analyses were evaluated 24 hours after surgery. Treatment of HF significantly improved neurological scores 24 hours after SAH. Single treatment with HF and Y27632, and two treatments with HF reduced brain water content in the ipsilateral hemisphere. HF reduced Evans blue extravasation in the ipsilateral hemisphere after SAH. Rock activity increased 24 hours after SAH, and HF reversed the activity. SAH significantly decreased the levels of tight junction proteins, occludin and zonula occludens-1 (ZO-1), and HF preserved the levels of occluding and ZO-1 in ipsilateral hemisphere. In conclusion, HF attenuated BBB permeability after SAH, possibly by protection of tight junction proteins.

Fujii, Mutsumi; Duris, Kamil; Altay, Orhan; Soejima, Yoshiteru; Sherchan, Prativa; Zhang, John H.



Protection of Vascular Endothelial Growth Factor to Brain Edema Following Intracerebral Hemorrhage and Its Involved Mechanisms: Effect of Aquaporin-4  

PubMed Central

Vascular endothelial growth factor (VEGF) has protective effects on many neurological diseases. However, whether VEGF acts on brain edema following intracerebral hemorrhage (ICH) is largely unknown. Our previous study has shown aquaporin-4 (AQP4) plays an important role in brain edema elimination following ICH. Meanwhile, there is close relationship between VEGF and AQP4. In this study, we aimed to test effects of VEGF on brain edema following ICH and examine whether they were AQP4 dependent. Recombinant human VEGF165 (rhVEGF165) was injected intracerebroventricularly 1 d after ICH induced by microinjecting autologous whole blood into striatum. We detected perihemotomal AQP4 protein expression, then examined the effects of rhVEGF165 on perihemotomal brain edema at 1 d, 3 d, and 7 d after injection in wild type (AQP4+/+) and AQP4 knock-out (AQP4?/?) mice. Furthermore, we assessed the possible signal transduction pathways activated by VEGF to regulate AQP4 expression via astrocyte cultures. We found perihemotomal AQP4 protein expression was highly increased by rhVEGF165. RhVEGF165 alleviated perihemotomal brain edema in AQP4+/+ mice at each time point, but had no effect on AQP4?/? mice. Perihemotomal EB extravasation was increased by rhVEGF165 in AQP4?/? mice, but not AQP4+/+ mice. RhVEGF165 reduced neurological deficits and increased Nissl’s staining cells surrounding hemotoma in both types of mice and these effects were related to AQP4. RhVEGF165 up-regulated phospharylation of C-Jun amino-terminal kinase (p-JNK) and extracellular signal-regulated kinase (p-ERK) and AQP4 protein in cultured astrocytes. The latter was inhibited by JNK and ERK inhibitors. In conclusion, VEGF reduces neurological deficits, brain edema, and neuronal death surrounding hemotoma but has no influence on BBB permeability. These effects are closely related to AQP4 up-regulation, possibly through activating JNK and ERK pathways. The current study may present new insights to treatment of brain edema following ICH.

Dong, Qiang



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

NASA Astrophysics Data System (ADS)

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 (?s') and BWC. By recording ?s' 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.

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



[Nuclear magnetic resonance (NMR) imaging of brain edema from sliced rat brain: preliminary report].  


A series of the sliced rat brain were imaged by proton nuclear magnetic resonance (1H-NMR) using a Carr-Purcell-Meiboom-Gill sequence. The slices were obtained from the adult male Wistar rats, normal or suffering from vasogenic brain edema at 2, 6, 24Hr, 2Wk and 2Mo period after the application of cryo-injury. The imaging time was arranged 17 to 22 minutes dependently upon signal to noise ratio. The slice thickness was 1.2 mm, and pixel dimensions were 0.2 X 0.2 mm. Whereas a voxel size in our images is mere 1/1,200 compared to that reported about the prototype human NMR imaging devices, high resolution has been realized. The spatial resolution is very fine, as evidenced by the appearance of major internal structures of rat brain, and the object contrast is so high that cerebral white-gray contrast is excellent, although the difference in water concentration between them is only 7%. It has been impossible to measure serially in vivo change in water concentration of small organs as rat brain, NMR has the capability to generate images in response to tissue state of hydration, therefore we can easily recognize the extent and intensity of the brain edema, which has been defined as an expansion of the brain volume resulting from an increase in its fluid content. And in this study, using the prototype mini-NMR-CT of excellent spatial and contrast resolution, we have been able to show this advantage of NMR as a new tool for research in the field of neurological surgery. PMID:7138701

Asato, R; Handa, H; Mishina, T; Hashi, T; Hatta, J; Komoike, M; Yazaki, T



Delayed onset of brain edema and mislocalization of aquaporin-4 in dystrophin-null transgenic mice  

Microsoft Academic Search

Cerebral water accumulation was studied during induction of brain edema in dystrophin-null transgenic mice (mdx-geo) and control mice. Immunofluorescence and immunoelectron microscopic analyses of dystrophin-null brains revealed a dramatic reduction of AQP4 (aquaporin-4) in astroglial end-feet surrounding capillaries (blood-brain barrier) and at the glia limitans (cerebrospinal fluid-brain interface). The AQP4 protein is mislocalized, because immunoblotting showed that the total AQP4

Zsolt Vajda; Michael Pedersen; Ernst-Martin Füchtbauer; Karin Wertz; Hans Stødkilde-Jørgensen; Endre Sulyok; Tamás Dóczi; John D. Neely; Peter Agre; Jørgen Frøkiær; Søren Nielsen



Three Dimensional Poroelastic Simulation of Brain Edema: Initial Studies on Intracranial Pressure  

Microsoft Academic Search

\\u000a Brain edema is one of the most common consequences of serious head injury because of the enhancement of water content and\\u000a thus the increased brain volume. Once the brain compensation mechanisms have been exhausted, the intracranial pressure (ICP)\\u000a will increase exponentially because the brain is enclosed in the rigid skull. Previous research suggests that the poroelastic\\u000a theory provides a solution

X. G. Li; H. von Holst; J. Ho; S. Kleiven


Polynitroxylated-pegylated hemoglobin attenuates fluid requirements and brain edema in combined traumatic brain injury plus hemorrhagic shock in mice.  


Polynitroxylated-pegylated hemoglobin (PNPH), a bovine hemoglobin decorated with nitroxide and polyethylene glycol moieties, showed neuroprotection vs. lactated Ringer's (LR) in experimental traumatic brain injury plus hemorrhagic shock (TBI+HS). Hypothesis: Resuscitation with PNPH will reduce intracranial pressure (ICP) and brain edema and improve cerebral perfusion pressure (CPP) vs. LR in experimental TBI+HS. C57/BL6 mice (n=20) underwent controlled cortical impact followed by severe HS to mean arterial pressure (MAP) of 25 to 27?mm?Hg for 35?minutes. Mice (n=10/group) were then resuscitated with a 20?mL/kg bolus of 4% PNPH or LR followed by 10?mL/kg boluses targeting MAP>70?mm?Hg for 90?minutes. Shed blood was then reinfused. Intracranial pressure was monitored. Mice were killed and %brain water (%BW) was measured (wet/dry weight). Mice resuscitated with PNPH vs. LR required less fluid (26.0±0.0 vs. 167.0±10.7?mL/kg, P<0.001) and had a higher MAP (79.4±0.40 vs. 59.7±0.83?mm?Hg, P<0.001). The PNPH-treated mice required only 20?mL/kg while LR-resuscitated mice required multiple boluses. The PNPH-treated mice had a lower peak ICP (14.5±0.97 vs. 19.7±1.12?mm?Hg, P=0.002), higher CPP during resuscitation (69.2±0.46 vs. 45.5±0.68?mm?Hg, P<0.001), and lower %BW vs. LR (80.3±0.12 vs. 80.9±0.12%, P=0.003). After TBI+HS, resuscitation with PNPH lowers fluid requirements, improves ICP and CPP, and reduces brain edema vs. LR, supporting its development. PMID:23801241

Brockman, Erik C; Bay?r, Hülya; Blasiole, Brian; Shein, Steven L; Fink, Ericka L; Dixon, Cedward; Clark, Robert Sb; Vagni, Vincent A; Ma, Li; Hsia, Carleton Jc; Tisherman, Samuel A; Kochanek, Patrick M



Role of a Hydrostatic Pressure Gradient in the Formation of Early Ischemic Brain Edema  

Microsoft Academic Search

Summary: We studied whether a hydrostatic pressure gradient between arterial blood and brain tissue plays a role in the formation of early ischemic cerebral edema after middle cerebral artery (MCA) occlusion in cats. Tissue pressure, regional CBF, and water content were measured from the cortex in the core and the peripheral zone of brain normally perfused by the MCA. Intraluminal

Shizuo Hatashita; Julian T. Hoff



Dynamics of Rabbit Brain Edema in Focal Lesion and Perilesion Area after Traumatic Brain Injury: A MRI Study  

PubMed Central

Abstract To understand the dynamics of brain edema in different areas after traumatic brain injury (TBI) in rabbit, we used dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and diffusion-weighted imaging (DWI) to monitor blood–brain barrier (BBB) permeability and cytotoxic brain edema after weight drop-induced TBI in rabbit. The dynamics of BBB permeability and brain edema were quantified using Ktrans and apparent diffusion coefficient (ADC) in the focal and perifocal lesion areas, as well as the area contralateral to the lesion. In the focal lesion area, Ktrans began to increase at 3?h post-TBI, peaked at 3 days, and decreased gradually while remaining higher than sham injury animals at 7 and 30 days. ADC was more variable, increased slightly at 3?h, decreased to its lowest value at 7 days, then increased to a peak at 30 days. In the perifocal lesion area, Ktrans began to increase at 1 day, peaked at 3–7 days, and returned to control level by 30 days. ADC showed a trend to increase at 1 day, followed by a continuous increase thereafter. In the contralateral area, no changes in Ktrans and ADC were observed at any time-point. These data demonstrate that different types of brain edema predominate in the focal and perifocal lesion areas. Specifically cytotoxic edema was predominant in the focal lesion area while vasogenic edema predominated in the perifocal area in acute phase. Furthermore, secondary opening of the BBB after TBI may appear if secondary injury is not controlled. BBB damage may be a driving force for cytotoxic brain edema and could be a new target for TBI intervention.

Wei, Xiao-Er; Zhang, Yu-Zhen; Li, Yue-Hua; Li, Ming-Hua



MRI Reveals Edema in Larynx (But Not in Brain) During Anaphylactic Hypotension in Anesthetized Rats  

PubMed Central

Purpose Anaphylactic shock is sometimes accompanied by local interstitial edema due to increased vascular permeability. We performed magnetic resonance imaging (MRI) to compare edema in the larynx and brain of anesthetized rats during anaphylactic hypotension versus vasodilator-induced hypotension. Methods Male Sprague Dawley rats were subjected to hypotension induced by the ovalbumin antigen (n=7) or a vasodilator sodium nitroprusside (SNP; n=7). Apparent diffusion coefficient (ADC) and T2-relaxation time (T2RT) were quantified on MRI performed repeatedly for up to 68 min after the injection of either agent. The presence of laryngeal edema was also examined by histological examination. Separately, the occurrence of brain edema was assessed by measuring brain water content using the wet/dry method in rats with anaphylaxis (n=5) or SNP (n=5) and the non-hypotensive control rats (n=5). Mast cells in hypothalamus were morphologically examined. Results Mean arterial blood pressure similarly decreased to 35 mmHg after an injection of the antigen or SNP. Hyperintensity on T2-weighted images (as reflected by elevated T2RT) was found in the larynx as early as 13 min after an injection of the antigen, but not SNP. A postmortem histological examination revealed epiglottic edema in the rats with anaphylaxis, but not SNP. In contrast, no significant changes in T2RT or ADC were detectable in the brains of any rats studied. In separate experiments, the quantified brain water content did not increase in either anaphylaxis or SNP rats, as compared with the non-hypotensive control rats. The numbers of mast cells with metachromatic granules in the hypothalamus were not different between rats with anaphylaxis and SNP, suggesting the absence of anaphylactic reaction in hypothalamus. Conclusion Edema was detected using the MRI technique in the larynx during rat anaphylaxis, but not in the brain.

Toyota, Ichiro; Tanida, Mamoru; Wang, Mofei; Kurata, Yasutaka; Tonami, Hisao



The effect of hypertonic fluid resuscitation on brain edema in rabbits subjected to brain injury and hemorrhagic shock.  


Small-volume resuscitation with 7.2% NaCl/10% dextran 60 (HHS) restores cardiovascular stability faster than all other therapeutic modalities currently known. This study was undertaken to elucidate the effects of HHS on the brain, specifically on the formation of posttraumatic brain edema. HHS was administered to anesthetized albino rabbits with or without a focal cryogenic brain lesion and hemorrhagic shock. Specific gravity of small tissue samples was determined 4 h after injury and values were topographically assembled to form a color-coded map of both hemispheres, allowing for a high resolution mapping of brain edema. Cerebral blood flow on the side of the lesion, as assessed by the H2 clearance method, increased transiently after injury but remained unchanged from baseline during shock and after infusion of HHS, indicating intact cerebrovascular autoregulation. The cryogenic lesion without subsequent HHS infusion resulted in significant brain edema formation in grey and white matter of the exposed hemisphere. In injured animals, resuscitation with HHS led to a global reduction of brain water content in both hemispheres. We conclude that small-volume resuscitation with HHS does not worsen posttraumatic brain edema. To the contrary, our results show that it decreases cerebral water content even in regions close to the injury. This makes it worthwhile to investigate the benefits of HHS for the treatment of intracranial hypertension. PMID:7541301

Härtl, R; Schürer, L; Goetz, C; Berger, S; Röhrich, F; Baethmann, A



Regional Differences in Cerebral Edema after Traumatic Brain Injury Identified by Impedance Analysis  

PubMed Central

Objective Cerebral edema is a common and potentially devastating sequel of traumatic brain injury. We developed and validated a system capable of tissue impedance analysis, which was found to correlate with cerebral edema. Design and Methods Constant sinusoidal current (50 ?A), at frequencies from 500 to 5000 Hz, was applied across a bipolar electrode unit superficially placed in a rat brain after traumatic brain injury. Rats were randomized to three groups: severe controlled cortical injury (CCI), mild CCI, or sham injury. At 60 hours post CCI, cerebral voltage and phase angle were measured at each frequency at the site of injury, at the penumbral region, at the ipsilateral frontal region, and in the contralateral hemisphere. Impedance measurements were also obtained in vivo. The electrical properties of varied injuries and specified locations were compared using a repeated measures analysis of variance (RMANOVA), were correlated with regional tissue water percentage using regression analyses, and were combined to generate polar coordinates. Results The measured voltage was significantly different at the site of injury (p<0.0001), in the penumbra (p=0.002), and in the contralateral hemisphere (p=0.005) when severe, mild, and sham CCI rats were compared. Severely injured rats had statistically different voltage measurements when the various sites were compared (p=0.002). The ex vivo measurements correlated with in vivo measurements. Further, the impedance measurements correlated with measured tissue water percentage at the site of injury (R2=0.69; p<0.0001). The creation of a polar coordinate graph, incorporating voltage and phase angle measurements, enabled the identification of impedance areas unique to normal, mild edema, and severe edema measurements in the rat brain. Conclusions Electrical measurements and tissue water percentages quantified regional and severity differences in rat brain edema after CCI. Impedance was inversely proportional to the tissue water percentage. Thus, impedance measurement can be used to quantify severity of cerebral edema in real time at specific sites.

Harting, Matthew T.; Smith, Carter T.; Radhakrishnan, Ravi S.; Aroom, Kevin R.; Dash, Pramod K.; Gill, Brijesh; Cox, Charles S.



Effect of uridine 5'-diphosphate on cryogenic brain edema in rabbits.  


This study was undertaken to examine the effect of uridine 5'-diphosphate, administered intravenously or intraperitoneally, on cold injury-induced brain edema in rabbits. Bolus injection or continuous intravenous infusion of uridine 5'-diphosphate 26 hours after a lesion was established had adverse effects, such as increased intracranial pressure and lowered systolic arterial blood pressure and cerebral perfusion pressure for approximately 10-29 minutes, but these parameters did not change appreciably from 29 minutes to 3 hours after administration. Intraperitoneally administered uridine 5'-diphosphate did not affect these parameters appreciably during 3 hours. Thus, the intravenous administration of uridine 5'-diphosphate is harmful under neurosurgical conditions. In contrast, 10 mg/kg/day i.p. uridine 5'-diphosphate pretreatment and posttreatment, beginning 24 hours before and continuing until 24 hours after the insult, significantly reduced neurologic abnormalities, Evans blue extravasation, water content in the injured gray matter, and intracranial pressure without affecting water content in the white matter. Intravenous dexamethasone pretreatment and posttreatment in this setting significantly reduced only neurologic abnormalities. However, there were no significant differences between intraperitoneal uridine 5'-diphosphate and intravenous dexamethasone effects on cold-injured brain. PMID:2595732

Yoshida, S; Alksne, J F; Seelig, J M; Bailey, M D; Moore, S S; Kitamura, K



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


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

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



The Effects of Shilajit on Brain Edema, Intracranial Pressure and Neurologic Outcomes following the Traumatic Brain Injury in Rat  

PubMed Central

Objective(s): Brain edema is one of the most serious causes of death within the first few days after trauma brain injury (TBI). In this study we have investigated the role of Shilajit on brain edema, blood-brain barrier (BBB) permeability, intracranial pressure (ICP) and neurologic outcomes following brain trauma. Materials and Methods: Diffuse traumatic brain trauma was induced in rats by drop of a 250 g weight from a 2 m high (Marmarou’s methods). Animals were randomly divided into 5 groups including sham, TBI, TBI-vehicle, TBI-Shi150 group and TBI-Shi250 group. Rats were undergone intraperitoneal injection of Shilajit and vehicle at 1, 24, 48 and 72 hr after trauma. Brain water content, BBB permeability, ICP and neurologic outcomes were finally measured. Results: Brain water and Evans blue dye contents showed significant decrease in Shilajit-treated groups compared to the TBI-vehicle and TBI groups. Intracranial pressure at 24, 48 and 72 hr after trauma had significant reduction in Shilajit-treated groups as compared to TBI-vehicle and TBI groups (P<0.001). The rate of neurologic outcomes improvement at 4, 24, 48 and 72 hr after trauma showed significant increase in Shilajit-treated groups in comparison to theTBI- vehicle and TBI groups (P <0.001). Conclusion: The present results indicated that Shilajit may cause in improvement of neurologic outcomes through decreasing brain edema, disrupting of BBB, and ICP after the TBI.

Khaksari, Mohammad; Mahmmodi, Reza; Shahrokhi, Nader; Shabani, Mohammad; Joukar, Siavash; Aqapour, Mobin



Attenuation of Ischemic Brain Edema and Cerebrovascular Injury After Ischemic Preconditioning in the Rat  

Microsoft Academic Search

Ischemic preconditioning (IPC) induces neuroprotection to subsequent severe ischemia, but its effect on the cerebrovasculature has not been studied extensively. This study evaluated the effects of IPC on brain edema formation and endothelial cell damage that follows subsequent permanent focal cerebral ischemia in the rat. Transient (15 minute) middle cerebral artery occlusion (MCAO) was used for IPC. Three days after

Tetsuya Masada; Ya Hua; Guohua Xi; Steven R Ennis; Richard F Keep



An improved Percoll density gradient for measurements of experimental brain edema  

Microsoft Academic Search

Microgravimetric methods are very useful for quantitative studies on brain edema. One of the techniques available is based on a gradient made up by NaCl and polyvinyl pyrrolidone-coated silica particles (Percoll). The present study was performed to find a way of minimizing fluid shifts between the gradient and the samples. For this purpose, five Percoll density gradients containing various concentrations

C. Tengvar; D. Hultström; Y. Olsson



Traumatic brain edema induced by ventricular puncture. A study by magnetic resonance imaging  

Microsoft Academic Search

Magnetic resonance imaging demonstrates after ventricular catheterization a focal brain hypersignal corresponding to a parenchymal edema along the drain track. In the course of our daily clinical activity, this hypersignal extention seemed more pronounced when catheterizing the frontal area than the junctional parieto-tempro-occipital parenchyma (or trigonal area). In order to confirm this impression, we prospectively studied ten consecutive patients with

Christian Raftopoulos; Daniel Balériaux; Cristo Chaskis; Florence Delecluse; Jacques Brotchi



Proton nuclear magnetic resonance studies on brain edema  

Microsoft Academic Search

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

Shoji Naruse; Yoshiharu Horikawa; Chuzo Tanaka; Kimiyoshi Hirakawa; Hiroyasu Nishikawa; Kazuo Yoshizaki



Noninvasive early detection of brain edema in mice by near-infrared light scattering.  


Brain edema accounts for significant morbidity and mortality in many neurologic conditions such as head trauma, stroke, meningitis, and brain tumor. The water channel aquaporin-4 (AQP4) has been found to be an important determinant of brain water accumulation and clearance of excess brain water. We report the development of a noninvasive near-infrared (NIR) light-scattering method to compare the early kinetics of brain swelling in normal and AQP4-deficient mice. Brain tissue was illuminated through the intact skull with NIR light at 850 nm, and steady-state scattered light intensity was monitored at an angle of 90 degrees at a position on the skull approximately 10 mm from the illuminated site. NIR light scattering reversibly increased with brain swelling (DeltaI/Io approximately 25% per 1% increase in brain water content), but was insensitive to changes in cerebral blood flow, blood oxygenation, or blood flow-related changes in intracranial pressure (ICP). DeltaI/Io increased approximately linearly with brain water content as measured by wet-to-dry weight ratios. Acute water intoxication (intraperitoneal water, 20% body weight) produced a gradual increase in DeltaI/Io of 12 +/- 4% in wild-type mice at 5 min, much greater than that of 2 +/- 1% in AQP4-null mice. Correlation of the NIR signal with ICP showed that increased DeltaI/Io preceded measurable increases in ICP, indicating the ability of the NIR method to detect early brain edema before ICP elevation. NIR light scattering provides a simple noninvasive method to monitor brain edema in mice, with potential clinical applications. PMID:15765520

Thiagarajah, Jay R; Papadopoulos, Marios C; Verkman, A S



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

SciTech Connect

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.

Datz, F.L.



Cerebral edema after rapid dialysis is not caused by an increase in brain organic osmolytes.  


Dialysis disequilibrium syndrome (DDS) is characterized by the neurologic deterioration and cerebral edema that occurs after hemodialysis. To investigate the pathogenesis of DDS, the effects of rapid hemodialysis on brain electrolytes, urea, and several organic osmolytes were studied in the rat. Forty-two h after bilateral ureteral ligation, 11 uremic rats were hemodialyzed for 90 min, yielding a decrease in plasma urea from 96 +/- 4 to 44 +/- 5 mM (p < 0.01). This group was compared with 10 uremic and 11 nonuremic animals that were not dialyzed. In dialyzed animals, compared with nondialyzed uremic controls, there was an increase in brain water (3.98 +/- 0.02 versus 3.77 +/- 0.02 L/kg dry wt; P < 0.01) and the brain to plasma (urea) ratio (1.32 versus 0.65). There was no significant difference in the brain content of sodium and potassium between groups. The retention of brain urea, despite the large decrease in plasma urea concentration, was able to account for the increase in brain water observed in rapidly dialyzed animals. Major organic osmolytes in the brain, including glutamine, glutamate, taurine and myoinositol, did not increase significantly after rapid dialysis. Cerebral edema in this model of DDS was primarily due to a large brain-to-plasma urea gradient, not to the formation of organic osmolytes. PMID:8749686

Silver, S M



Activation of peroxisome proliferator activated receptor ? in brain inhibits inflammatory pain, dorsal horn expression of Fos, and local edema  

PubMed Central

Systemic administration of thiazolidinediones reduces peripheral inflammation in vivo, presumably by acting at peroxisome proliferator-activated receptor ? (PPAR?) in peripheral tissues. Based on a rapidly growing body of literature indicating the CNS as a functional target of PPAR? actions, we postulated that brain PPAR? modulates peripheral edema and the processing of inflammatory pain signals in the dorsal horn of the spinal cord. To test this in the plantar carrageenan model of inflammatory pain, we measured paw edema, heat hyperalgesia, and dorsal horn expression of the immediate-early gene c-fos after intracerebroventricular (ICV) administration of PPAR? ligands or vehicle. We found that ICV rosiglitazone (0.5–50 µg) or 15d-PGJ2 (50–200 µg), but not vehicle, dose-dependently reduced paw thickness, paw volume and behavioral withdrawal responses to noxious heat. These anti-inflammatory and anti-hyperalgesia effects result from direct actions in the brain and not diffusion to other sites, because intraperitoneal and intrathecal administration of rosiglitazone (50 µg) and 15d-PGJ2 (200 µg) had no effect. PPAR? agonists changed neither overt behavior nor motor coordination, indicating that non-specific behavioral effects do not contribute to PPAR ligand-induced anti-hyperalgesia. ICV administration of structurally dissimilar PPAR? antagonists (either GW9662 or BADGE) reversed the anti-inflammatory and anti-hyperalgesic actions of both rosiglitazone and 15d-PGJ2. To evaluate the effects of PPAR? agonists on a classic marker of noxious stimulus-evoked gene expression, we quantified Fos protein expression in the dorsal horn. The number of carrageenan-induced Fos-like immunoreactive profiles was less in rosiglitazone-treated rats as compared to vehicle controls. We conclude that pharmacological activation of PPAR? in the brain rapidly inhibits local edema and the spinal transmission of noxious inflammatory signals.

Morgenweck, J.; Abdel-aleem, O.S.; McNamara, K.C.; Donahue, R.R.; Badr, M.Z.; Taylor, B.K.



Protective effect of albumin on VEGF and brain edema in acute ischemia in rats  

Microsoft Academic Search

Vascular endothelial growth factor (VEGF) is known to be an important stroke-related pathogenic factor for the formation of brain edema. We examined the therapeutic effect of human serum albumin on VEGF expression in acute ischemic stroke. Adult male Sprague–Dawley (SD) rats were subjected to Middle Cerebral Artery Occlusion (MCAO), the suture was withdrawn 2h later, and 25% albumin (1.25g\\/kg) or

Xiaomei Yao; Wei Miao; Min Li; Min Wang; Jun Ma; Yongming Wang; Li Miao; Hong Feng



Invasive Pressure Monitoring Saves from Tuberculous Meningitis with Fulminant Generalized Brain Edema  

PubMed Central

We report a 57-year old female patient with a rapid and dramatic dynamic of whole brain edema caused by tuberculous meningitis. After initiation of tuberculostatic medication, general condition of the patient worsened and finally she was intubated due to a progredient loss of consciousness and respiratory insufficiency. Repeated cerebral computer tomography (CCT) revealed a global brain edema with slit ventricles and a dramatic progress of generalized brain swelling. Highly interesting, a rapid expanded regime of brain pressure monitoring and treatment according to a neurosurgical intensive standard ICP/CPP management protocol, which was complemented by the tuberculostatic therapy and high dose steroid application, dramatically improved the general conditions, so that the patient is now in a general condition which corresponds that before the occurrence of tuberculous meningitis. Thus, it is mandatory in situations with a rapid progressive brain swelling caused by bacterial meningitis to consider an intensified cerebral monitoring and stratified treatment protocol in order to avoid the devasting effects of a long lasting increase in intracranical pressure.

Trendelenburg, George; Jussen, Daniel; Grimmer, Steffen; Jakob, Wibke; Hiemann, Nicola E.; Horn, Peter



Tumor-associated edema in brain cancer patients: pathogenesis and management.  


The long-term treatment of peritumoral edema remains a major challenge in clinical neuro-oncology. Steroids have been and will remain the backbone of any anti-edematous therapy because of their striking activity, convenient oral administration and also because of their cost-effectiveness. Their side effects, however, can compromise quality of life, particularly upon continuous administration. Therapeutic alternatives which may replace or - at least - help to reduce the steroid dose are limited. However, with the development of new agents such as corticorelin acetate, there is a hope that steroid-induced side effects can be delayed and reduced. The administration of anti-angiogenic agents with steroid-sparing effects, for example, bevacizumab, is limited due to their costs. Increased knowledge on boswellic acids and cyclooxygenase-2 inhibitors which are available for clinical application may help to exploit their anti-edema activity more efficiently in the future. PMID:24152171

Roth, Patrick; Regli, Luca; Tonder, Michaela; Weller, Michael



A new method for the early diagnosis of brain edema/brain swelling. An experimental study in rabbits.  


The aim of the present work is to develop a non-destructive, non-invasive technique for the early diagnosis of an oncoming brain edema based on the variation of vibration characteristics of the head system (i.e. eigenfrequency spectrum and modal damping). Besides the theoretical model that supports the basic principle, the proposed technique has been verified experimentally in animal tests. The advantage of such an approach is that the relative information is available well in advance an increase of intracranial pressure is detected. The uncontrolled intracranial hypertension is associated with increased mortality or vegetative state in head trauma. Traumatic lesions located on temporal lobe render particularly impeding the transtendorial herniation. From the medical point of view, intracranial pressure (ICP) monitoring represents an effective way for early consideration of neurological decompensation in various neurosurgical conditions particularly in the head-injured setting. However, the use of ICP monitoring is not an effective way of brain edema detection, since ICP increase very often causes irreversible problems to the patient's brain. Therefore, the determination of an earlier, less invasive and more sensitive indicator of the oncoming intracranial hypertension and of the impeding neurological deterioration is of profound importance. The present work aims at experimental verification of both eigenfrequency shifting and modal damping increase of the spectral response of the head system of rabbits, wherever a mass increase in the content of cranial shell appears. The conducted analysis concludes that the eigenfrequency spectrum and its modal damping characteristics are sufficiently sensitive parameters in order to characterize mass increase in the cranial shell. Therefore the combination of both the above parameters could be used with confidence for the early diagnosis of brain edema. PMID:16413930

Kostopoulos, V; Douzinas, E E; Kypriades, E M; Pappas, Y Z



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

PubMed Central

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

Criscuolo, G. R.



Extent of peritumoral brain edema correlates with prognosis, tumoral growth pattern, HIF1a expression and angiogenic activity in patients with single brain metastases.  


To analyze the prognostic value of the extent of peritumoral brain edema in patients operated for single brain metastases (BM), we retrospectively evaluated pre-operative magnetic resonance images in a discovery cohort of 129 patients and a validation cohort of 118 patients, who underwent neurosurgical resection of a single BM in two different hospitals. We recorded clinical parameters and immunohistochemically assessed the Ki67 index, the microvascularization patterns and the expression of hypoxia-induced factor 1 alpha (HIF1a) in the BM tissue specimens retrieved at neurosurgery. Statistical analysis including uni- and multivariate survival analyses were performed. Baseline characteristics were well balanced between the discovery and validation cohorts. In univariate analysis, we found a significant association of favorable overall survival time with young patient age, high Karnofsky performance score, low graded prognostic assessment (GPA) class, absence of extracranial metastases, adjuvant treatment with whole brain radiotherapy and, surprisingly, large brain edema. In multivariate analysis, only GPA and extent of brain edema remained independent prognostic parameters. The prognostic impact of the extent of brain edema was consistent in the two patient cohorts. Furthermore, we found a significant correlation of small brain edema with brain-invasive tumor growth pattern as assessed intraoperatively by the neurosurgeon, low neo-angiogenic activity and low expression of HIF1a. Extent of brain edema independently correlates with prognosis in patients operated for single BM. In conclusion, patients with small peritumoral edema have shorter survival times and their tumors are characterized by a more brain-invasive growth, lower HIF1a expression and less angiogenic activity. PMID:23076770

Spanberger, Thomas; Berghoff, Anna S; Dinhof, Carina; Ilhan-Mutlu, Aysegül; Magerle, Manuel; Hutterer, Markus; Pichler, Josef; Wöhrer, Adelheid; Hackl, Monika; Widhalm, Georg; Hainfellner, Johannes A; Dieckmann, Karin; Marosi, Christine; Birner, Peter; Prayer, Daniela; Preusser, Matthias



Agonist of growth hormone-releasing hormone reduces pneumolysin-induced pulmonary permeability edema  

PubMed Central

Aggressive treatment with antibiotics in patients infected with Streptococcus pneumoniae induces release of the bacterial virulence factor pneumolysin (PLY). Days after lungs are sterile, this pore-forming toxin can still induce pulmonary permeability edema in patients, characterized by alveolar/capillary barrier dysfunction and impaired alveolar liquid clearance (ALC). ALC is mainly regulated through Na+ transport by the apically expressed epithelial sodium channel (ENaC) and the basolaterally expressed Na+/K+-ATPase in type II alveolar epithelial cells. Because no standard treatment is currently available to treat permeability edema, the search for novel therapeutic candidates is of high priority. We detected mRNA expression for the active receptor splice variant SV1 of the hypothalamic polypeptide growth hormone-releasing hormone (GHRH), as well as for GHRH itself, in human lung microvascular endothelial cells (HL-MVEC). Therefore, we have evaluated the effect of the GHRH agonist JI-34 on PLY-induced barrier and ALC dysfunction. JI-34 blunts PLY-mediated endothelial hyperpermeability in monolayers of HL-MVEC, in a cAMP-dependent manner, by means of reducing the phosphorylation of myosin light chain and vascular endothelial (VE)-cadherin. In human airway epithelial H441 cells, PLY significantly impairs Na+ uptake, but JI-34 restores it to basal levels by means of increasing cAMP levels. Intratracheal instillation of PLY into C57BL6 mice causes pulmonary alveolar epithelial and endothelial hyperpermeability as well as edema formation, all of which are blunted by JI-34. These findings point toward a protective role of the GHRH signaling pathway in PLY-induced permeability edema.

Lucas, Rudolf; Sridhar, Supriya; Rick, Ferenc G.; Gorshkov, Boris; Umapathy, Nagavedi S.; Yang, Guang; Oseghale, Aluya; Verin, Alexander D.; Chakraborty, Trinad; Matthay, Michael A.; Zemskov, Evgeny A.; White, Richard; Block, Norman L.; Schally, Andrew V.



Protective effect of albumin on VEGF and brain edema in acute ischemia in rats.  


Vascular endothelial growth factor (VEGF) is known to be an important stroke-related pathogenic factor for the formation of brain edema. We examined the therapeutic effect of human serum albumin on VEGF expression in acute ischemic stroke. Adult male Sprague-Dawley (SD) rats were subjected to Middle Cerebral Artery Occlusion (MCAO), the suture was withdrawn 2 h later, and 25% albumin (1.25 g/kg) or saline (5 ml/kg) was administered intravenously after reperfusion. The model was evaluated by 2,3,5-triphenyl-tetrazolium chloride (TTC) staining, neurological deficits and brain water content. Serum albumin level was determined. VEGF expression was studied by enzyme linked immunosorbent assay (ELISA), quantitative real-time PCR and immunohistochemistry. We demonstrated that albumin administration maintained the serum albumin at a higher level than the sham group at 6 h, 1 d, 2 d and 3 d after MCAO, and significantly improved the neurological deficits and decreased the brain water content. In addition, the strong up-regulation of VEGF expression at 6 h and 1d after MCAO can be attenuated by albumin administration. However, albumin administration had no significant depressing effect on VEGF expression at 2 d, 3 d and 5 d after MCAO in the cortex and hippocampus. Strong up-regulation of VEGF immunoreactivity was noted in the saline group in the blood-brain barrier (BBB), and in neurons surrounding the peri-infarct area and periventricular area at 24 h after MCAO. The expression of VEGF in the albumin group was much weaker. Furthermore, there were high correlations between the brain water content with the serum albumin level, with serum VEGF protein level, and with brain VEGF mRNA expression at 24 h after MCAO. In conclusion, maintaining the serum albumin at a higher level, and attenuating endogenous VEGF expression at 6 h and 1d, but not 2 d, 3 d, or 5 d after MCAO, may partially contribute to the protective effects of albumin on reduction of brain edema in the early stage of ischemia. PMID:20138968

Yao, Xiaomei; Miao, Wei; Li, Min; Wang, Min; Ma, Jun; Wang, Yongming; Miao, Li; Feng, Hong



Inhibition of carbonic anhydrase reduces brain injury after intracerebral hemorrhage  

PubMed Central

Carbonic anhydrase-1 (CA-1) is a metalloenzyme present at high concentrations in erythrocytes. Our previous studies showed that erythrocyte lysis contributes to brain edema formation after intracerebral hemorrhage (ICH) and a recent study indicates that CA-1 can cause blood-brain barrier disruption. The present study investigated the role of CA-1 in ICH-induced brain injury. There were three groups in the study. In the first, adult male Sprague-Dawley rats received 100 ?l autologous blood injection into the right caudate. Sham rats had a needle insertion. Rat brains were used for brain CA-1 level determination. In the second group, rats received an intracaudate injection of either 50 ?l CA-1 (1 ?g/?l) or saline. Brain water content, microglia activation and neuronal death (Fluoro-Jade C staining) were examined 24 hours later. In the third group, acetazolamide (AZA, 5 ?l, 1 mM), an inhibitor of carbonic anhydrases, or vehicle was co-injected with 100 ?l blood. Brain water content, neuronal death and behavioral deficits were measured. We found that CA-I levels were elevated in the ipsilateral basal ganglia at 24 hours after ICH. Intracaudate injection of CA-1 induced brain edema (79.0 ± 0.6 vs. 78.0±0.2% in saline group, p<0.01), microglia activation and neuronal death (p<0.01) at 24 hours. AZA, an inhibitor of CA, reduced ICH-induced brain water content (79.3 ± 0.7 vs. 81.0 ± 1.0% in the vehicle-treated group, p<0.05), neuronal death and improved functional outcome (p<0.05). These results suggest that CA-1 from erythrocyte lysis contributes to brain injury after ICH.

Guo, Fuyou; Hua, Ya; Wang, Jinhu; Keep, Richard F.; Xi, Guohua



Severity profile of penetrating ballistic-like brain injury on neurofunctional outcome, blood-brain barrier permeability, and brain edema formation.  


This study evaluated the injury severity profile of unilateral, frontal penetrating ballistic-like brain injury (PBBI) on neurofunctional outcome, blood-brain barrier (BBB) permeability, and brain edema formation. The degree of injury severity was determined by the delivery of a water-pressure pulse designed to produce a temporary cavity by rapid (<40?ms) expansion of the probe's elastic balloon calibrated to equal 5%, 10%, 12.5%, or 15% of total rat brain volume (control groups consisted of sham surgery or insertion of the probe only). Neurofunctional assessments revealed motor and cognitive deficits related to the degree of injury severity, with the most clear-cut profile of PBBI injury severity depicted by the Morris water maze (MWM) results. A biphasic pattern of BBB leakage was detected in the injured hemisphere at all injury severity levels at 4?h post-injury, and again at 48-72?h post-injury, which remained evident out to 7 days post-PBBI in the 10% and 12.5% PBBI groups. Likewise, significant brain edema was detected in the injured hemisphere by 4?h post-injury and remained elevated out to 7 days post-injury in the 10% and 12.5% PBBI groups. However, following 5% PBBI, significant levels of edema were only detected from 24?h to 48h post-injury. These results identify an injury severity profile of BBB permeability, brain edema, and neurofunctional impairment that provides sensitive and clinically relevant outcome metrics for studying potential therapeutics. PMID:21644814

Shear, Deborah A; Lu, Xi-Chun May; Pedersen, Rebecca; Wei, Guo; Chen, Zhiyong; Davis, Angela; Yao, Changping; Dave, Jitendra; Tortella, Frank C



Decompressive craniectomy with multi-dural stabs - A combined (SKIMS) technique to evacuate acute subdural hematoma with underlying severe traumatic brain edema  

PubMed Central

Context: The decompressive craniotomy alone or with dural flap opening to evacuate acute subdural hematoma with underlying brain edema in severe traumatic brain injury has proved either insufficient in the first place or has fatal complications secondly. Aims: To reduce the fatality of conventional procedures and to evacuate acute subdural hematoma with severe brain edema by a combination of decompressive craniotomy and multi-dural stabs (SKIMS-Technique) without brain pouting and lacerations in low Glasgow coma scale (GCS) score patients. Settings and Design: The prospective study was conducted in the Department of Neurosurgery, from June, 2006 to June 2011, under a uniform protocol. Materials and Methods: A total of 225 patients of severe brain trauma were admitted to the accident and emergency unit of Neurosurgery and after initial resuscitation a CT brain was performed. All patients had a GCS score of 8 and below. All patients were ventilated postoperatively and ICP was monitored. Statistical Analysis Used: The data was analyzed and evaluated by the statistical methods like student's T-test. The analysis of Variance was used where-ever applicable. Results: The survival of multi-dural stab group was 77.31% (92/119) with good recovery in 42.02% (50/119) and a mortality of 22.69% (27/119) as compared with 46.23% (49/106) survival in open dural flap (control) group with 15.09% (16/106) good recovery and mortality of 53.77% (57/106). Conclusions: This new approach, known as SKIMS-Technique or Combined Technique i.e., “decompressive craniectomy with multi-dural stabs”, proved much effective in increasing survival of low GCS and severe traumatic brain edema patients with acute subdural hematoma.

Bhat, Abdul Rashid; Kirmani, Altaf Rehman; Wani, Mohammed Afzal



Midline-shift corresponds to the amount of brain edema early after hemispheric stroke--an MRI study in rats.  


Vasogenic brain edema formation is a serious complication in hemispheric stroke. Its space-occupying effect can lead to midline-shift (MLS), cerebral herniation, and death. Clinical studies indicate that quantification of MLS can predict cerebral herniation and subsequent death at early time-points, even before clinical deterioration becomes apparent. The present experimental study was designed to determine the relation between MLS, absolute edema volume, lesion size, and clinical findings in a rat stroke model. Middle cerebral artery-occlusion was performed in 24 rats using the suture technique. Clinical evaluation and magnetic resonance imaging (MRI) (Bruker PharmaScan 7.0T) was performed 24 hours later. Lesion volume, the volume-increase within the affected hemisphere (%HEV), and MLS were quantified on T2-weighted images. The absolute increase of hemispheric water content (DeltaH2O) was determined in a subgroup using the wet-dry method (n=12). MLS correlated significantly with the total amount of brain edema (magnetic resonance imaging study: r=0.82; P<0.01; wet-dry analysis r=0.80; P<0.01). MLS correlated only moderately with T2-lesion volume (r=0.55; P<0.01). No significant correlation could be detected between MLS and clinical scores (r=0.26; P>0.05). MLS thus quantitatively reflects the amount of vasogenic brain edema within the affected hemisphere at early time-points. MLS quantification can be regarded as an easily assessable and valid global quantitative parameter for brain edema and thus might facilitate the surgical and nonsurgical management of edema in acute stroke patients. PMID:17413996

Walberer, Maureen; Blaes, Franz; Stolz, Erwin; Müller, Clemens; Schoenburg, Markus; Tschernatsch, Marlene; Bachmann, Georg; Gerriets, Tibo



Brain damage due to episodic alcohol exposure in vivo and in vitro: furosemide neuroprotection implicates edema-based mechanism  

Microsoft Academic Search

Adult rats intubated with a single dose of ethanol (alcohol;Ç5 g\\/kg) for 5 to 10 successive days incur neurodegeneration in the entorhinal cor- tex, dentate gyrus, and olfactory bulbs accompanied by cerebrocortical edema and electrolyte (Na\\/ ,K \\/ ) accumulation. The brain damage is not lessened by cotreatment with the NMDA receptor antagonist MK- 801; also, as reported elsewhere, MK-801



Antibodies to Dynorphin A (1–17) Attenuate Closed Head Injury Induced Blood–Brain Barrier Disruption, Brain Edema Formation and Brain Pathology in the Rat  

Microsoft Academic Search

\\u000a The potential neuroprotective efficacy of dynorphin A antiserum on BBB dysfunction, edema formation and brain pathology was\\u000a examined in a closed head injury (CHI) model in the rat. The CHI was produced by an impact of 0.224 N on the right parietal\\u000a bone under anesthesia by dropping a weight of 114.6 g on the skull from a height of 20

H. S. Sharma; R. Patnaik; S. Patnaik; A. Sharma; S. Mohanty; P. Vannemreddy


Effect of Propofol Post-treatment on Blood-Brain Barrier Integrity and Cerebral Edema After Transient Cerebral Ischemia in Rats.  


Although propofol has been reported to offer neuroprotection against cerebral ischemia injury, its impact on cerebral edema following ischemia is not clear. The objective of this investigation is to evaluate the effects of propofol post-treatment on blood-brain barrier (BBB) integrity and cerebral edema after transient cerebral ischemia and its mechanism of action, focusing on modulation of aquaporins (AQPs), matrix metalloproteinases (MMPs), and hypoxia inducible factor (HIF)-1?. Cerebral ischemia was induced in male Sprague-Dawley rats (n = 78) by occlusion of the right middle cerebral artery for 1 h. For post-treatment with propofol, 1 mg kg(-1) min(-1) of propofol was administered for 1 h from the start of reperfusion. Nineteen rats undergoing sham surgery were also included in the investigation. Edema and BBB integrity were assessed by quantification of cerebral water content and extravasation of Evans blue, respectively, following 24 h of reperfusion. In addition, the expression of AQP-1, AQP-4, MMP-2, and MMP-9 was determined 24 h after reperfusion and the expression of HIF-1? was determined 8 h after reperfusion. Propofol post-treatment significantly reduced cerebral edema (P < 0.05) and BBB disruption (P < 0.05) compared with the saline-treated control. The expression of AQP-1, AQP-4, MMP-2, and MMP-9 at 24 h and of HIF-1? at 8 h following ischemia/reperfusion was significantly suppressed in the propofol post-treatment group (P < 0.05). Propofol post-treatment attenuated cerebral edema after transient cerebral ischemia, in association with reduced expression of AQP-1, AQP-4, MMP-2, and MMP-9. The decreased expression of AQPs and MMPs after propofol post-treatment might result from suppression of HIF-1? expression. PMID:23990224

Lee, Jae Hoon; Cui, Hui Song; Shin, Seo Kyung; Kim, Jeong Min; Kim, So Yeon; Lee, Jong Eun; Koo, Bon-Nyeo



Brain edema formation correlates with perfusion deficit during the first six hours after experimental subarachnoid hemorrhage in rats  

PubMed Central

Background Severe brain edema is observed in a number of patients suffering from subarachnoid hemorrhage (SAH). Little is known about its pathogenesis and time-course in the first hours after SAH. This study was performed to investigate the development of brain edema and its correlation with brain perfusion after experimental SAH. Methods Male Sprague–Dawley rats, randomly assigned to one of six groups (n = 8), were subjected to SAH using the endovascular filament model or underwent a sham operation. Animals were sacrificed 15, 30, 60, 180 or 360 minutes after SAH. Intracranial pressure (ICP), mean arterial blood pressure (MABP), cerebral perfusion pressure (CPP) and bilateral local cerebral blood flow (LCBF) were continuously measured. Brain water content (BWC) was determined by the wet/dry-weight method. Results After SAH, CPP and LCBF rapidly decreased. The decline of LCBF markedly exceeded the decline of CPP and persisted until the end of the observation period. BWC continuously increased. A significant correlation was observed between the BWC and the extent of the perfusion deficit in animals sacrificed after 180 and 360 minutes. Conclusions The significant correlation with the perfusion deficit after SAH suggests that the development of brain edema is related to the extent of ischemia and acute vasoconstriction in the first hours after SAH.



PGJ2 Provides Prolonged CNS Stroke Protection by Reducing White Matter Edema  

PubMed Central

Few clinically effective approaches reduce CNS-white matter injury. After early in-vivo white matter infarct, NF?B-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-?12,14-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 NF?B 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.

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



Edaravone Attenuates Brain Edema and Neurologic Deficits in a Rat Model of Acute Intracerebral Hemorrhage  

Microsoft Academic Search

Background and Purpose—Our previous studies have demonstrated that oxidative DNA injury occurs in the brain after intracerebral hemorrhage (ICH). We therefore examined whether edaravone, a free-radical scavenger, could reduce ICH-induced brain injury. Methods—These experiments used pentobarbital-anesthetized, male Sprague-Dawley rats that received an infusion of either 100 L autologous whole blood (ICH), FeCl2, or thrombin into the right basal ganglia. The

Takehiro Nakamura; Yasuhiro Kuroda; Susumu Yamashita; Xia Zhang; Osamu Miyamoto; Takashi Tamiya; Seigo Nagao; Guohua Xi; Richard F. Keep; Toshifumi Itano



Progesterone attenuates cerebral edema in neonatal rats with hypoxic-ischemic brain damage by inhibiting the expression of matrix metalloproteinase-9 and aquaporin-4  

PubMed Central

The aim of this study was to investigate the effects of progesterone (PROG) on blood-brain barrier (BBB) permeability, cerebral edema and the expression of matrix metalloproteinase-9 (MMP-9) and aquaporin-4 (AQP-4) in neonatal rats with hypoxic-ischemic brain damage (HIBD) and to explore the mechanism of its neuroprotective effect. Sixty 7-day-old Wistar rats were divided into sham surgery, hypoxic ischemia (HI) and drug prophylaxis (PROG) groups. HIBD animal models were established. All the animals were sacrificed after 24 h. The BBB was assessed using Evans blue. Cerebral moisture capacity was determined using the dry-wet method. MMP-9 was detected in the brain tissues using enzyme-linked immunosorbent assay. The expression of AQP-4 and MMP-9 in the cerebral cortex was observed using immunohistochemistry and real-time polymerase chain reaction. The MMP-9 levels in the cortex, BBB permeability, cerebral moisture capacity and expression of AQP-4 and MMP-9 in the HI group were significantly higher compared with those in the sham surgery group (P<0.01), and they were significantly lower in the drug prophylaxis group compared with those in the HI group (P<0.05). In conclusion, PROG reduces BBB damage and cerebral edema and inhibits MMP-9 generation to protect rat brains against HIBD. The protective effect of PROG may be correlated with downregulated expression of AQP-4 and MMP-9 in the cerebral cortex.




Tumor necrosis factor-? neutralization reduced cerebral edema through inhibition of matrix metalloproteinase production after transient focal cerebral ischemia  

Microsoft Academic Search

After focal cerebral ischemia, tumor necrosis factor-? deteriorates cerebral edema and survival rate. Therefore, tumor necrosis factor-? neutralization could reduce cerebral microvascular permeability in acute cerebral ischemia. Left middle cerebral artery occlusion for 120 mins followed by reperfusion was performed with the thread method under halothane anesthesia in Sprague–Dawley rats. Antirat tumor necrosis factor-? neutralizing monoclonal antibody with a rat

Naohisa Hosomi; Camelia R Ban; Takayuki Naya; Tsutomu Takahashi; Peng Guo; Xiao-yu R Song; Masakazu Kohno



Exacerbated Brain Damage, Edema and Inflammation in Type-2 Diabetic Mice Subjected to Focal Ischemia  

PubMed Central

One of the limiting factors in stroke therapeutic development is the use of animal models that do not well represent the underlying medical conditions of patients. In humans, diabetes increases the risk of stroke incidence as well as post-stroke mortality. To understand the mechanisms that render diabetics to increased brain damage, we evaluated the effect of transient middle cerebral artery occlusion (MCAO) in adult db/db mice. The db/db mouse is a model of type-2 diabetes with 4 times higher blood sugar than its normoglycemic genetic control (db/+ mouse). Following transient MCAO, the db/db mice showed significantly higher mortality, bigger infarcts, increased cerebral edema, worsened neurological status compared to db/+ mice. The db/db mice also showed significantly higher post-ischemic inflammatory markers (ICAM1+ capillaries, extravasated macrophages/neutrophils and exacerbated proinflammatory gene expression) compared to db/+ mice. In addition, the post-ischemic neuroprotective heat-shock chaperone gene expression was curtailed in the db/db compared to db/+ mice.

Tureyen, Kudret; Bowen, Kellie; Liang, Jin; Dempsey, Robert J; Vemuganti, Raghu



Zinc protoporphyrin IX attenuates closed head injury-induced edema formation, blood-brain barrier disruption, and serotonin levels in the rat.  


The role of heme oxygenase (HO) in closed head injury (CHI) was examined using a potent HO and guanylyl cyclase inhibitor, zinc protoporphyrin (Zn-PP) in the rat. Blood-brain barrier (BBB) permeability to Evans blue and radioiodine, edema formation, and plasma and brain levels of serotonin were measured in control, CHI, and Zn-PP-treated CHI rats. CHI was produced by an impact of 0.224 N on the right parietal bone by dropping 114.6 g weight from a height of 20 cm in anesthetized rats. This concussive injury resulted in edema formation and brain swelling 5 hours after insult that was most pronounced in the contralateral hemisphere. The whole brain was edematous and remained in a semi-fluid state. Microvascular permeability disturbances to protein tracers were prominent in both cerebral hemispheres and the underlying cerebral structures. Plasma and brain serotonin showed pronounced increases and correlated with edema formation. Pretreatment with Zn-PP (10 mg/ kg, i.p) 30 minutes before or after CHI attenuated edema formation, brain swelling, plasma and brain serotonin levels, and microvascular permeability at 5 hours. Brain edema, BBB permeability, and serotonin levels were not attenuated when the compound was administered 60 minutes post-CHI suggesting that HO is involved in cellular and molecular mechanisms of edema formation and BBB breakdown early after CHI. PMID:16671445

Vannemreddy, P; Ray, A K; Patnaik, R; Patnaik, S; Mohanty, S; Sharma, H S



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

SciTech Connect

[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.

Fike, J.R.; Seilhan, T.M.; Gobbel, G.T. (Univ. of California, San Francisco, CA (United States)); Marton, L.J. (Univ. of Wisconsin, Madison, WI (United States))



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


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

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; Schütze, Stefan; Krause, Martin F



Effects of blockade of cerebral lymphatic drainage on regional cerebral blood flow and brain edema after subarachnoid hemorrhage.  


The study was designed to observe the influence of blockade of cerebral lymphatic drainage on the regional cerebral blood flow (rCBF) and brain edema after experimental subarachnoid hemorrhage (SAH). Wistar rats were divided into non-SAH, SAH, and SAH plus cervical lymphatic blockade (SAH + CLB) groups. Autologous arterial hemolysate was injected into rat's cisterna magna to induce SAH. The rCBF was recorded continuously by a laser Doppler flowmeter. Intracranial pressure (ICP) was also monitored. After 24 hours and 72 hours of SAH, the rats were sacrificed and the brain was harvested for water content detection. It was found that there was no obvious change of rCBF and brain water content during the experiment in non-SAH group. An immediate and persistent drop in rCBF was found in SAH group. The drop in rCBF was more obvious in SAH + CLB group. CLB also worsened the SAH-induced increase in ICP. The brain water content 24 hours and 72 hours after induction of SAH in SAH group increased significantly. CLB led to a further increase of brain water content. In conclusion, blockade of cerebral lymphatic drainage pathway deteriorates the secondary cerebral ischemia and brain edema after SAH. PMID:16543641

Sun, Bao-Liang; Xia, Zuo-Li; Wang, Jing-Ru; Yuan, Hui; Li, Wen-Xia; Chen, Yu-She; Yang, Ming-Feng; Zhang, Su-Ming



Delayed progression of edema formation around a hematoma expressing high levels of VEGF and mmp-9 in a patient with traumatic brain injury: case report.  


The mechanisms accounting for the development of tissue damage following traumatic brain injury (TBI) have been studied for several decades. A variety of mediators, such as vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9), which play a crucial role in edema formation after TBI, have been identified. We experienced a case of brain edema that progressed continuously at least until 13 days after head injury. The brain edema occurred around the hemorrhage from an intracerebral contusion. The evacuated hematoma was investigated based on the inference that the unexpected expansion of edema was induced by the mediators within the hematoma itself. A 64-year-old woman was admitted to our hospital following a traffic injury. Left brain contusion was revealed by head computed tomography (CT) on admission. Three hours later, formation of an intracerebral hematoma became evident. Serial CT examination revealed that brain edema had developed progressively till 13 days after the injury. A hematoma removal operation was performed on Day 13. The hematoma was centrifuged and the supernatant was analyzed for the expression of VEGF and MMP-9. The values of both (4400 pg/ml and 920 ng/ml, respectively) were extremely high compared with values reported previously in serum and cerebrospinal fluid collected from patients with intracranial infection or injury. This case suggested that the delayed exacerbation of edema following traumatic intracranial hemorrhage was possibly induced by secretory factors such as VEGF and MMP-9 released from within and around the hematoma. PMID:24067772

Hirose, Tomoya; Matsumoto, Naoya; Tasaki, Osamu; Nakamura, Hajime; Akagaki, Fuyuko; Shimazu, Takeshi



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


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

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


Effect of acute poly(ADP-ribose) polymerase inhibition by 3-AB on blood-brain barrier permeability and edema formation after focal traumatic brain injury in rats.  


Recent evidence supports a crucial role for matrix metalloproteinase-9 (MMP-9) in blood-brain barrier (BBB) disruption and vasogenic edema formation after traumatic brain injury (TBI). Although the exact causes of MMP-9 upregulation after TBI are not fully understood, several arguments suggest a contribution of the enzyme poly(ADP-ribose)polymerase (PARP) in the neuroinflammatory response leading to MMP-9 activation. The objectives of this study were to evaluate the effect of PARP inhibition by 3-aminobenzamide (3-AB) (1) on MMP-9 upregulation and BBB integrity, (2) on edema formation as assessed by magnetic resonance imaging (MRI), (3) on neuron survival as assessed by (1)H magnetic resonance spectroscopy ((1)H-MRS), and (4) on neurological deficits at the acute phase of TBI. Western blots and zymograms showed blunting of MMP-9 upregulation 6 h after TBI. BBB permeability was decreased at the same time point in 3-AB-treated rats compared to vehicle-treated rats. Cerebral MRI showed less "free" water in 3-AB-treated than in vehicle-treated rats 6 h after TBI. MRI findings 24 h after TBI indicated predominant cytotoxic edema, and at this time point no significant differences were found between 3-AB- and vehicle-treated rats with regard to MMP-9 upregulation, BBB permeability, or MRI changes. At both 6 and 24 h, neurological function was better in the 3-AB-treated than in the vehicle-treated rats. These data suggest that PARP inhibition by 3-AB protected the BBB against hyperpermeability induced by MMP-9 upregulation, thereby decreasing vasogenic edema formation 6 h after TBI. Furthermore, our data confirm the neuroprotective effect of 3-AB at the very acute phase of TBI. PMID:20380552

Lescot, Thomas; Fulla-Oller, Laurence; Palmier, Bruno; Po, Christelle; Beziaud, Tiphaine; Puybasset, Louis; Plotkine, Michel; Gillet, Brigitte; Meric, Philippe; Marchand-Leroux, Catherine



Cerebrolysin reduces blood-cerebrospinal fluid barrier permeability change, brain pathology, and functional deficits following traumatic brain injury in the rat.  


Traumatic brain injuries (TBIs) induce profound breakdown of the blood-brain and blood-cerebrospinal fluid barriers (BCSFB), brain pathology/edema, and sensory-motor disturbances. Because neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), insulin-like growth factor-1 (IGF-1), and glial cell-derived neurotrophic factor (GDNF), are neuroprotective in models of brain and spinal cord injuries, we hypothesized that a combination of neurotrophic factors would enhance neuroprotective efficacy. In the present investigation, we examined the effects of Cerebrolysin, a mixture of different neurotrophic factors (Ebewe Neuro Pharma, Austria) on the brain pathology and functional outcome in a rat model of TBI. TBI was produced under Equithesin (3 mL/kg, i.p.) anesthesia by making a longitudinal incision into the right parietal cerebral cortex. Untreated injured rats developed profound disruption of the blood-brain barrier (BBB) to proteins, edema/cell injury, and marked sensory-motor dysfunctions on rota-rod and grid-walking tests at 5 h TBI. Intracerebroventricular administration of Cerebrolysin (10 or 30 microL) either 5 min or 1 h after TBI significantly reduced leakage of Evans blue and radioiodine tracers across the BBB and BCSFB, and attenuated brain edema formation/neuronal damage in the cortex as well as underlying subcortical regions. Cerebrolysin-treated animals also had improved sensory-motor functions. However, administration of Cerebrolysin 2 h after TBI did not affect these parameters significantly. These observations in TBI demonstrate that early intervention with Cerebrolysin reduces BBB and BCSFB permeability changes, attenuates brain pathology and brain edema, and mitigates functional deficits. Taken together, our observations suggest that Cerebrolysin has potential therapeutic value in TBI. PMID:20633118

Sharma, Hari Shanker; Zimmermann-Meinzingen, Sibilla; Johanson, Conrad E



Astrocytic tissue remodeling by the meningitis neurotoxin pneumolysin facilitates pathogen tissue penetration and produces interstitial brain edema.  


Astrocytes represent a major component of brain tissue and play a critical role in the proper functioning and protection of the brain. Streptococcus pneumoniae, the most common cause of bacterial meningitis, has a high lethality and causes serious disabilities in survivors. Pneumolysin (PLY), a member of the cholesterol-dependent cytolysin group and a major S. pneumoniae neurotoxin, causes deterioration over the course of experimental S. pneumoniae meningitis. At disease-relevant sub-lytic concentrations, PLY produces actin and tubulin reorganization and astrocyte cell shape changes in vitro. In this article, we show that sub-lytic amounts of PLY remodel brain tissue and produce astrocytic process retraction, cortical astroglial reorganization and increased interstitial fluid retention, which is manifested as tissue edema. These changes caused increased tissue permeability to macromolecules and bacteria. The pore-forming capacity of PLY remained necessary for these changes because none of the nonpore-forming mutants were capable of producing similar effects. We suggest that PLY can increase the permeability of brain tissue toward pathogenic factors and bacteria in the course of meningitis, thus contributing to the deterioration caused by the disease. PMID:21989652

Hupp, Sabrina; Heimeroth, Vera; Wippel, Carolin; Förtsch, Christina; Ma, Jiangtao; Mitchell, Timothy J; Iliev, Asparouh I



Forebrain Ischemia-Reperfusion Simulating Cardiac Arrest in Mice Induces Edema and DNA Fragmentation in the Brain  

PubMed Central

Brain injury affects one-third of persons who survive after heart attack, even with restoration of spontaneous circulation by cardiopulmonary resuscitation. We studied brain injury resulting from transient bilateral carotid artery occlusion (BCAO) and reperfusion by simulating heart attack and restoration of circulation, respectively, in live C57Black6 mice. This model is known to induce neuronal death in the hippocampus, striatum, and cortex. We report the appearance of edema after transient BCAO of 60 minutes and 1 day of reperfusion. Hyperintensity in diffusion-weighted magnetic resonance imaging (MRI) was detectable in the striatum, thalamus, and cortex but not in the hippocampus. To determine whether damage to the hippocampus can be detected in live animals, we infused a T2 susceptibility magnetic resonance contrast agent (superparamagnetic iron oxide nanoparticles [SPIONs]) that was linked to single-stranded deoxyribonucleic acid (DNA) complementary in sequence to c-fos messenger ribonucleic acid (SPION-cfos); we acquired in vivo T2*-weighted MRI 3 days later. SPION retention was measured as T2* (milliseconds) signal reduction or R2* value (s?1) elevation. We found that animals treated with 60-minute BCAO and 7-day reperfusion exhibited significantly less SPION retention in the hippocampus and cortex than sham-operated animals. These findings suggest that brain injury induced by cardiac arrest can be detected in live animals.

Liu, Christina H.; Huang, Shuning; Kim, Young R.; Rosen, Bruce R.; Liu, Philip K.



Vulvar edema.  


Vulvar edema is associated with a variety of conditions. The edema can result from inflammatory conditions, infections, infestations, trauma, pregnancy, tumors and iatrogenic causes. At times, it is difficult to determine the cause of the vulvar edema. Treatment consists of determining the origin of the edema and giving the appropriate therapy for that diagnosis as well as the use of compression and, at times, lymphatic massage. PMID:20883919

Amankwah, Yaa; Haefner, Hope



[Drug-induced edema].  


It is well known that there are many drugs which induce edema. Drug-induced edema can be divided into three types by the mechanism as follows, 1) sodium overload, 2) renal dysfunction and 3) hyperpermeability of blood vessel. In the category of sodium overload, edema is induced by much fluid replacement and antibiotics which contain large amount of sodium and sodium bicarbonate. As the category of renal dysfunction, NSAIDs, antihypertensive drugs, anticancer drugs and so on induce edema in patients with renal dysfunction. In the category of hyperpermeability of blood vessel, edema is induced by calcium antagonist, insuline and so on. In order to diagnose drug-induced edema early, it is important that we interrupt or reduce the quantity of suspicious drug. PMID:15675326

Kaizu, Kazo; Abe, Masanori



Nanoparticles aggravate heat stress induced cognitive deficits, blood–brain barrier disruption, edema formation and brain pathology  

Microsoft Academic Search

Our knowledge regarding the influence of nanoparticles on brain function in vivo during normal or hyperthermic conditions is still lacking. Few reports indicate that when nanoparticles enter into the central nervous system (CNS) they may induce neurotoxicity. On the other hand, nanoparticle-induced drug delivery to the brain enhances neurorepair processes. Thus, it is likely that the inclusion of nanoparticles in

Hari Shanker Sharma; Aruna Sharma



A case of delayed emergence from anesthesia caused by postoperative brain edema associated with unexpected cerebral venous sinus thrombosis.  


Cerebral venous sinus thrombosis (CVST) is rare but displays various and often dramatic clinical symptoms. Few cases of CVST have been reported in the field of anesthesiology. We encountered an unexpected case of CVST that presented with delayed emergence from anesthesia after resection of a brain tumor. A 55-year-old man was scheduled for resection of an oligoastrocytoma in his right frontal lobe. After smooth induction of general anesthesia, anesthesia was maintained uneventfully for about 7 h with target-controlled infusion (TCI) of propofol and remifentanil, except for a seizure generated when the right anterior central gyrus was stimulated to allow motor evoked potential monitoring. Immediately after the cessation of TCI, spontaneous respiration was restored. However, the patient was unexpectedly comatose, and no response to painful stimuli or coughing during tracheal suctioning was observed. A computed tomogram taken 2 h after surgery showed diffuse brain edema, even though the neurosurgeons did not notice any cerebral swelling during closing of the dura mater. A magnetic resonance venogram revealed thromboses in the superior sagittal and straight sinuses. On the 9th postoperative day, the patient died without recovering consciousness or his brainstem reflexes. Anesthesiologists should be aware of CVST as a cause of delayed emergence from anesthesia after craniotomy. PMID:23526037

Kozasa, Yuko; Takaseya, Hikari; Koga, Yukari; Hiraki, Teruyuki; Mishima, Yasunori; Niiyama, Shuhei; Ushijima, Kazuo



SM20220, a Na +\\/H + exchanger inhibitor: effects on ischemic brain damage through edema and neutrophil accumulation in a rat middle cerebral artery occlusion model  

Microsoft Academic Search

The Na+\\/H+ exchanger (NHE) is activated during ischemia–reperfusion in an effort to restore intracellular pH to normal levels. The NHE is recognized to exist as a distinct protein in the plasma membranes of a variety of cells. We investigated the pharmacological effects of a Na+\\/H+ exchanger inhibitor, SM-20220 (N-(aminoiminomethyl)-1-methyl-1-H-indole-2-carboxamide methanesulfonate), on ischemic brain damage, edema and neutrophil accumulation at 72

Yasuhiro Suzuki; Yuji Matsumoto; Yasuhiko Ikeda; Kazunao Kondo; Naohito Ohashi; Kazuo Umemura



Idiopathic edema  

Microsoft Academic Search

Idiopathic edema is a syndrome of real or perceived excessive weight gain. This article reviews what is known about the possible causes, evaluation, and treatment. Although the cause is unknown but often thought to be due to secondary hyperaldosteronism, primary abnormalities of the hypothalamus, thyroid, dopaminergic release or renal dopaminergic metabolism, vascular basement membrane, or capillary sphincter control could perhaps

Alex Kay; Connie L. Davis



Molecular pathology of brain edema after severe burns in forensic autopsy cases with special regard to the importance of reference gene selection.  


Brain edema is believed to be linked to high mortality incidence after severe burns. The present study investigated the molecular pathology of brain damage and responses involving brain edema in forensic autopsy cases of fire fatality (n?=?55) compared with sudden cardiac death (n?=?11), mechanical asphyxia (n?=?13), and non-brain injury cases (n?=?22). Postmortem mRNA and immunohistochemical expressions of aquaporins (AQPs), claudin5 (CLDN5), and matrix metalloproteinases (MMPs) were examined. Prolonged deaths due to severe burns showed an increase in brain water content, but relative mRNA quantification, using different normalization methods, showed inconsistent results: in prolonged deaths due to severe burns, higher expression levels were detected for all markers when three previously validated reference genes, PES1, POLR2A, and IPO8, were used for normalization, higher for AQP1 and MMP9 when GAPDH alone was used for normalization and higher for MMP9, but lower for MMP2 when B2M alone was used for normalization. Additionally, when B2M alone was used for normalization, higher expression of AQP4 was detected in acute fire deaths. Furthermore, the expression stability values of these five reference genes calculated by geNorm demonstrated that B2M was the least stable one, followed by GAPDH. In immunostaining, only AQP1 and MMP9 showed differences among the causes of death: they were evident in most prolonged deaths due to severe burns. These findings suggest that systematic analysis of gene expressions using real-time PCR might be a useful procedure in forensic death investigation, and validation of reference genes is crucial. PMID:23702882

Wang, Qi; Ishikawa, Takaki; Michiue, Tomomi; Zhu, Bao-Li; Guan, Da-Wei; Maeda, Hitoshi



Cerebral edema and a transtentorial brain herniation syndrome associated with pandemic swine influenza A (H1N1) virus infection  

Microsoft Academic Search

Acute encephalitis, encephalopathy, and seizures are known rare neurologic sequelae of respiratory tract infection with seasonal influenza A and B virus, but the neurological complications of the pandemic 2009 swine influenza A (H1N1) virus, particularly in adults, are ill-defined. We document two young adults suffering from H1N1-associated acute respiratory distress syndrome and renal failure who developed cerebral edema. The patients

Kristopher T. Kahle; Brian P. Walcott; Brian V. Nahed; Zachary R. Barnard; Eng H. Lo; Ferdinando S. Buonanno; Nagagopal Venna; MingMing Ning



Postconditioning by mild hypoxic exposures reduces rat brain injury caused by severe hypoxia.  


A potent neuroprotective effect of ischemic postconditioning has previously been described using cerebral artery occlusion but this is not a practical therapeutic option. The present study has been performed to determine whether postconditioning by mild episodes of hypobaric hypoxia (hypoxic postconditioning, HP) can reduce post-hypoxic brain injury in rats. Male Wistar rats were submitted to severe hypobaric hypoxia (180 Torr, 3 h) followed by HP (360 Torr, 2 h, 3 trials spaced at 24 h) starting either 3h (early HP) or 24 h (delayed HP) after severe hypoxia. The structural and functional brain injury was assessed by a complex of histological techniques, behavioral methods, and by testing the functions of the hypothalamic-pituitary-adrenal axis (HPA). It was found that early and delayed HP considerably attenuated post-hypoxic injury, reducing pyknosis, hyperchromatosis, and interstitial brain edema, as well as the rates of neuronal loss in hippocampus and neocortex. Delayed HP produced prominent anxiolytic effect on rat behavior, preventing development of post-hypoxic anxiety. Both modes of HP had beneficial effect on the functioning of HPA, but only delayed HP normalized completely the baseline HPA activity and its reactivity to stress. The results obtained demonstrate that postconditioning by using repetitive episodes of mild hypobaric hypoxia may provide a powerful neuroprotective procedure that can be easily adopted for clinical practice and recommended as a research tool for identification of endogenous mechanisms involved in post-ischemic neuroprotection. PMID:22366259

Rybnikova, Elena; Vorobyev, Maksim; Pivina, Svetlana; Samoilov, Mikhail



Acute ethanol administration reduces the cognitive deficits associated with traumatic brain injury in rats.  


The present study was designed to determine whether a low dose of acute ethanol administration could attenuate cognitive deficits associated with traumatic brain injury. Adult male rats received oral administration of ethanol or drinking water 2 h prior to surgery to produce a blood ethanol concentration of 100 mg% and then received bilateral contusion injuries of the medial prefrontal cortex. Seven days after surgery, the rats began 10 days of testing for acquisition of spatial localization in the Morris water maze where they were required to find a hidden platform to escape from the water. The results indicate that the rats given ethanol at the time of injury later spent significantly less time searching for the hidden platform than their water-treated counterparts. On a memory probe test given on the final day of testing, in which the platform was removed from the pool, rats given the ethanol spent more time in the area where the platform had been located indicating that they learned its location better than the lesion/water controls. In addition, acute ethanol treatment reduced some of the histopathology that typically occurs following severe contusion of the medial frontal cortex but did not attenuate post-traumatic formation of edema. These results indicate that acute ethanol intoxication can reduce the severity of cognitive impairments caused by contusive traumatic brain injury and support the contention that there is a dose-response relationship of acute ethanol intoxication in the setting of traumatic brain injury. PMID:9512086

Janis, L S; Hoane, M R; Conde, D; Fulop, Z; Stein, D G



Enhanced macromolecular diffusion in brain extracellular space in mouse models of vasogenic edema measured by cortical surface photobleaching  

Microsoft Academic Search

Diffusion of solutes and macromolecules in brain extracellular space (ECS) is important for normal brain function and efficient drug delivery, and is thought to be impaired in edematous brain. Here we measured the diffusion of an inert macromolecular fluorescent marker (FITC- dextran, 70 kDa) in the ECS by fluorescence recovery after photobleaching after staining the exposed cerebral cortex in vivo.

Marios C. Papadopoulos; Devin K. Binder; A. S. Verkman



Reducing Test Anxiety: A Right Brain Approach.  

ERIC Educational Resources Information Center

Methods of helping students reduce test anxiety are discussed, including guided fantasy which leads students to imagine a setting in which they feel competent and relaxed. Catastrophic-anastrophic expectations teach that different expectations create different feelings and make students aware that they are in charge of their own attitudes. Anxiety…

Cohen, Ruth I.


Caveolin-1 Deletion Reduces Early Brain Injury after Experimental Intracerebral Hemorrhage  

PubMed Central

Intracerebral hemorrhage (ICH) is a subtype of stroke with high rates of morbidity and mortality. Caveolin-1 (Cav-1) is the main structural protein of caveolae and is involved in regulating signal transduction and cholesterol trafficking in cells. Although a recent study suggests a protective role of Cav-1 in cerebral ischemia, its function in ICH remains unknown. In this study, we examined the role of Cav-1 and in a model of collagenase-induced ICH and in neuronal cultures. Our results indicate that Cav-1 was up-regulated in the perihematomal area predominantly in endothelial cells. Cav-1 knockout mice had smaller injury volumes, milder neurologic deficits, less brain edema, and neuronal death 1 day after ICH than wild-type mice. The protective mechanism in Cav-1 knockout mice was associated with marked reduction in leukocyte infiltration, decreased expression of inflammatory mediators, including macrophage inflammatory protein (MIP)-2 and cyclooxygenase (COX)-2, and reduced matrix metalloproteinase-9 activity. Deletion of Cav-1 also suppressed heme oxygenase-1 expression and attenuated reactive oxygen species production after ICH. Moreover, deletion or knockdown of Cav-1 decreased neuronal vulnerability to hemin-induced toxicity and reduced heme oxygenase (HO)-1 induction in vitro. These data suggest that Cav-1 plays a deleterious role in early brain injury after ICH. Inhibition of Cav-1 may provide a novel therapeutic approach for the treatment of hemorrhagic stroke.

Chang, Che-Feng; Chen, Shu-Fen; Lee, Tzong-Shyuan; Lee, Hung-Fu; Chen, Szu-Fu; Shyue, Song-Kun



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

PubMed Central

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.

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



Wogonin Improves Histological and Functional Outcomes, and Reduces Activation of TLR4/NF-?B Signaling after Experimental Traumatic Brain Injury  

PubMed Central

Background Traumatic brain injury (TBI) initiates a neuroinflammatory cascade that contributes to neuronal damage and behavioral impairment. This study was undertaken to investigate the effects of wogonin, a flavonoid with potent anti-inflammatory properties, on functional and histological outcomes, brain edema, and toll-like receptor 4 (TLR4)- and nuclear factor kappa B (NF-?B)-related signaling pathways in mice following TBI. Methodology/Principal Findings Mice subjected to controlled cortical impact injury were injected with wogonin (20, 40, or 50 mg·kg?1) or vehicle 10 min after injury. Behavioral studies, histology analysis, and measurement of blood-brain barrier (BBB) permeability and brain water content were carried out to assess the effects of wogonin. Levels of TLR4/NF-?B-related inflammatory mediators were also examined. Treatment with 40 mg·kg?1 wogonin significantly improved functional recovery and reduced contusion volumes up to post-injury day 28. Wogonin also significantly reduced neuronal death, BBB permeability, and brain edema beginning at day 1. These changes were associated with a marked reduction in leukocyte infiltration, microglial activation, TLR4 expression, NF-?B translocation to nucleus and its DNA binding activity, matrix metalloproteinase-9 activity, and expression of inflammatory mediators, including interleukin-1?, interleukin-6, macrophage inflammatory protein-2, and cyclooxygenase-2. Conclusions/Significance Our results show that post-injury wogonin treatment improved long-term functional and histological outcomes, reduced brain edema, and attenuated the TLR4/NF-?B-mediated inflammatory response in mouse TBI. The neuroprotective effects of wogonin may be related to modulation of the TLR4/NF-?B signaling pathway.

Chen, Chien-Cheng; Hung, Tai-Ho; Wang, Yen-Ho; Lin, Chii-Wann; Wang, Pei-Yi; Lee, Chun-Yen; Chen, Szu-Fu



The effect of dexamethasone on serum protein extravasation and edema development in experimental brain tumors of cat  

Microsoft Academic Search

Experimental brain tumors were produced in 20 cats by stereotaxic xenotransplantation of a blastomatous glial cell clone into the internal capsule of the left hemisphere. Ten of these animals were treated after 2 weeks with a single injection of 10 mg dexamethasone in crystalline suspension. Three weeks after xenotransplantation vascular permeability was studied by electron microscopy with horseradish peroxidase as

K.-A. Hossmann; T. Hürter; U. Oschlies



Astaxanthin reduces ischemic brain injury in adult rats  

PubMed Central

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.

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.



Distribution of exudated FITC-dextrans in experimental vasogenic brain edema produced by a focal cryogenic injury  

Microsoft Academic Search

Mice were subjected to cortical cryogenic brain injury, and FITC-dextrans (mol. wt. 20,000 or 150,000) were injected intravenously (i.v.). After a survival period of 4 h the distribution of the FITC-dextrans was determined by a histotechnical procedure described recently (Hultström et al. 1982a). This technique is based on freeze-drying and vapor fixation to immobilize the tracer and to provide tissue

D. Hultström; C. Tengvar; M. Forssén; Y. Olsson



Posttraumatic reduction of edema with aquaporin-4 RNA interference improves acute and chronic functional recovery.  


Traumatic brain injury (TBI) is common in young children and adolescents and is associated with long-term disability and mortality. The neuropathologic sequelae that result from juvenile TBI are a complex cascade of events that include edema formation and brain swelling. Brain aquaporin-4 (AQP4) has a key role in edema formation. Thus, development of novel treatments targeting AQP4 to reduce edema could lessen the neuropathologic sequelae. We hypothesized that inhibiting AQP4 expression by injection of small-interfering RNA (siRNA) targeting AQP4 (siAQP4) after juvenile TBI would decrease edema formation, neuroinflammation, neuronal cell death, and improve neurologic outcomes. The siAQP4 or a RNA-induced silencing complex (RISC)-free control siRNA (siGLO) was injected lateral to the trauma site after controlled cortical impact in postnatal day 17 rats. Magnetic resonance imaging, neurologic testing, and immunohistochemistry were performed to assess outcomes. Pups treated with siAQP4 showed acute (3 days after injury) improvements in motor function and in spatial memory at long term (60 days after injury) compared with siGLO-treated animals. These improvements were associated with decreased edema formation, increased microglial activation, decreased blood-brain barrier disruption, reduced astrogliosis and neuronal cell death. The effectiveness of our treatment paradigm was associated with a 30% decrease in AQP4 expression at the injection site. PMID:23899928

Fukuda, Andrew M; Adami, Arash; Pop, Viorela; Bellone, John A; Coats, Jacqueline S; Hartman, Richard E; Ashwal, Stephen; Obenaus, Andre; Badaut, Jerome



Frequency of edema in patients with pulmonary arterial hypertension receiving ambrisentan.  


Edema is a common side effect of endothelin receptor antagonists. Ambrisentan is an endothelin type A-selective endothelin receptor antagonist approved for the treatment of pulmonary arterial hypertension. We examined the clinical outcomes of patients who developed edema with and without ambrisentan treatment in 2 phase III, randomized placebo-controlled trials, ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2 (ARIES-1 and ARIES-2) (n = 393). Edema-related adverse events were extracted using broad adverse event search terms. The present post hoc analysis included 132 placebo patients and 261 ambrisentan patients. Of these patients, 14% of the placebo patients and 23% of the ambrisentan patients experienced edema-related adverse events. Overall, the patients who experienced edema tended to have a worse baseline World Health Organization (WHO) functional class (edema 76%, WHO functional class III-IV; no edema 56%, WHO functional class III-IV). In the ambrisentan patients, those with edema were older (mean age 58 ± 13 years) and heavier (mean weight 75 ± 19 kg) than those without edema (mean age 49 ± 15 years; mean weight 70 ± 17 kg). At week 12 of treatment, the ambrisentan patients had significantly increased their 6-minute walk distance (6MWD) by 34.4 m compared to the placebo patients in whom the 6MWD had deteriorated by -9.0 m (p <0.001). Among the ambrisentan patients, those without edema had a 6MWD increase of 38.9 m and those with edema had a 6MWD increase of 19.4 m. Ambrisentan significantly improved the brain natriuretic peptide levels by -34% compared to the brain natriuretic peptide levels in the placebo group that had worsened by +11% (p <0.001). Ambrisentan reduced the brain natriuretic peptide concentrations similarly in patients with and without edema. In conclusion, the present subanalysis of patients with pulmonary arterial hypertension has revealed that ambrisentan therapy provides clinical benefit compared to placebo, even in the presence of edema. PMID:22858181

Shapiro, Shelley; Pollock, David M; Gillies, Hunter; Henig, Noreen; Allard, Martine; Blair, Christiana; Anglen, Crystal; Kohan, Donald E



Erythropoietin reduces brain injury after intracerebral hemorrhagic stroke in rats.  


Erythropoietin (EPO) has been shown to be neuroprotective in various models of neuronal injury. The aim of the present study was to investigate the beneficial effect of recombinant human EPO (rhEPO) following intracerebral hemorrhage (ICH) and the underlying molecular and cellular mechanisms. ICH was induced using autologous blood injection in adult rats. rhEPO (5000 IU/kg) or vehicle was administered to rats with ICH 2 h following surgery and every 24 h for 1 or 3 days. To study the involvement of the PI3K signaling pathway in the rhEPO?mediated effect, the PI3K inhibitor wortmannin (15 µg/kg), was intravenously administered to rats with ICH 90 min prior to rhEPO treatment. Brain edema was measured 3 days following ICH and behavioral outcomes were measured at 1, 7, 14, 21 and 28 days following ICH using the modified neurological severity score (mNSS) and the corner turn test. Proinflammatory cytokines, including tumor necrosis factor (TNF)??, interleukin (IL)?1? and IL?6, in the ipsilateral striatum were analyzed using an enzyme?linked immunosorbent assay 24 h following ICH. Neuronal apoptosis in the perihematomal area was determined by NeuN and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) double?staining. The results showed that rhEPO treatment reversed ICH, increased brain water content, upregulated proinflammatory cytokines, neuronal loss and apoptosis in the perihematomal area and rescued behavioral deficits in injured rats. Inhibiting the PI3K pathway with wortmannin abolished the rhEPO?mediated neuroprotective effects. Moreover, western blot analysis showed that rhEPO induced the upregulation of Akt phosphorylation and downregulation of glycogen synthase kinase (GSK)?3? phosphorylation, which were reversed by pretreatment with wortmannin, indicating the involvement of PI3K signaling in rhEPO-mediated anti?apoptotic and anti?inflammatory effects following ICH. In conclusion, these results suggested that rhEPO may exert its beneficial effects in ICH through the activation of the PI3K signaling pathway. PMID:24008820

Yu, Zhen; Tang, Ling; Chen, Lifen; Li, Jinfang; Wu, Wanfu; Hu, Changlin



N-arachidonoyl-L-serine is neuroprotective after traumatic brain injury by reducing apoptosis.  


N-arachidonoyl-L-serine (AraS) is a brain component structurally related to the endocannabinoid family. We investigated the neuroprotective effects of AraS following closed head injury induced by weight drop onto the exposed fronto-parietal skull and the mechanisms involved. A single injection of AraS following injury led to a significant improvement in functional outcome, and to reduced edema and lesion volume compared with vehicle. Specific antagonists to CB2 receptors, transient receptor potential vanilloid 1 (TRPV1) or large conductance calcium-activated potassium (BK) channels reversed these effects. Specific binding assays did not indicate binding of AraS to the GPR55 cannabinoid receptor. N-arachidonoyl-L-serine blocked the attenuation in phosphorylated extracellular-signal-regulated kinase 1/2 (ERK) levels and led to an increase in pAkt in both the ipsilateral and contralateral cortices. Increased levels of the prosurvival factor Bcl-xL were evident 24 hours after injury in AraS-treated mice, followed by a 30% reduction in caspase-3 activity, measured 3 days after injury. Treatment with a CB2 antagonist, but not with a CB1 antagonist, reversed this effect. Our results suggest that administration of AraS leads to neuroprotection via ERK and Akt phosphorylation and induction of their downstream antiapoptotic pathways. These protective effects are related mostly to indirect signaling via the CB2R and TRPV1 channels but not through CB1 or GPR55 receptors. PMID:21505478

Cohen-Yeshurun, Ayelet; Trembovler, Victoria; Alexandrovich, Alexander; Ryberg, Erik; Greasley, Peter J; Mechoulam, Raphael; Shohami, Esther; Leker, Ronen R



N-arachidonoyl--serine is neuroprotective after traumatic brain injury by reducing apoptosis  

PubMed Central

N-arachidonoyl--serine (AraS) is a brain component structurally related to the endocannabinoid family. We investigated the neuroprotective effects of AraS following closed head injury induced by weight drop onto the exposed fronto-parietal skull and the mechanisms involved. A single injection of AraS following injury led to a significant improvement in functional outcome, and to reduced edema and lesion volume compared with vehicle. Specific antagonists to CB2 receptors, transient receptor potential vanilloid 1 (TRPV1) or large conductance calcium-activated potassium (BK) channels reversed these effects. Specific binding assays did not indicate binding of AraS to the GPR55 cannabinoid receptor. N-arachidonoyl--serine blocked the attenuation in phosphorylated extracellular-signal-regulated kinase 1/2 (ERK) levels and led to an increase in pAkt in both the ipsilateral and contralateral cortices. Increased levels of the prosurvival factor Bcl-xL were evident 24?hours after injury in AraS-treated mice, followed by a 30% reduction in caspase-3 activity, measured 3 days after injury. Treatment with a CB2 antagonist, but not with a CB1 antagonist, reversed this effect. Our results suggest that administration of AraS leads to neuroprotection via ERK and Akt phosphorylation and induction of their downstream antiapoptotic pathways. These protective effects are related mostly to indirect signaling via the CB2R and TRPV1 channels but not through CB1 or GPR55 receptors.

Cohen-Yeshurun, Ayelet; Trembovler, Victoria; Alexandrovich, Alexander; Ryberg, Erik; Greasley, Peter J; Mechoulam, Raphael; Shohami, Esther; Leker, Ronen R



Cytotoxic edema: mechanisms of pathological cell swelling  

PubMed Central

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.

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




PubMed Central

1. Guinea pigs die shortly after bilateral cervical vagotomy, even when continuous artificial respiration effected through a tracheal cannula is carried out. Death is caused by severe pulmonary edema and congestion. 2. Direct observation of the lungs after bilateral vagotomy demonstrates that pulmonary edema develops gradually and increases slowly in amount and severity. Congestion precedes and accompanies the development of the edema. 3. Neuropathic pulmonary edema in the guinea pig is caused by disturbance to or abolition of the pulmonary vasomotor nerves. 4. The evidence obtained by experiments on animals suggests that neuropathic pulmonary edema in man is caused by disturbances, either central or peripheral, to the vasomotor control of the pulmonary vessels.

Farber, Sidney



Pioglitazone reduces secondary brain damage after experimental brain trauma by PPAR-?-independent mechanisms.  


Inflammatory and ischemic processes contribute to the development of secondary brain damage after mechanical brain injury. Recent data suggest that thiazolidinediones (TZDs), a class of drugs approved for the treatment of non-insulin-dependent diabetes mellitus, effectively reduces inflammation and brain lesion by stimulation of the peroxisome proliferator-activated receptor-? (PPAR-?). The present study investigates the influence of the TZD pioglitazone and rosiglitazone on inflammation and secondary brain damage after experimental traumatic brain injury (TBI). A controlled cortical impact (CCI) injury was induced in male C57BL/6 mice to investigate following endpoints: (1) mRNA expression of PPAR-? and PPAR-? target genes (LPL, GLT1, and IRAP/Lnpep), and inflammatory markers (TNF-?, IL-1?, IL-6, and iNOS), at 15 min, 3 h, 6 h, 12 h, and 24 h post-trauma; (2) contusion volume, neurological function, and gene expression after 24 h in mice treated with pioglitazone (0.5 and 1 mg/kg) or rosiglitazone (5 and 10 mg/kg IP at 30 min post-trauma); and (3) the role of PPAR-? to mediate protection was determined in animals treated with pioglitazone, the PPAR-? inhibitor T0070907, and a combination of both. Inflammatory marker genes, but not PPAR-? gene expression, was upregulated after trauma. Pioglitazone reduced the histological damage and inflammation in a dose-dependent fashion. In contrast, rosiglitazone failed to suppress inflammation and histological damage. PPAR-? and PPAR-? target gene expression was not induced by pioglitazone and rosiglitazone. In line with these results, pioglitazone-mediated protection was not reversed by T0070907. The results indicate that the neuroprotective effects of pioglitazone are not solely related to PPAR-?-dependent mechanisms. PMID:21501066

Thal, Serge C; Heinemann, Marius; Luh, Clara; Pieter, Dana; Werner, Christian; Engelhard, Kristin



Restoring Blood-Brain Barrier P-Glycoprotein Reduces Brain Amyloid-? in a Mouse Model of Alzheimer's DiseaseS?  

PubMed Central

Reduced clearance of amyloid-? (A?) from brain partly underlies increased A? brain accumulation in Alzheimer's disease (AD). The mechanistic basis for this pathology is unknown, but recent evidence suggests a neurovascular component in AD etiology. We show here that the ATP-driven pump, P-glycoprotein, specifically mediates efflux transport of A? from mouse brain capillaries into the vascular space, thus identifying a critical component of the A? brain efflux mechanism. We demonstrate in a transgenic mouse model of AD [human amyloid precursor protein (hAPP)-overexpressing mice; Tg2576 strain] that brain capillary P-glycoprotein expression and transport activity are substantially reduced compared with wild-type control mice, suggesting a mechanism by which A? accumulates in the brain in AD. It is noteworthy that dosing 12-week-old, asymptomatic hAPP mice over 7 days with pregnenolone-16?-carbonitrile to activate the nuclear receptor pregnane X receptor restores P-glycoprotein expression and transport activity in brain capillaries and significantly reduces brain A? levels compared with untreated control mice. Thus, targeting intracellular signals that up-regulate blood-brain barrier P-glycoprotein in the early stages of AD has the potential to increase A? clearance from the brain and reduce A? brain accumulation. This mechanism suggests a new therapeutic strategy in AD.

Hartz, Anika M. S.; Miller, David S.



Macular edema: miscellaneous.  


This article provides the reader with practical information to be applied to the various remaining causes of macular edema. Some macular edemas linked to ocular diseases like radiotherapy after ocular melanomas remained of poor functional prognosis due to the primary disease. On the contrary, macular edemas occurring after retinal detachment or after some systemic or local treatment use are often temporary. Macular edema associated with epiretinal membranes or vitreomacular traction is the main cause of poor functional recovery. However, the delay to observe a significant improvement of vision after surgery should be long, as usually observed in tractional myopic vitreoschisis. Finally, some circumstances of macular edemas such as hemangiomas or macroaneurysms should be treated, if symptomatic, with the treatments currently used in diabetic macular edema or exudative macular degeneration. PMID:23264332

Creuzot-Garcher, Catherine; Jonas, Jost; Wolf, Sebastian



[Hyponatremic encephalopathy with non-cardiogenic pulmonary edema. Development following marathon run].  


This article presents the case of a 52-year-old woman who developed exercise-associated hyponatremia (EAH) complicated by non-cardiogenic pulmonary edema after a marathon run. The condition of EAH is a potentially life-threatening complication of endurance exercise. The main cause seems to be inadequate intake of free water during or following exercise with enduring antidiuresis due to nonosmotic stimulation of ADH secretion. Known risk factors are female gender, slow running pace and lack of weight loss. Emergency therapy is fluid restriction and bolus infusion of 3% NaCl solution to rapidly reduce brain edema. PMID:23381723

Wellershoff, G



Pathophysiology of Macular Edema  

Microsoft Academic Search

Macular edema is defined as an accumulation of fluid in the outer plexiform layer and the inner nuclear layer as well as a swelling of Müller cells of the retina. It consists of a localized expansion of the retinal extracellular space (sometimes associated with the intracellular space) in the macular area. Macular edema is a common cause of a sudden

Stefan Scholl; Janna Kirchhof; Albert J. Augustin



Transient hypothermia reduces focal ischemic brain injury in the rat.  


The effect of transient hypothermia on focal cerebral ischemia was evaluated using a rat model of permanent middle cerebral artery (MCA) occlusion. MCA occlusion was performed on 10 rats at a temporalis muscle temperature of 24 degrees C (hypothermic group) and on 10 rats at 36 degrees C (normothermic group). Rats in the hypothermic group were maintained at 24 degrees C for 1 hour after MCA occlusion and then allowed to rewarm to 36 degrees C over the next 2 hours. Animals in both groups were killed 24 hours after MCA occlusion. Cerebral infarcts were visualized by staining of coronal brain sections with 2,3,5-triphenyltetrazolium chloride. Normothermic rats displayed an average infarct volume of 233.1 +/- 13.2 mm3 (standard error of the mean), whereas hypothermic rats had an average infarct volume of 166.2 +/- 22.8 mm3 (P less than 0.01). Expressed as a percentage of the volume of the right hemisphere, the normothermic group had an infarct volume of 22.1 +/- 1.5% and the hypothermic group an infarct volume of 16.0 +/- 2.2% (P less than 0.05). These results demonstrate that transient hypothermia to a temporalis muscle temperature of 24 degrees C significantly reduces subsequent infarct size in an experimental model of permanent arterial occlusion. PMID:1922703

Onesti, S T; Baker, C J; Sun, P P; Solomon, R A



Endogenous levels of 5 alpha-reduced progestins and androgens in fetal vs. adult rat brains  

Microsoft Academic Search

5 Alpha-reduced metabolites of certain steroids have been shown to have important functions in adult brains and may play a role in brain development. To assess which 5 alpha-reduced steroid metabolites may have an impact during development, endogenous levels of 5 alpha-reduced androgens and progestins and their parent hormones were measured in male and female fetal brains over the last

Carol K. Kellogg; Cheryl A. Frye



Psychic trauma causing grossly reduced brain metabolism and cognitive deterioration  

Microsoft Academic Search

While amnesia and other cognitive disturbances are usually caused by structural brain damage, there are a few instances in which environmental stress may induce neuronal death in memory-sensitive brain regions such as the hippocampus. Here we report on a patient who, after a single brief exposure to an event reminding him of a similar stressful event from his childhood, deteriorated

Hans J. Markowitsch; Josef Kessler; Christian Van Der Ven; Gerald Weber-Luxenburger; Manfred Albers; Wolf-Dieter Heiss



Acute blast injury reduces brain abeta in two rodent species.  


Blast-induced traumatic brain injury (TBI) has been a major cause of morbidity and mortality in the conflicts in Iraq and Afghanistan. How the primary blast wave affects the brain is not well understood. In particular, it is unclear whether blast injures the brain through mechanisms similar to those found in non-blast closed impact injuries (nbTBI). The ?-amyloid (A?) peptide associated with the development of Alzheimer's disease is elevated acutely following TBI in humans as well as in experimental animal models of nbTBI. We examined levels of brain A? following experimental blast injury using enzyme-linked immunosorbent assays for A? 40 and 42. In both rat and mouse models of blast injury, rather than being increased, endogenous rodent brain A? levels were decreased acutely following injury. Levels of the amyloid precursor protein (APP) were increased following blast exposure although there was no evidence of axonal pathology based on APP immunohistochemical staining. Unlike the findings in nbTBI animal models, levels of the ?-secretase, ?-site APP cleaving enzyme 1, and the ?-secretase component presenilin-1 were unchanged following blast exposure. These studies have implications for understanding the nature of blast injury to the brain. They also suggest that strategies aimed at lowering A? production may not be effective for treating acute blast injury to the brain. PMID:23267342

De Gasperi, Rita; Gama Sosa, Miguel A; Kim, Soong Ho; Steele, John W; Shaughness, Michael C; Maudlin-Jeronimo, Eric; Hall, Aaron A; Dekosky, Steven T; McCarron, Richard M; Nambiar, Madhusoodana P; Gandy, Sam; Ahlers, Stephen T; Elder, Gregory A



Oral branched-chain amino acid supplements that reduce brain serotonin during exercise in rats also lower brain catecholamines.  


Exercise raises brain serotonin release and is postulated to cause fatigue in athletes; ingestion of branched-chain amino acids (BCAA), by competitively inhibiting tryptophan transport into brain, lowers brain tryptophan uptake and serotonin synthesis and release in rats, and reputedly in humans prevents exercise-induced increases in serotonin and fatigue. This latter effect in humans is disputed. But BCAA also competitively inhibit tyrosine uptake into brain, and thus catecholamine synthesis and release. Since increasing brain catecholamines enhances physical performance, BCAA ingestion could lower catecholamines, reduce performance and thus negate any serotonin-linked benefit. We therefore examined in rats whether BCAA would reduce both brain tryptophan and tyrosine concentrations and serotonin and catecholamine synthesis. Sedentary and exercising rats received BCAA or vehicle orally; tryptophan and tyrosine concentrations and serotonin and catecholamine synthesis rates were measured 1 h later in brain. BCAA reduced brain tryptophan and tyrosine concentrations, and serotonin and catecholamine synthesis. These reductions in tyrosine concentrations and catecholamine synthesis, but not tryptophan or serotonin synthesis, could be prevented by co-administering tyrosine with BCAA. Complete essential amino acid mixtures, used to maintain or build muscle mass, were also studied, and produced different effects on brain tryptophan and tyrosine concentrations and serotonin and catecholamine synthesis. Since pharmacologically increasing brain catecholamine function improves physical performance, the finding that BCAA reduce catecholamine synthesis may explain why this treatment does not enhance physical performance in humans, despite reducing serotonin synthesis. If so, adding tyrosine to BCAA supplements might allow a positive action on performance to emerge. PMID:23904096

Choi, Sujean; Disilvio, Briana; Fernstrom, Madelyn H; Fernstrom, John D



Ion leakage is reduced during anoxia in turtle brain: a potential survival strategy.  


The turtle brain maintains ATP levels, ion homeostasis, and some neural function during prolonged anoxia despite significant decreases in the rate of ATP production. To test the hypothesis that reduced ATP production during anoxia was compensated partly by conserving energy through reduced ion leakage, the rate of K+ leakage was measured in normoxic and anoxic turtle brains in which Na(+)-K(+)-adenosinetriphosphatase was inhibited with ouabain. Rates of K+ leakage were significantly lower in brains subjected to 2 h of anoxia than in normoxic brains. These data support the suggestion that reduced ion leakage is an important mechanism for energy conservation during anoxia. PMID:2604013

Chih, C P; Rosenthal, M; Sick, T J



Edema: diagnosis and management.  


Edema is an accumulation of fluid in the interstitial space that occurs as the capillary filtration exceeds the limits of lymphatic drainage, producing noticeable clinical signs and symptoms. The rapid development of generalized pitting edema associated with systemic disease requires timely diagnosis and management. The chronic accumulation of edema in one or both lower extremities often indicates venous insufficiency, especially in the presence of dependent edema and hemosiderin deposition. Skin care is crucial in preventing skin breakdown and venous ulcers. Eczematous (stasis) dermatitis can be managed with emollients and topical steroid creams. Patients who have had deep venous thrombosis should wear compression stockings to prevent postthrombotic syndrome. If clinical suspicion for deep venous thrombosis remains high after negative results are noted on duplex ultrasonography, further investigation may include magnetic resonance venography to rule out pelvic or thigh proximal venous thrombosis or compression. Obstructive sleep apnea may cause bilateral leg edema even in the absence of pulmonary hypertension. Brawny, nonpitting skin with edema characterizes lymphedema, which can present in one or both lower extremities. Possible secondary causes of lymphedema include tumor, trauma, previous pelvic surgery, inguinal lymphadenectomy, and previous radiation therapy. Use of pneumatic compression devices or compression stockings may be helpful in these cases. PMID:23939641

Trayes, Kathryn P; Studdiford, James S; Pickle, Sarah; Tully, Amber S



[Edema and the tropics].  


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

Holzer, B R



Proline reduces brain cytochrome c oxidase: prevention by antioxidants.  


In the present study, we initially investigated the in vivo (acute and chronic) and in vitro effects of proline on cytochrome c oxidase (complex IV) activity in rat cerebral cortex to test the hypothesis that proline might alter energy metabolism and that this alteration could be provoked by oxidative stress. The action of alpha-tocopherol and ascorbic acid on the effects produced by proline was also evaluated. For acute administration, 29- and 60-day-old rats received one subcutaneous injection of proline (18.2 micromol/g body weight) or an equivalent volume of 0.9% saline solution (control) and were sacrificed 1h later. For chronic treatment, proline was injected subcutaneously twice a day at 10h intervals from the 6(th) to the 28(th) day of age. Rats were sacrificed 12h (29(th)) or 31 days (60(th)) after the last injection. Results showed that acute administration of proline significantly diminished the activity of cytochrome c oxidase in the cerebral cortex of 29- and 60-day-old rats. On the other hand, chronic hyperprolinemia reduced this complex activity only on day 29, but not on the 60(th) day of life. In another set of experiments, 22-day-old rats or 53-day-old rats were pretreated for 1 week with daily intraperitoneal administration of alpha-tocopherol (40 mg/kg) and ascorbic acid (100mg/kg) or saline. Twelve hours after the last antioxidant injection, rats received a single injection of proline or saline and were killed 1h later. In parallel to chronic treatment, rats received a daily intraperitoneal injection of alpha-tocopherol and ascorbic acid from the 6(th) to the 28(th) day of life and were killed 12h after the last injection. Results showed that the pretreatment with alpha-tocopherol and ascorbic acid before acute proline administration or concomitant to chronic proline administration significantly prevented these effects. We also observed that proline (3.0 microM-1.0 mM) when added to the incubation medium (in vitro studies) did not alter cytochrome c oxidase activity. Data suggest that the inhibitory effect of proline on cytochrome c oxidase activity is possibly associated with oxidative stress and that this parameter may be involved in the brain dysfunction observed in hyperprolinemia. PMID:17197150

Delwing, Daniela; Delwing, Débora; Chiarani, Fábria; Kurek, Andréa G; Wyse, Angela T S



Sleep deprivation reduces neuroglobin immunoreactivity in the rat brain.  


Neuroglobin (Ngb), a protein located in the mammal's brain, is involved in oxygen transport and free radical scavenging inside the neurons. Ngb colocalizes with choline acetyltransferase in the laterodorsal tegmental nucleus and in the pontine tegmental nucleus, both involved in the sleep-wake cycle regulation. Some studies have shown that free radicals accumulated during prolonged wakefulness are removed during sleep. Therefore, Ngb could act as a regulator of free radicals generated during prolonged wakefulness in the brain. The aim of this study was to determine whether prolonged wakefulness affects Ngb immunoreactivity because of increases in the oxidative stress induced by continuous neuronal activity. For this purpose, male adult Wistar rats were implanted with electrodes for sleep recordings and were divided into control and sleep-deprived groups. Sleep deprivation was carried out for 24 h by gentle handling of the animals. Sleep-wake activity was determined during the deprivation period or 24?h of control conditions. Subsequently, both groups of animals were killed and their brains were obtained and processed for Ngb immunohistochemical analysis and detection of lipid peroxidation. Our data found no evidence of increased oxidative stress in the brains of sleep-deprived animals compared with the controls. The number of Ngb-positive cells was decreased in the sleep-deprived animals in all analyzed areas of the brain compared with the control group. Our results suggest that Ngb could be involved in sleep regulation, independent of its role in the control of oxidative stress. PMID:23262504

Melgarejo-Gutiérrez, Montserrat; Acosta-Peña, Eva; Venebra-Muñoz, Arturo; Escobar, Carolina; Santiago-García, Juan; Garcia-Garcia, Fabio



Etanercept Attenuates Traumatic Brain Injury in Rats by Reducing Brain TNF-? Contents and by Stimulating Newly Formed Neurogenesis  

PubMed Central

It remains unclear whether etanercept penetrates directly into the contused brain and improves the outcomes of TBI by attenuating brain contents of TNF-? and/or stimulating newly formed neurogenesis. Rats that sustained TBI are immediately treated with etanercept. Acute neurological and motor injury is assessed in all rats the day prior to and 7 days after surgery. The numbers of the colocalizations of 5-bromodeoxyuridine and doublecortin specific markers in the contused brain injury that occurred during TBI were counted by immunofluorescence staining. Enzyme immunoassay for quantitative determination of TNF-? or etanercept in brain tissues is also performed. Seven days after systemic administration of etanercept, levels of etanercept can be detected in the contused brain tissues. In addition, neurological and motor deficits, cerebral contusion, and increased brain TNF-? contents caused by TBI can be attenuated by etanercept therapy. Furthermore, the increased numbers of the colocalizations of 5-bromodeoxyuridine and doublecortin specific markers in the contused brain tissues caused by TBI can be potentiated by etanercept therapy. These findings indicate that systemically administered etanercept may penetrate directly into the contused brain tissues and may improve outcomes of TBI by reducing brain contents of TNF-? and by stimulating newly formed neurogenesis.

Cheong, Chong-Un; Chao, Chien-Ming; Cheng, Bor-Chih; Yang, Chung-Zhing; Chio, Chung-Ching



Aquaporin 4: a player in cerebral edema and neuroinflammation  

PubMed Central

Neuroinflammation is a common pathological event observed in many different brain diseases, frequently associated with blood brain barrier (BBB) dysfunction and followed by cerebral edema. Neuroinflammation is characterized with microglia activation and astrogliosis, which is a hypertrophy of the astrocytes. Astrocytes express aquaporin 4, the water channel protein, involved in water homeostasis and edema formation. Aside from its function in water homeostasis, recent studies started to show possible interrelations between aquaporin 4 and neuroinflammation. In this review the roles of aquaporin 4 in neuroinflammation associated with BBB disruption and cerebral edema will be discussed with recent studies in the field.



The use of Hypertonic Saline in the Treatment of Post-Traumatic Cerebral Edema: A Review  

Microsoft Academic Search

Effective methods for treating cerebral edema have recently become a matter of both extensive research and significant debate within the neurosurgery and trauma surgery communities. The pathophysiologic progression and outcome of different forms of cerebral edema associated with traumatic brain injury have yet to be fully elucidated. There are heterogeneous factors influencing the onset and progress of post-traumatic cerebral edema,

Jeffrey E. Catrambone; Wenzhuan He; Charles J. Prestigiacomo; Tracy K. McIntosh; Peter W. Carmel; Allen Maniker



Cystoid macular edema  

PubMed Central

We review the epidemiology, pathophysiology, and etiology of cystoid macular edema (CME). Inflammatory, diabetic, post-cataract, and macular edema due to age-related macular degeneration is described. The role of chronic inflammation and hypoxia and direct macular traction is evaluated in each case according to different views from the literature. The different diagnostic methods for evaluating the edema are described. Special attention is given to fluoroangiography and the most modern methods of macula examination, such as ocular coherence tomography and multifocal electroretinography. Finally, we discuss the treatment of cystoid macular edema in relation to its etiology. In this chapter we briefly refer to the therapeutic value of laser treatment especially in diabetic maculopathy or vitrectomy in some selected cases. Our paper is focused mainly on recent therapeutic treatment with intravitreal injection of triamcinolone acetonide and anti-VEGF factors like bevacizumab (Avastin), ranibizumab (Lucentis), pegaptamid (Macugen), and others. The goal of this paper is to review the current status of this treatment for macular edema due to diabetic maculopathy, central retinal vein occlusion and post-cataract surgery. For this reason the results of recent multicenter clinical trials are quoted, as also our experience on the use of intravitreal injections of anti-VEGF factors and we discuss its value in clinical practice.

Rotsos, Tryfon G; Moschos, Marilita M



Knockdown of brain-derived neurotrophic factor in specific brain sites precipitates behaviors associated with depression and reduces neurogenesis  

Microsoft Academic Search

Depression has been associated with reduced expression of brain-derived neurotrophic factor (BDNF) in the hippocampus. In addition, animal studies suggest an association between reduced hippocampal neurogenesis and depressive-like behavior. These associations were predominantly established based on responses to antidepressant drugs and alterations in BDNF levels and neurogenesis in depressive patients or animal models for depressive behavior. Nevertheless, there is no

D Taliaz; N Stall; D E Dar; A Zangen



Targeting blood-brain barrier sphingolipid signaling reduces basal P-glycoprotein activity and improves drug delivery to the brain.  


P-glycoprotein, an ATP-driven drug efflux pump, is a major obstacle to the delivery of small-molecule drugs across the blood-brain barrier and into the CNS. Here we test a unique signaling-based strategy to overcome this obstacle. We used a confocal microscopy-based assay with isolated rat brain capillaries to map a signaling pathway that within minutes abolishes P-glycoprotein transport activity without altering transporter protein expression or tight junction permeability. This pathway encompasses elements of proinflammatory- (TNF-?) and sphingolipid-based signaling. Critical to this pathway was signaling through sphingosine-1-phosphate receptor 1 (S1PR1). In brain capillaries, S1P acted through S1PR1 to rapidly and reversibly reduce P-glycoprotein transport activity. Sphingosine reduced transport by a sphingosine kinase-dependent mechanism. Importantly, fingolimod (FTY720), a S1P analog recently approved for treatment of multiple sclerosis, also rapidly reduced P-glycoprotein activity; similar effects were found with the active, phosphorylated metabolite (FTY720P). We validated these findings in vivo using in situ brain perfusion in rats. Administration of S1P, FTY720, or FTY729P increased brain uptake of three radiolabeled P-glycoprotein substrates, (3)H-verapamil (threefold increase), (3)H-loperamide (fivefold increase), and (3)H-paclitaxel (fivefold increase); blocking S1PR1 abolished this effect. Tight junctional permeability, measured as brain (14)C-sucrose accumulation, was not altered. Therefore, targeting signaling through S1PR1 at the blood-brain barrier with the sphingolipid-based drugs, FTY720 or FTY720P, can rapidly and reversibly reduce basal P-glycoprotein activity and thus improve delivery of small-molecule therapeutics to the brain. PMID:22949658

Cannon, Ronald E; Peart, John C; Hawkins, Brian T; Campos, Christopher R; Miller, David S



IL10 reduces rat brain injury following focal stroke  

Microsoft Academic Search

The effects of the anti-inflammatory cytokine, IL-10, on brain injury following permanent focal ischemia were determined. Rats subjected to occlusion of the right middle cerebral artery (MCAO) were administered IL-10 (1 ?g) centrally into the lateral ventricle 30 min and 3 h post MCAO or systemically into the tail vein (5 or 15 ?g\\/h) starting 30 min post MCAO for

Patricia A. Spera; Julie A. Ellison; Giora Z. Feuerstein; Frank C. Barone



[Toxic, allergic, and inflamatory edema].  


Edema is defined as the condition in which intraluminal lymph fluid components leak into the tissues and the interstitium fluid is abnormally increased. At the site of edema, toxication, allergy or inflammation occasionally occurs. This paper will focus on local skin and mucosal edema. Toxic edema is locally caused by intake of industrial goods or medical products (pharmaceuticals). Like urticaria, allergic edema is attributed to the increased vascular permeability caused by a chemical mediator. Inflammatory edema is the state in which increased inflammatory reaction in local skin causes increases in osmotic pressure of the tissues and metabolism and then inflammatory effusion accumulate there. It includes burn and cellulites. PMID:15675328

Takada, Yuko; Yoshida, Shunji



Differential Reinforcement of other Behavior (DRO) to Reduce Aggressive Behavior Following Traumatic Brain Injury  

Microsoft Academic Search

Severe brain injury can result in significant neurobehavioral and social functioning impairment. In rehabilitation settings, behavioral problems of aggression and nonadherence to therapeutic activities can pose barriers to maximal recovery of function. Behavioral interventions seem to be effective in reducing problem behavior among individuals recovering from severe brain trauma, but well-controlled studies examining the efficacy of such interventions are sparse.

Mark T. Hegel; Robert J. Ferguson



Post-traumatic brain hypothermia reduces histopathological damage following concussive brain injury in the rat  

Microsoft Academic Search

The purposes of this study were (1) to document the histopathological consequences of moderate traumatic brain injury (TBI) in anesthetized Sprague-Dawley rats, and (2) to determine whether posttraumatic brain hypothermia (30°C) would protect histopathologically. Twenty-four hours prior to TBI, the fluid percussion interface was positioned over the right cerebral cortex. On the 2nd day, fasted rats were anesthetized with 70%

W. Dalton Dietrich; Ofelia Alonso; Raul Busto; Mordecai Y.-T. Globus; Myron D. Ginsberg



TPI-287, a new taxane family member, reduces the brain metastatic colonization of breast cancer cells.  


Brain metastases of breast and other cancers remain resistant to chemotherapeutic regimens that are effective systemically, in part due to the blood-brain barrier. We report that TPI-287, a new microtubule-stabilizing agent, displays in vitro cytotoxic activity similar to taxanes and epothilones. Unlike the taxanes, TPI-287 is permeable through the blood-brain barrier. Brain-to-plasma ratios of TPI-287 after a single injection typically exceeded one and were as high as 63.8 in the rat and 14.1 in the mouse. A brain-tropic derivative of the MDA-MB-231 triple-negative breast cancer cell line, 231-BR, was used to test whether TPI-287 may be efficacious at preventing or treating brain metastases. TPI-287 had growth inhibitory effects comparable with paclitaxel when 231-BR tumor cells were injected into the mammary fat pad. Brain metastatic colonization was determined by intracardiac injection of 231-BR cells, with treatment beginning on day 3 to 4 postinjection, culminating in a histologic count of brain metastases in brains necropsied days 25 to 28 postinjection. In this assay, paclitaxel, ixabepilone, and nab paclitaxel did not have significant inhibitory activity. TPI-287 was ineffective in the same assay using a 6 mg/kg every week schedule; however an 18 mg/kg dose delivered on days 3, 7, and 11 significantly reduced the outgrowth of brain metastases (55% reduction, P = 0.028) and reduced proliferation in brain metastases (16% reduction, P = 0.008). When TPI-287 treatment was delayed until days 18, 22, and 26 postinjection, efficacy was reduced (17% reduction, not significant). These data suggest that TPI-287 may have efficacy when administered early in the course of the disease. PMID:22622283

Fitzgerald, Daniel P; Emerson, David L; Qian, Yongzhen; Anwar, Talha; Liewehr, David J; Steinberg, Seth M; Silberman, Sandra; Palmieri, Diane; Steeg, Patricia S



Prostaglandin FP receptor inhibitor reduces ischemic brain damage and neurotoxicity  

PubMed Central

Bioactive lipids such as the prostaglandins have been reported to have various cytoprotective or toxic properties in acute and chronic neurological conditions. The roles of PGF2? and its receptor (FP) are not clear in the pathogenesis of ischemic brain injury. Considering that this G-protein coupled receptor has been linked to intracellular calcium regulation, we hypothesized that its blockade would be protective. We used FP antagonist (AL-8810) and FP receptor knockout (FP?/?) mice in in vivo and in vitro stroke models. Mice that were treated with AL-8810 had 35.7 ± 6.3% less neurologic dysfunction and 36.4 ± 6.0% smaller infarct volumes than did vehicle-treated mice after 48 hours of permanent middle cerebral artery occlusion (pMCAO); FP?/? mice also had improved outcomes after pMCAO. Blockade of the FP receptor also protected against oxygen-glucose deprivation (OGD)-induced cell death and reactive oxygen species formation in slice cultures. Finally, we found that an FP receptor agonist dose dependently increased intracellular Ca2+ levels in cultured neurons and established that FP-related Ca2+ signaling is related to ryanodine receptor signaling. These results indicate that the FP receptor is involved in cerebral ischemia-induced damage and could promote development of drugs for treatment of stroke and acute neurodegenerative disorders.

Kim, Yun Tai; Moon, Sang Kwan; Maruyama, Takayuki; Narumiya, Shuh; Dore, Sylvain



Association Between Influenza Vaccination and Reduced Risk of Brain Infarction  

Microsoft Academic Search

the risk of stroke was reduced in the subjects vaccinated during the year of the study and in those vaccinated during the last 5 years, with an odds ratio of 0.50 (95% CI, 0.26 to 0.94; P0.033) and 0.42 (95% CI, 0.21 to 0.81; P0.009), respectively. Similar associations were observed in cases and controls free of previous cardiovascular history. Subjects

Philippa Lavallée; Véronique Perchaud; Marion Gautier-Bertrand; David Grabli; Pierre Amarenco



Transient Idiopathic Primary Penoscrotal Edema  

PubMed Central

We present the case of a male born prematurely at 32 weeks gestation by cesarean section following overt symptoms of maternal preeclampsia. He developed severe penoscrotal edema anew one month from birth. No remarkable exposure or trauma was identified. This unexplained swelling remained uniform till 4 months of age, while the penile edema resolved spontaneously. A small benign hydrocele remained unchanged, since onset of the edema and continued after the edema subsided. This is the first report of persistent, but transient penoscrotal edema resolving in a 3 months course, without any apparent explanation, a possible pathogenetic mechanism was suggested.

Namir, Sody A; Trattner, Akiva



Intraoperative solumedrol helps prevent postpneumonectomy pulmonary edema  

Microsoft Academic Search

BackgroundPostpneumonectomy pulmonary edema and pneumonia are life threatening and seemingly unavoidable complications after pneumonectomy. We theorized that an intraoperative dose of intravenous steroids (as a prophylactic measure to reduce pulmonary injury to the remaining lung) just before pulmonary artery ligation might decrease this problem.

Robert J Cerfolio; Ayesha S Bryant; John S Thurber; Cynthia Sales Bass; William A Lell; Alfred A Bartolucci



Delayed administration of interleukin-1 receptor antagonist reduces ischemic brain damage and inflammation in comorbid rats.  


Many neuroprotective agents have been effective in experimental stroke, yet few have translated into clinical application. One reason for this may be failure to consider clinical comorbidities/risk factors in experimental models. We have shown that a naturally occurring interleukin-1 receptor antagonist (IL-1Ra) is protective against ischemic brain damage in healthy animals. However, protective effects of IL-1Ra have not been determined in comorbid animals. Thus, we tested whether IL-1Ra protects against brain injury induced by experimental ischemia in aged JCR-LA (corpulent) rats, which have clinically relevant risk factors. Male, aged, lean, and corpulent rats exposed to transient (90 minutes) occlusion of the middle cerebral artery (tMCAO) were administered two doses of IL-1Ra (25 mg/kg, subcutaneously) during reperfusion. Brain injury and neuroinflammatory changes were assessed 24 hours after tMCAO. Our results show that IL-1Ra administered at reperfusion significantly reduced infarct volume measured by magnetic resonance imaging (50%, primary outcome) and blood-brain barrier disruption in these comorbid animals. Interleukin-1Ra also reduced microglial activation, neutrophil infiltration, and cytokines levels in the brain. These data are the first to indicate that IL-1Ra protects against ischemic brain injury when administered via a clinically relevant route and time window in animals with multiple risk factors for stroke. PMID:22781338

Pradillo, Jesus M; Denes, Adam; Greenhalgh, Andrew D; Boutin, Herve; Drake, Caroline; McColl, Barry W; Barton, Eleanor; Proctor, Spencer D; Russell, James C; Rothwell, Nancy J; Allan, Stuart M



Delayed administration of interleukin-1 receptor antagonist reduces ischemic brain damage and inflammation in comorbid rats  

PubMed Central

Many neuroprotective agents have been effective in experimental stroke, yet few have translated into clinical application. One reason for this may be failure to consider clinical comorbidities/risk factors in experimental models. We have shown that a naturally occurring interleukin-1 receptor antagonist (IL-1Ra) is protective against ischemic brain damage in healthy animals. However, protective effects of IL-1Ra have not been determined in comorbid animals. Thus, we tested whether IL-1Ra protects against brain injury induced by experimental ischemia in aged JCR-LA (corpulent) rats, which have clinically relevant risk factors. Male, aged, lean, and corpulent rats exposed to transient (90?minutes) occlusion of the middle cerebral artery (tMCAO) were administered two doses of IL-1Ra (25?mg/kg, subcutaneously) during reperfusion. Brain injury and neuroinflammatory changes were assessed 24?hours after tMCAO. Our results show that IL-1Ra administered at reperfusion significantly reduced infarct volume measured by magnetic resonance imaging (50%, primary outcome) and blood–brain barrier disruption in these comorbid animals. Interleukin-1Ra also reduced microglial activation, neutrophil infiltration, and cytokines levels in the brain. These data are the first to indicate that IL-1Ra protects against ischemic brain injury when administered via a clinically relevant route and time window in animals with multiple risk factors for stroke.

Pradillo, Jesus M; Denes, Adam; Greenhalgh, Andrew D; Boutin, Herve; Drake, Caroline; McColl, Barry W; Barton, Eleanor; Proctor, Spencer D; Russell, James C; Rothwell, Nancy J; Allan, Stuart M



Learning from other subjects helps reducing Brain-Computer Interface calibration time  

Microsoft Academic Search

A major limitation of Brain-Computer Interfaces (BCI) is their long calibration time, as much data from the user must be collected in order to tune the BCI for this target user. In this paper, we propose a new method to reduce this calibra- tion time by using data from other subjects. More precisely, we propose an algorithm to regularize the

Fabien Lotte; Cuntai Guan



Cerebral embolism: local CBF and edema measured by CT scanning and Xe inhalation  

SciTech Connect

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. Supplementary 133Xe CBF measurements were made at corresponding intervals. 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. Overylng cortex was relatively spared. Reduced lambda values attributed to edema appeared with in 3 to 5 minutes and progressed up to 60 minutes. Damage to BBB with visible transvascular seepage of iodine began to appear 1-11/2 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).

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



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

SciTech Connect

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).

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



Inhibition of the prostaglandin receptor EP2 following status epilepticus reduces delayed mortality and brain inflammation  

PubMed Central

Prostaglandin E2 is now widely recognized to play critical roles in brain inflammation and injury, although the responsible prostaglandin receptors have not been fully identified. We developed a potent and selective antagonist for the prostaglandin E2 receptor subtype EP2, TG6-10-1, with a sufficient pharmacokinetic profile to be used in vivo. We found that in the mouse pilocarpine model of status epilepticus (SE), systemic administration of TG6-10-1 completely recapitulates the effects of conditional ablation of cyclooxygenase-2 from principal forebrain neurons, namely reduced delayed mortality, accelerated recovery from weight loss, reduced brain inflammation, prevention of blood–brain barrier opening, and neuroprotection in the hippocampus, without modifying seizures acutely. Prolonged SE in humans causes high mortality and morbidity that are associated with brain inflammation and injury, but currently the only effective treatment is to stop the seizures quickly enough with anticonvulsants to prevent brain damage. Our results suggest that the prostaglandin receptor EP2 is critically involved in neuroinflammation and neurodegeneration, and point to EP2 receptor antagonism as an adjunctive therapeutic strategy to treat SE.

Jiang, Jianxiong; Quan, Yi; Ganesh, Thota; Pouliot, Wendy A.; Dudek, F. Edward; Dingledine, Raymond



Human amnion epithelial cells reduce fetal brain injury in response to intrauterine inflammation.  


Intrauterine infection, such as occurs in chorioamnionitis, is a principal cause of preterm birth and is a strong risk factor for neurological morbidity and cerebral palsy. This study aims to examine whether human amnion epithelial cells (hAECs) can be used as a potential therapeutic agent to reduce brain injury induced by intra-amniotic administration of lipopolysaccharide (LPS) in preterm fetal sheep. Pregnant ewes underwent surgery at approximately 110 days of gestation (term is approx. 147 days) for implantation of catheters into the amniotic cavity, fetal trachea, carotid artery and jugular vein. LPS was administered at 117 days; hAECs were labeled with carboxyfluorescein succinimidyl ester and administered at 0, 6 and 12 h, relative to LPS administration, into the fetal jugular vein, trachea or both. Control fetuses received an equivalent volume of saline. Brains were collected 7 days later for histological assessment of brain injury. Microglia (Iba-1-positive cells) were present in the brain of all fetuses and were significantly increased in the cortex, subcortical and periventricular white matter in fetuses that received LPS, indicative of inflammation. Inflammation was reduced in fetuses that received hAECs. In LPS fetuses, the number of TUNEL-positive cells was significantly elevated in the cortex, periventricular white matter, subcortical white matter and hippocampus compared with controls, and reduced in fetuses that received hAECs in the cortex and periventricular white matter. Within the fetal brains studied there was a significant positive correlation between the number of Iba-1-immunoreactive cells and the number of TUNEL-positive cells (R(2) = 0.19, p < 0.001). The administration of hAECs protects the developing brain when administered concurrently with the initiation of intrauterine inflammation. PMID:23571644

Yawno, Tamara; Schuilwerve, Joyce; Moss, Timothy J M; Vosdoganes, Patricia; Westover, Alana J; Afandi, Ezzat; Jenkin, Graham; Wallace, Euan M; Miller, Suzanne L



Hydrogen is neuroprotective against surgically induced brain injury  

PubMed Central

Background Neurosurgical operations cause unavoidable damage to healthy brain tissues. Direct surgical injury as well as surgically induced oxidative stress contributes to the subsequent formation of brain edema. Therefore, we tested the neuroprotective effects of hydrogen (H2) in an established surgical brain injury (SBI) model in rats. Materials and methods Adult male Sprague - Dawley rats (weight 300-350g) were divided into three groups to serve as sham operated, SBI without treatment, and SBI treated with H2 (2.9%). Brain water content, myeloperoxidase (MPO) assay, lipid peroxidation (LPO), and neurological function were measured at 24 hrs after SBI. Results SBI resulted in localized brain edema (p = < 0.001). Hydrogen (2.9%) administered concurrently with surgery significantly decreased the formation of cerebral edema (p = 0.028) and improved neurobehavioral score (p = 0.022). However, hydrogen treatment failed to reduce oxidative stress (LPO assay) or inflammation (MPO assay) in brain tissues. Conclusions Hydrogen appears to be promising as an effective, yet inexpensive way to reduce cerebral edema caused by surgical procedures. Hydrogen has the potential to improve clinical outcome, decrease hospital stay, and reduce overall cost to patients and the health care system.



Neurogenic pulmonary edema associated with pediatric status epilepticus.  


Neurogenic pulmonary edema (NPE) can result from various central nervous system disorders such as brain malignancies, traumatic brain injuries, infections, and seizures. Although the pathogenesis is not completely understood, NPE creates an increase in pulmonary interstitial and alveolar fluid. In adults, it has been reported with prolonged seizure activity. In pediatric patients, pulmonary edema has rarely been reported after status epilepticus, and respiratory compromise is most often due to anticonvulsant-related respiratory depression. Treatment for NPE is largely supportive. If unrecognized, it can lead to hypoxia and respiratory arrest. We report a case of status epilepticus-related pulmonary edema in a female toddler, the youngest patient to be reported in the literature. PMID:21975498

Reuter-Rice, Karin; Duthie, Susan; Hamrick, Justin



Drug-induced macular edema.  


Macular edema constitutes a serious pathologic entity of ophthalmology resulting in vision loss with a remarkable impact on the quality of life of patients. It is the final common pathway of various systemic diseases and underlying intraocular conditions, with diabetes mellitus being the most frequent cause. Other causes include venous occlusive disease, intraocular surgery, and inflammatory conditions of the posterior segment of the eye. Macular edema is a recognized side effect of various systemic and local medications and requires special consideration among ophthalmologists and other clinicians. Recently, antidiabetic thiazolidinediones have been implicated in the development of macular edema, and a review of the English literature revealed that other systemically administered drugs like fingolimod, recently approved for relapsing forms of multiple sclerosis, the anticancer agents tamoxifen and the taxanes, as well as niacin and interferons have been reported to cause macular edema. Ophthalmologic pharmaceutical agents, like prostaglandin analogs, epinephrine, timolol, and ophthalmic preparation preservatives have also been reported to cause macular edema as an adverse event. The purpose of this article is to provide a short, balanced overview of the available evidence in this regard. The available data and the possible pathophysiologic mechanisms leading to the development of macular edema are discussed. Possible therapeutic strategies for drug-induced macular edema are also proposed. PMID:23640687

Makri, Olga E; Georgalas, Ilias; Georgakopoulos, Constantine D



Acute hemorrhagic edema of infancy.  


Acute hemorrhagic edema of infancy is a distinctive, cutaneous small vessel leukocytoclastic vasculitis of young children with dramatic characteristic skin findings. It is characterized by low- grade fever, erythematous edema, and purpuric lesions mainly on the face and extremities. Visceral involvement is uncommon, and spontaneous recovery usually occurs within one to three weeks without sequelae. The main differential diagnosis is Henoch-Schönlein purpura. We report this case to highlight the condition and emphasize its benign nature. We describe a classic case of acute hemorrhagic edema of infancy, and comment on the clinical features, pathology, treatment, and prognosis. The disease has spontaneous recovery without sequelae. PMID:18154430

Javidi, Zari; Maleki, Masoud; Mashayekhi, Vahid; Tayebi-Maybodi, Naser; Nahidi, Yalda



Volatile Anesthetics Influence Blood-Brain Barrier Integrity by Modulation of Tight Junction Protein Expression in Traumatic Brain Injury  

PubMed Central

Disruption of the blood-brain barrier (BBB) results in cerebral edema formation, which is a major cause for high mortality after traumatic brain injury (TBI). As anesthetic care is mandatory in patients suffering from severe TBI it may be important to elucidate the effect of different anesthetics on cerebral edema formation. Tight junction proteins (TJ) such as zonula occludens-1 (ZO-1) and claudin-5 (cl5) play a central role for BBB stability. First, the influence of the volatile anesthetics sevoflurane and isoflurane on in-vitro BBB integrity was investigated by quantification of the electrical resistance (TEER) in murine brain endothelial monolayers and neurovascular co-cultures of the BBB. Secondly brain edema and TJ expression of ZO-1 and cl5 were measured in-vivo after exposure towards volatile anesthetics in native mice and after controlled cortical impact (CCI). In in-vitro endothelial monocultures, both anesthetics significantly reduced TEER within 24 hours after exposure. In BBB co-cultures mimicking the neurovascular unit (NVU) volatile anesthetics had no impact on TEER. In healthy mice, anesthesia did not influence brain water content and TJ expression, while 24 hours after CCI brain water content increased significantly stronger with isoflurane compared to sevoflurane. In line with the brain edema data, ZO-1 expression was significantly higher in sevoflurane compared to isoflurane exposed CCI animals. Immunohistochemical analyses revealed disruption of ZO-1 at the cerebrovascular level, while cl5 was less affected in the pericontusional area. The study demonstrates that anesthetics influence brain edema formation after experimental TBI. This effect may be attributed to modulation of BBB permeability by differential TJ protein expression. Therefore, selection of anesthetics may influence the barrier function and introduce a strong bias in experimental research on pathophysiology of BBB dysfunction. Future research is required to investigate adverse or beneficial effects of volatile anesthetics on patients at risk for cerebral edema.

Schaible, Eva-Verena; Timaru-Kast, Ralph; Hedrich, Jana; Luhmann, Heiko J.; Engelhard, Kristin



Neuroprotection of lipoic acid treatment promotes angiogenesis and reduces the glial scar formation after brain injury.  


After trauma brain injury, a large number of cells die, releasing neurotoxic chemicals into the extracellular medium, decreasing cellular glutathione levels and increasing reactive oxygen species that affect cell survival and provoke an enlargement of the initial lesion. Alpha-lipoic acid is a potent antioxidant commonly used as a treatment of many degenerative diseases such as multiple sclerosis or diabetic neuropathy. Herein, the antioxidant effects of lipoic acid treatment after brain cryo-injury in rat have been studied, as well as cell survival, proliferation in the injured area, gliogenesis and angiogenesis. Thus, it is shown that newborn cells, mostly corresponded with blood vessels and glial cells, colonized the damaged area 15 days after the lesion. However, lipoic acid was able to stimulate the synthesis of glutathione, decrease cell death, promote angiogenesis and decrease the glial scar formation. All those facts allow the formation of new neural tissue. In view of the results herein, lipoic acid might be a plausible pharmacological treatment after brain injury, acting as a neuroprotective agent of the neural tissue, promoting angiogenesis and reducing the glial scar formation. These findings open new possibilities for restorative strategies after brain injury, stroke or related disorders. PMID:22917609

Rocamonde, B; Paradells, S; Barcia, J M; Barcia, C; García Verdugo, J M; Miranda, M; Romero Gómez, F J; Soria, J M



Mesencephalic astrocyte-derived neurotrophic factor reduces ischemic brain injury and promotes behavioral recovery in rats.  


Mesencephalic astrocyte-derived neurotrophic factor (MANF), also known as arginine-rich, mutated in early stage of tumors (ARMET), is a secreted protein that reduces endoplasmic reticulum (ER) stress. Previous studies have shown that MANF mRNA expression and protein levels are increased in the cerebral cortex after brain ischemia, a condition that induces ER stress. The function of MANF during brain ischemia is still not known. The purpose of this study was to examine the protective effect of MANF after ischemic brain injury. Recombinant human MANF was administrated locally to the cerebral cortex before a 60-min middle cerebral artery occlusion (MCAo) in adult rats. Triphenyltetrazolium chloride (TTC) staining indicated that pretreatment with MANF significantly reduced the volume of infarction at 2 days after MCAo. MANF also attenuated TUNEL labeling, a marker of cell necrosis/apoptosis, in the ischemic cortex. Animals receiving MANF pretreatment demonstrated a decrease in body asymmetry and neurological score as well as an increase in locomotor activity after MCAo. Taken together, these data suggest that MANF has neuroprotective effects against cerebral ischemia, possibly through the inhibition of cell necrosis/apoptosis in cerebral cortex. PMID:19399876

Airavaara, Mikko; Shen, Hui; Kuo, Chi-Chung; Peränen, Johan; Saarma, Mart; Hoffer, Barry; Wang, Yun



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


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 5weeks after trauma, but not early initiation of exercise at 1week, significantly reduced working and retention memory impairment at 3months, 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

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



Dosimetric Predictors of Laryngeal Edema  

SciTech Connect

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.

Sanguineti, Giuseppe [Department of Radiation Oncology, University of Texas Medical Branch, Galveston, TX (United States)]. E-mail:; Adapala, Prashanth [Department of Radiation Oncology, University of Texas Medical Branch, Galveston, TX (United States); Endres, Eugene J. C [Department of Medical Physics, University of Texas Medical Branch, Galveston, TX (United States); Brack, Collin [Department of Medical Physics, University of Texas Medical Branch, Galveston, TX (United States); Fiorino, Claudio [Department of Physics, Ospedale San Raffaele, Milan (Italy); Sormani, Maria Pia [Biostatistics Unit, University of Genoa, Genoa (Italy); Parker, Brent [Department of Medical Physics, University of Texas Medical Branch, Galveston, TX (United States)



Anandamide (Arachidonylethanolamide), a Brain Cannabinoid Receptor Agonist, Reduces Sperm Fertilizing Capacity in Sea Urchins by Inhibiting the Acrosome Reaction  

Microsoft Academic Search

Anandamide (arachidonylethanolamide) is an endogenous cannabinoid receptor agonist in mammalian brain. Sea urchin sperm contain a high-affinity cannabinoid receptor similar to the cannabinoid receptor in mammalian brain. (-)-Delta^9-Tetrahydrocannabinol (THC), the primary psychoactive cannabinoid in marihuana, reduces the fertilizing capacity of sea urchin sperm by blocking the acrosome reaction that normally is stimulated by a specific ligand in the egg's jelly

Herbert Schuel; Elaine Goldstein; Raphael Mechoulam; Arthur M. Zimmerman; Selma Zimmerman



Targeted Over-Expression of Glutamate Transporter 1 (GLT-1) Reduces Ischemic Brain Injury in a Rat Model of Stroke  

Microsoft Academic Search

Following the onset of an ischemic brain injury, the excitatory neurotransmitter glutamate is released. The excitotoxic effects of glutamate are a major contributor to the pathogenesis of a stroke. The aim of this study was to examine if overexpression of a glutamate transporter (GLT-1) reduces ischemic brain injury in a rat model of stroke. We generated an adeno-associated viral (AAV)

Brandon K. Harvey; Mikko Airavaara; Jason Hinzman; Emily M. Wires; Matthew J. Chiocco; Douglas B. Howard; Hui Shen; Greg Gerhardt; Barry J. Hoffer; Yun Wang



Administration of an omega-conopeptide one hour following traumatic brain injury reduces 45calcium accumulation.  


The omega-conopeptide, SNX-111 (NEUREX Corporation) was administered to rats 1 hour following a lateral fluid percussion brain injury to determine if the drug could reduced the extent and duration of trauma-induced calcium accumulation. Administration at doses of 3 or 5 mg/kg (i.v.) markedly reduced the extent of calcium accumulation as determined using 45calcium autoradiography primarily within the cerebral cortex and hippocampus. The reduction of calcium accumulation was particularly event within the parietal cortex beginning as early as 6 hours and lasting out to 48 hours following injury. Although not as effective as in the cerebral cortex, SNX-111 did exhibit a reduction of calcium accumulation within the dorsal hippocampus especially at 24 and 48 hours after the insult. These preliminary results demonstrate that SNX-111 can reduce the injury-induced accumulation of calcium even when administered 1 hour after the insult and offers this compound as a potential therapeutic treatment for traumatic brain injury. PMID:7976637

Hovda, D A; Fu, K; Badie, H; Samii, A; Pinanong, P; Becker, D P



Reduced Expression of Integrin ?v?8 Is Associated with Brain Arteriovenous Malformation Pathogenesis  

PubMed Central

Brain arteriovenous malformations (BAVMs) are a rare but potentially devastating hemorrhagic disease. Transforming growth factor-? signaling is required for proper vessel development, and defective transforming growth factor-? superfamily signaling has been implicated in BAVM pathogenesis. We hypothesized that expression of the transforming growth factor-? activating integrin, ?v?8, is reduced in BAVMs and that decreased ?8 expression leads to defective neoangiogenesis. We determined that ?8 protein expression in perivascular astrocytes was reduced in human BAVM lesional tissue compared with controls and that the angiogenic response to focal vascular endothelial growth factor stimulation in adult mouse brains with local Cre-mediated deletion of itgb8 and smad4 led to vascular dysplasia in newly formed blood vessels. In addition, common genetic variants in ITGB8 were associated with BAVM susceptibility, and ITGB8 genotypes associated with increased risk of BAVMs correlated with decreased ?8 immunostaining in BAVM tissue. These three lines of evidence from human studies and a mouse model suggest that reduced expression of integrin ?8 may be involved in the pathogenesis of sporadic BAVMs.

Su, Hua; Kim, Helen; Pawlikowska, Ludmila; Kitamura, Hideya; Shen, Fanxia; Cambier, Stephanie; Markovics, Jennifer; Lawton, Michael T.; Sidney, Stephen; Bollen, Andrew W.; Kwok, Pui-Yan; Reichardt, Louis; Young, William L.; Yang, Guo-Yuan; Nishimura, Stephen L.



Treatment with ginseng total saponins reduces the secondary brain injury in rat after cortical impact.  


The present study was designed to investigate the neuroprotective effect of ginseng total saponins (GTSs) and its underlying mechanisms in a rat model of traumatic brain injury (TBI). Rats were injected with GTSs (20 mg/kg, i.p.) or vehicle for 14 days after TBI. Neurological functions were determined using beam balance and prehensile traction tests at 1-14 days after trauma. Brain samples were extracted at 1 day after trauma for determination of water content, Nissl staining, enzyme-linked immunosorbent assay, immunohistochemistry, terminal deoxynucleotidyl transferase-mediated biotin-dUTP nick end labeling, and measurement of oxidative stress variables and inflammatory cytokines. Moreover, the dose response of the neuroprotective effect and time window of the efficacy of GTSs were also determined. We found that treatment of GTSs 1) improved the neurological function with an effective dosage of 5-80 mg/kg and an efficacy time window of 3-6 hr after TBI; 2) reduced brain water content and neuronal loss in the hippocampal CA3 area; 3) increased the activity of superoxide dismutase and decreased the activity of nitric oxide synthase and the amount of malondialdehyde and nitric oxide; 4) down-regulated interleukin-1?, interleukin-6, and tumor necrosis factor-? and upregulated interleukin-10 in the cortical area surrounding the injured core; and 5) inhibited the apoptotic cell death and expression of caspase-3 and bax and raised the expression of bcl-2. These findings suggest that administration of GTSs after TBI could reduce the secondary injury through inhibiting oxidative and nitrative stress, attenuating inflammatory response, and reducing apoptotic cell death. PMID:22434648

Xia, Lei; Jiang, Zheng-Lin; Wang, Guo-Hua; Hu, Bao-Yin; Ke, Kai-Fu



Inhaled nitric oxide improves short term memory and reduces the inflammatory reaction in a mouse model of mild traumatic brain injury.  


Although the mechanisms underlying mild traumatic brain injury (mTBI) are becoming well understood, treatment options are still limited. In the present study, mTBI was induced by a weight drop model to produce a closed head injury to mice and the effect of inhaled nitric oxide (INO) was evaluated by a short term memory task (object recognition task) and immunohistochemical staining of glial fibrillary acidic protein (GFAP) and CD45 for the detection of reactive astrocytes and microglia. Results showed that mTBI model did not produce brain edema, skull fracture or sensorimotor coordination dysfunctions. Mice did however exhibit a significant deficit in short term memory (STM) and strong inflammatory reaction in the ipsilateral cortex and hippocampus compared to sham-injured controls 24h after mTBI. Additional groups of untreated mice tested 3 and 7 days later, demonstrated that recognition memory had recovered to normal levels by Day 3. Mice treated with 10ppm INO for 4 or 8h, beginning immediately after TBI demonstrated significantly improved STM at 24h when compared with room air controls (p<0.05). Whereas mice treated with 10ppm INO for 24h showed no improvement in STM. Mice treated with INO 10ppm for 8h exhibited significantly reduced microglia and astrocyte activation compared with room air controls. These data demonstrate that mTBI produces a disruption of STM which is evident 24h after injury and persists for 2-3 days. Treatment with low concentration or short durations of INO prevents this memory loss and also attenuates the inflammatory response. These findings may have relevance for the treatment of patients diagnosed with concussion. PMID:23743262

Liu, Ping; Li, Yong-Sheng; Quartermain, David; Boutajangout, Allal; Ji, Yong



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


In the reward circuitry of the brain, ?-7-nicotinic acetylcholine receptors (?7nAChRs) modulate effects of ?(9)-tetrahydrocannabinol (THC), marijuana's main psychoactive ingredient. Kynurenic acid (KYNA) is an endogenous negative allosteric modulator of ?7nAChRs. 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 ?7nAChRs. 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

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



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


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, rich in omega fatty acids, have been shown to improve memory, cognition and neuronal effects related to oxidative stress (OS) and inflammation (INF) in animals and human trials. The current study found that feeding 19-month-old rats with a 6% or 9% walnut diet significantly reduced the aggregation of polyubiquitinated proteins and activated autophagy, a neuronal housekeeping function, in the striatum and hippocampus. Walnut-fed animals exhibited up-regulation of autophagy through inhibiting phosphorylation of mTOR, up-regulating ATG7 and Beclin 1, and turnover of MAP1BLC3 proteins. The clearance of polyubiquitinated protein aggregates such as p62/SQSTM1 was more profound in hippocampus, a critical region in the brain involved in memory and cognitive performance, than striatum. The clearance of ubiquitinated aggregates was in tandem with significant reductions in OS/INF, as indicated by the levels of P38-MAP kinase and phosphorylations of nuclear factor kappa B and cyclic AMP response element binding protein. The results demonstrate the effectiveness of a walnut-supplemented diet in activating the autophagy function in brain beyond its traditionally known antioxidant and anti-inflammatory benefits. PMID:22917841

Poulose, Shibu M; Bielinski, Donna F; Shukitt-Hale, Barbara



Reduced Brain Gray Matter Concentration in Patients With Obstructive Sleep Apnea Syndrome  

PubMed Central

Study Objectives: To investigate differences in brain gray matter concentrations or volumes in patients with obstructive sleep apnea syndrome (OSA) and healthy volunteers. Designs: Optimized voxel-based morphometry, an automated processing technique for MRI, was used to characterize structural differences in gray matter in newly diagnosed male patients. Setting: University hospital Patients and Participants: The study consisted of 36 male OSA and 31 non-apneic male healthy volunteers matched for age (mean age, 44.8 years). Interventions: Using the t-test, gray matter differences were identified. The statistical significance level was set to a false discovery rate P < 0.05 with an extent threshold of kE > 200 voxels. Measurements and Results: The mean apnea-hypopnea index (AHI) of patients was 52.5/ h. On visual inspection of MRI, no structural abnormalities were observed. Compared to healthy volunteers, the gray matter concentrations of OSA patients were significantly decreased in the left gyrus rectus, bilateral superior frontal gyri, left precentral gyrus, bilateral frontomarginal gyri, bilateral anterior cingulate gyri, right insular gyrus, bilateral caudate nuclei, bilateral thalami, bilateral amygdalo-hippocampi, bilateral inferior temporal gyri, and bilateral quadrangular and biventer lobules in the cerebellum (false discovery rate P < 0.05). Gray matter volume was not different between OSA patients and healthy volunteers. Conclusions: The brain gray matter deficits may suggest that memory impairment, affective and cardiovascular disturbances, executive dysfunctions, and dysregulation of autonomic and respiratory control frequently found in OSA patients might be related to morphological differences in the brain gray matter areas. Citation: Joo EY; Tae WS; Lee MJ; Kang JW; Park HS; Lee JY; Suh M; Hong SB. Reduced brain gray matter concentration in patients with obstructive sleep apnea syndrome. SLEEP 2010;33(2):235-241.

Joo, Eun Yeon; Tae, Woo Suk; Lee, Min Joo; Kang, Jung Woo; Park, Hwan Seok; Lee, Jun Young; Suh, Minah; Hong, Seung Bong



Measurement of the Extracellular Space in Brain Tumors Using 76Br-Bromide and PET  

Microsoft Academic Search

Brain edema significantly contributes to the clinical course of human brain tumor patients. There is evidence that an enlarge- ment of the extracellular space (ECS) is involved in the devel- opment of brain edema. Although T2-weighted magnetic reso- nance (T2-MR) images represent brain edema by its increased water content, they do not differentiate ECS enlargement from increased intracellular water content.

Matthias Bruehlmeier; Ulrich Roelcke; Peter Blauenstein; John Missimer; Pius A. Schubiger; Raimo Pellikka; Simon M. Ametamey


Pediatric mumps with laryngeal edema.  


Mumps virus infection primarily affects the salivary glands and may incur various complications. Laryngeal edema is such a rare complication that few adult cases have been reported. We report the first known pediatric patient with mumps with laryngeal edema. An 8-year-old boy developed dyspnea after a rapidly progressive swelling of his face and neck. Laryngoscopy revealed edematous changes in the supraglottic and subglottic regions, and computed tomography confirmed significant laryngeal edema in addition to swelling of the cervical soft tissue and the salivary glands. Laboratory findings revealed a high serum amylase level and confirmed the diagnosis of mumps. Intravenous steroid administration alleviated the dyspnea, although the patient required temporary tracheal intubation to maintain airway patency. He did not need tracheotomy and did not experience any other complications. Laryngeal edema must be regarded as a rare, potentially life-threatening complication of mumps. When mumps is diagnosed with significant swelling of the neck, an emergency airway should be established to prevent airway obstruction. PMID:24084609

Hattori, Yujiro; Oi, Yasufumi; Matsuoka, Ryo; Daimon, Yumi; Ito, Asami; Kubota, Wataru; Konishi, Kyoko; Onguchi, Toshimi; Sato, Akihiro; Yamashita, Yukio; Ishihara, Jun



Treatment with gelsolin reduces brain inflammation and apoptotic signaling in mice following thermal injury  

PubMed Central

Background Burn survivors develop long-term cognitive impairment with increased inflammation and apoptosis in the brain. Gelsolin, an actin-binding protein with capping and severing activities, plays a crucial role in the septic response. We investigated if gelsolin infusion could attenuate neural damage in burned mice. Methods Mice with 15% total body surface area burns were injected intravenously with bovine serum albumin as placebo (2 mg/kg), or with low (2 mg/kg) or high doses (20 mg/kg) of gelsolin. Samples were harvested at 8, 24, 48 and 72 hours postburn. The immune function of splenic T cells was analyzed. Cerebral pathology was examined by hematoxylin/eosin staining, while activated glial cells and infiltrating leukocytes were detected by immunohistochemistry. Cerebral cytokine mRNAs were further assessed by quantitative real-time PCR, while apoptosis was evaluated by caspase-3. Neural damage was determined using enzyme-linked immunosorbent assay of neuron-specific enolase (NSE) and soluble protein-100 (S-100). Finally, cerebral phospho-ERK expression was measured by western blot. Results Gelsolin significantly improved the outcomes of mice following major burns in a dose-dependent manner. The survival rate was improved by high dose gelsolin treatment compared with the placebo group (56.67% vs. 30%). Although there was no significant improvement in outcome in mice receiving low dose gelsolin (30%), survival time was prolonged against the placebo control (43.1 ± 4.5 h vs. 35.5 ± 5.0 h; P < 0.05). Burn-induced T cell suppression was greatly alleviated by high dose gelsolin treatment. Concurrently, cerebral abnormalities were greatly ameliorated as shown by reduced NSE and S-100 content of brain, decreased cytokine mRNA expressions, suppressed microglial activation, and enhanced infiltration of CD11b+ and CD45+ cells into the brain. Furthermore, the elevated caspase-3 activity seen following burn injury was remarkably reduced by high dose gelsolin treatment along with down-regulation of phospho-ERK expression. Conclusion Exogenous gelsolin infusion improves survival of mice following major burn injury by partially attenuating inflammation and apoptosis in brain, and by enhancing peripheral T lymphocyte function as well. These data suggest a novel and effective strategy to combat excessive neuroinflammation and to preserve cognition in the setting of major burns.



[Gly14]-Humanin reduces histopathology and improves functional outcome after traumatic brain injury in mice.  


Humanin (HN) has been identified as an endogenous peptide that inhibited AD-relevant neuronal cell death. HNG, a variant of HN in which the 14th amino acid serine was replaced with glycine, can reduce infarct volume and improve neurological deficits after ischemia/reperfusion injury. In this study, we aimed to examine the neuroprotective effect of HNG on traumatic brain injury (TBI) in mice and explored whether the protective effect was associated with regulating apoptosis and autophagy. Compared to vehicle-treated groups, mice administered HNG intracerebroventricularly (i.c.v.) prior to TBI had decreased cells with plasmalemma permeability in the injured cortex and hippocampus (48 h, P<0.01), reduced brain lesion volume (days 14 and 28, P<0.05), improved motor performance (days 1-4, P<0.05) and ameliorated performance in the Morris water maze test (days 11-13, P<0.05) post TBI. Reduced lesion volume (day 14, P<0.05) was also observed even when HNG was administered intraperitoneally (i.p.) at 1h and 2h post TBI, and minor amelioration in motor and Morris water maze test deficits was also observed. Immunoblotting results showed that HNG pretreatment (i.c.v.) reversed TBI-induced cleavage of cysteinyl aspartate-specific protease-3 and poly ADPribose-polymerase and decline of Bcl-2, suppressed LC3II, Beclin-1 and vacuolar sorting protein 34 activation and maintained p62 levels in the injured cortex and hippocampus post TBI (compared with vehicle). In conclusion, HNG treatment improved morphological and functional outcomes after TBI in mice and the protective effect of HNG against TBI may be associated with down-regulating apoptosis and autophagy. PMID:23178909

Wang, T; Zhang, L; Zhang, M; Bao, H; Liu, W; Wang, Y; Wang, L; Dai, D; Chang, P; Dong, W; Chen, X; Tao, L



Reduced efficiency of functional brain network underlying intellectual decline in patients with low-grade glioma.  


Low-grade glioma (LGG) patients are typically accompanied by varying degrees of intellectual impairments. However, the neural mechanisms underlying intellectual decline have not yet been well understood. The aim of this study is to investigate the relationship between possibly altered functional brain network properties and intellectual decline in LGG patients. Chinese revised Wechsler adult intelligence scale (WAIS-RC) was used to assess the intelligence of 21 LGG patients and 20 healthy controls, matched in age, gender and education. Resting-state functional magnetic resonance imaging (fMRI) was performed for all the subjects to analyze functional network characteristics with graph theory. The LGG patients showed significantly poor performance on intelligence test than controls (P<0.05). Compared with controls, the patients displayed disturbed small-world manner (increased characteristic path length L and normalized characteristic path length ?) and decreased global efficiency Eglob. Specially, we found that Eglob was positively correlated with intelligence quotient (IQ) test scores in LGG group. Furthermore, network hubs, which could significantly affect the network efficiency, were in the right insula and right posterior cingulate cortex in controls, while in the right thalamus and right posterior cingulate cortex in the patients. From the perspective of brain network, our results provided evidence of reduced global efficiency for poorer intellectual performance in LGG patients, which contributed to understanding the basis of intellectual impairments. PMID:23562503

Xu, Huazhong; Ding, Shangwen; Hu, Xinhua; Yang, Kun; Xiao, Chaoyong; Zou, Yuanjie; Chen, Yijun; Tao, Ling; Liu, Hongyi; Qian, Zhiyu



Molecular Mechanisms of Ischemic Cerebral Edema: Role of Electroneutral Ion Transport  

NSDL National Science Digital Library

The brain achieves homeostasis of its intracellular and extracellular fluids by precisely regulating the transport of solute and water across its major cellular barriers: endothelia of the blood-brain barrier (BBB), choroid plexus epithelia, and neuroglial cell membranes. Cerebral edema, the pathological accumulation of fluid in the brainÃÂs intracellular and extracellular spaces, is a major cause of morbidity and mortality following stroke and other forms of ischemic brain injury. Until recently, mechanisms of cerebral edema formation have been obscure; consequently, its treatment has been empiric and suboptimal. Here, we provide a paradigm for understanding ischemic cerebral edema, showing that its molecular pathogenesis is a complex yet step-wise process that results largely from impaired astrocytic cell volume regulation and permeability alterations in the cerebral microvasculature, both of which arise from pathological changes in the activities of specific ion channels and transporters. Recent data has implicated the bumetanide-sensitive NKCC1, an electroneutral cotransporter expressed in astrocytes and the BBB, in cerebral edema formation in several different rodent models of stroke. Pharmacological inhibition or genetic deficiency of NKCC1 decreases ischemia-induced cell swelling, BBB breakdown, cerebral edema, and neurotoxicity. Combination pharmacological strategies that include NKCC1 as a target might thus prove beneficial for the treatment of ischemic, and potentially other types of, cerebral edema.

Kristopher Kahle (Massachusetts General Hospital and Harvard Medical School Neurosurgery)



Diabetic Macular Edema: Pathogenesis and Treatment  

Microsoft Academic Search

Diabetic macular edema is a major cause of visual impairment. The pathogenesis of macular edema appears to be multifactorial. Laser photocoagulation is the standard of care for macular edema. However, there are cases that are not responsive to laser therapy. Several therapeutic options have been proposed for the treatment of this condition. In this review we discuss several factors and

Neelakshi Bhagat; Ruben A. Grigorian; Arthur Tutela; Marco A. Zarbin



9-Cis-Retinoic acid reduces ischemic brain injury in rodents via bone morphogenetic protein  

PubMed Central

Retinoic acid (RA), a biologically active derivative of vitamin A, has protective effects against damage caused by H2O2 or oxygen-glucose deprivation in mesangial and PC12 cells. In cultured human osteosarcoma cells, RA enhances the expression of bone morphogenetic protein -7 (BMP7), a trophic factor that reduces ischemia- or neurotoxin –mediated neurodegeneration in vivo. The purpose of this study is to examine whether RA reduces ischemic brain injury through a BMP7 mechanism. We found that intracerebroventricular administration of 9-cis-retinoic acid (9cRA) enhanced BMP7 mRNA expression, detected by RTPCR, in rat cerebral cortex at 24 hours after injection. Rats were also subjected to transient focal ischemia induced by ligation of the middle cerebral artery (MCA) at one day after 9cRA injection. Pretreatment with 9cRA increased locomotor activity and attenuated neurological deficits 2 days after MCA ligation. 9cRA also reduced cerebral infarction and TUNEL labeling. These protective responses were antagonized by BMP antagonist noggin given at one day after 9cRA injection. Taken together, our data suggest that 9cRA has protective effects against ischemia -induced injury and these effects involve BMPs.

Shen, Hui; Luo, Yu; Kuo, Chi-Chung; Deng, Xiaolin; Chang, Chen-Fu; Harvey, Brandon K.; Hoffer, Barry J; Wang, Yun



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


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

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



Decreased Intrinsic Brain Connectivity is Associated with Reduced Clinical Pain in Fibromyalgia  

PubMed Central

OBJECTIVE A major impediment toward the development of novel treatment strategies for fibromyalgia (FM) is the lack of an objective marker which tracks with spontaneous clinical pain report. Resting state intrinsic brain connectivity in FM has demonstrated increased insular connectivity to the default mode network (DMN), a network whose activity is increased during rest. Moreover increased insular connectivity to the DMN was associated with increased spontaneous pain levels. However as these analyses were cross-sectional in nature, they provided no insight to dynamic changes in connectivity and their relationship with variation in clinical pain report. METHODS 17 FM patients underwent resting state fMRI at baseline and following 4 weeks of a non-pharmacological intervention to diminish pain. Intrinsic DMN connectivity was evaluated using probabilistic independent component analysis. A paired analysis evaluated longitudinal changes in intrinsic DMN connectivity and a multiple linear regression investigated correlations between longitudinal changes in clinical pain and changes in intrinsic DMN connectivity. Changes in clinical pain were assessed with the Short Form of the McGill Pain Questionnaire (SF-MPQ). RESULTS Clinical pain was reduced following therapy (SF-MPQ sensory scale: p<0.02). Intrinsic DMN connectivity to the insula was reduced, and this reduction was correlated with reductions in pain (corrected p<0.05). CONCLUSIONS Our findings suggest that intrinsic brain connectivity can be used as a candidate objective marker that tracks intra-subject with changes in spontaneous chronic pain in FM. We propose that intrinsic connectivity measures could potentially be used either in research or clinical settings as a complementary, more objective outcome.

Napadow, Vitaly; Kim, Jieun; Clauw, Daniel J; Harris, Richard E



Preventing flow-metabolism uncoupling acutely reduces axonal injury after traumatic brain injury.  


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 ¹?F-fluorodeoxyglucose and ¹?C-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 ?-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 ?-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

Harris, Neil G; Mironova, Yevgeniya A; Chen, Szu-Fu; Richards, Hugh K; Pickard, John D



Reduced steady-state levels of mitochondrial RNA and increased mitochondrial DNA amount in human brain with aging  

Microsoft Academic Search

The contribution of the mitochondrial genetic system in the degenerative processes of senescence remains unclear. This study deals with age-related changes in brain mtDNA expression in humans. Brain tissue from the frontal lobe cortex was obtained from autopsy of 13 humans aged between 21 and 84 years. No structural changes were detected in mtDNA, increased mtDNA content and reduced steady-state

Antoni Barrientos; Jordi Casademont; Francesc Cardellach; Xavier Estivill; Alvaro Urbano-Marquez; Virginia Nunes



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

PubMed Central

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.



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

SciTech Connect

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.

Chang, Eric L. [Department of Radiation Oncology, University of Texas, M. D. Anderson Cancer Center, Houston, TX (United States)]. E-mail:; Akyurek, Serap [Department of Radiation Oncology, University of Texas, M. D. Anderson Cancer Center, Houston, TX (United States); Avalos, Tedde C [Department of Radiation Oncology, University of Texas, M. D. Anderson Cancer Center, Houston, TX (United States); Rebueno, Neal C [Department of Radiation Oncology, University of Texas, M. D. Anderson Cancer Center, Houston, TX (United States); Spicer, Chris C [Department of Radiation Oncology, University of Texas, M. D. Anderson Cancer Center, Houston, TX (United States); Garcia, John C [Department of Radiation Oncology, University of Texas, M. D. Anderson Cancer Center, Houston, TX (United States); Famiglietti, Robin [Department of Radiation Oncology, University of Texas, M. D. Anderson Cancer Center, Houston, TX (United States); Allen, Pamela K. [Department of Radiation Oncology, University of Texas, M. D. Anderson Cancer Center, Houston, TX (United States); Chao, K.S. Clifford [Department of Radiation Oncology, University of Texas, M. D. Anderson Cancer Center, Houston, TX (United States); Mahajan, Anita [Department of Radiation Oncology, University of Texas, M. D. Anderson Cancer Center, Houston, TX (United States); Woo, Shiao Y. [Department of Radiation Oncology, University of Texas, M. D. Anderson Cancer Center, Houston, TX (United States); Maor, Moshe H. [Department of Radiation Oncology, University of Texas, M. D. Anderson Cancer Center, Houston, TX (United States)



A multimodal RAGE-specific inhibitor reduces amyloid ?-mediated brain disorder in a mouse model of Alzheimer disease.  


In Alzheimer disease (AD), amyloid ? peptide (A?) accumulates in plaques in the brain. Receptor for advanced glycation end products (RAGE) mediates A?-induced perturbations in cerebral vessels, neurons, and microglia in AD. Here, we identified a high-affinity RAGE-specific inhibitor (FPS-ZM1) that blocked A? binding to the V domain of RAGE and inhibited A?40- and A?42-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 A?-precursor protein, a transgenic mouse model of AD with established A? pathology, FPS-ZM1 inhibited RAGE-mediated influx of circulating A?40 and A?42 into the brain. In brain, FPS-ZM1 bound exclusively to RAGE, which inhibited ?-secretase activity and A? production and suppressed microglia activation and the neuroinflammatory response. Blockade of RAGE actions at the BBB and in the brain reduced A?40 and A?42 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 A?-mediated brain disorder and that it may have the potential to be a disease-modifying agent for AD. PMID:22406537

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



Diabetic macular edema: pathogenesis and treatment.  


Diabetic macular edema is a major cause of visual impairment. The pathogenesis of macular edema appears to be multifactorial. Laser photocoagulation is the standard of care for macular edema. However, there are cases that are not responsive to laser therapy. Several therapeutic options have been proposed for the treatment of this condition. In this review we discuss several factors and mechanisms implicated in the etiology of macular edema (vasoactive factors, biochemical pathways, anatomical abnormalities). It seems that combined pharmacologic and surgical therapy may be the best approach for the management of macular edema in diabetic patients. PMID:19171208

Bhagat, Neelakshi; Grigorian, Ruben A; Tutela, Arthur; Zarbin, Marco A


Monensin and the Prevention of Tryptophan-Induced Acute Bovine Pulmonary Edema and Emphysema  

Microsoft Academic Search

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

A. C. Hammond; J. R. Carlson; R. G. Breeze



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

PubMed Central

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.

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



Reduced neuroplasticity in aged rats: a role for the neurotrophin brain-derived neurotrophic factor.  


Aging is a physiological process characterized by a significant reduction of neuronal plasticity that might contribute to the functional defects observed in old subjects. Even if the neurobiological mechanisms that contribute to such impairment remain largely unknown, a role for neurotrophic molecules, such as the neurotrophin brain-derived neurotrophic factor (BDNF), has been postulated. On this basis, the purpose of this study was to provide a detailed investigation of the BDNF system, at transcriptional and translational levels, in the ventral and dorsal hippocampus and in the prefrontal cortex of middle-aged and old rats, compared with in adult animals. The expression of major players in BDNF regulation and response, including the transcription factors, calcium-responsive transcription factor, cyclic adenosine monophosphate (cAMP) responsive element-binding protein (CREB), and neuronal Per Arnt Sim (PAS) domain protein 4, and the high-affinity receptor tropomyosin receptor kinase B (TrkB), was also analyzed. Our results demonstrate that the BDNF system is affected at different levels in aged rats with global impairment including reduced transcription, impaired protein synthesis and processing, and decreased activation of the TrkB receptors. These modifications might contribute to the cognitive deficits associated with aging and suggest that pharmacological strategies aimed at restoring reduced neurotrophism might be useful to counteract age-related cognitive decline. PMID:23870838

Calabrese, Francesca; Guidotti, Gianluigi; Racagni, Giorgio; Riva, Marco A



Cyclooxygenase-2-specific Inhibitor Improves Functional Outcomes, Provides Neuroprotection, and Reduces Inflammation in a Rat Model of Traumatic Brain Injury  

PubMed Central

OBJECTIVE Increases in brain cyclooxygenase-2 (COX2) are associated with the central inflammatory response and with delayed neuronal death, events that cause secondary insults after traumatic brain injury. A growing literature supports the benefit of COX2-specific inhibitors in treating brain injuries. METHODS DFU [5,5-dimethyl-3(3-fluorophenyl)-4(4-methylsulfonyl)phenyl-2(5H)-furanone] is a third-generation, highly specific COX2 enzyme inhibitor. DFU treatments (1 or 10 mg/kg intraperitoneally, twice daily for 3 d) were initiated either before or after traumatic brain injury in a lateral cortical contusion rat model. RESULTS DFU treatments initiated 10 minutes before injury or up to 6 hours after injury enhanced functional recovery at 3 days compared with vehicle-treated controls. Significant improvements in neurological reflexes and memory were observed. DFU initiated 10 minutes before injury improved histopathology and altered eicosanoid profiles in the brain. DFU 1 mg/kg reduced the rise in prostaglandin E2 in the brain at 24 hours after injury. DFU 10 mg/kg attenuated injury-induced COX2 immunoreactivity in the cortex (24 and 72 h) and hippocampus (6 and 72 h). This treatment also decreased the total number of activated caspase-3–immunoreactive cells in the injured cortex and hippocampus, significantly reducing the number of activated caspase-3–immunoreactive neurons at 72 hours after injury. DFU 1 mg/kg amplified potentially anti-inflammatory epoxyeicosatrienoic acid levels by more than fourfold in the injured brain. DFU 10 mg/kg protected the levels of 2-arachidonoyl glycerol, a neuro-protective endocannabinoid, in the injured brain. CONCLUSION These improvements, particularly when treatment began up to 6 hours after injury, suggest exciting neuroprotective potential for COX2 inhibitors in the treatment of traumatic brain injury and support the consideration of Phase I/II clinical trials.

Gopez, Jonas J.; Yue, Hongfei; Vasudevan, Ram; Malik, Amir S.; Fogelsanger, Lester N.; Lewis, Shawn; Panikashvili, David; Shohami, Esther; Jansen, Susan A.; Narayan, Raj K.; Strauss, Kenneth I.



Reduced expression of TAC1, PENK and SOCS2 in Hcrtr-2 mutated narcoleptic dog brain  

PubMed Central

Background Narcolepsy causes dramatic behavioral alterations in both humans and dogs, with excessive sleepiness and cataplexy triggered by emotional stimuli. Deficiencies in the hypocretin system are well established as the origin of the condition; both from studies in humans who lack the hypocretin ligand (HCRT) and in dogs with a mutation in hypocretin receptor 2 (HCRTR2). However, little is known about molecular alterations downstream of the hypocretin signals. Results By using microarray technology we have screened the expression of 29760 genes in the brains of Doberman dogs with a heritable form of narcolepsy (homozygous for the canarc-1 [HCRTR-2-2] mutation), and their unaffected heterozygous siblings. We identified two neuropeptide precursor molecules, Tachykinin precursor 1 (TAC1) and Proenkephalin (PENK), that together with Suppressor of cytokine signaling 2 (SOCS2), showed reduced expression in narcoleptic brains. The difference was particularly pronounced in the amygdala, where mRNA levels of PENK were 6.2 fold lower in narcoleptic dogs than in heterozygous siblings, and TAC1 and SOCS2 showed 4.4 fold and 2.8 fold decrease in expression, respectively. The results obtained from microarray experiments were confirmed by real-time RT-PCR. Interestingly, it was previously shown that a single dose of amphetamine-like stimulants able to increase wakefulness in the dogs, also produce an increase in the expression of both TAC1 and PENK in mice. Conclusion These results suggest that TAC1, PENK and SOCS2 might be intimately connected with the excessive daytime sleepiness not only in dogs, but also in other species, possibly including humans.

Lindberg, Julia; Saetre, Peter; Nishino, Seiji; Mignot, Emmanuel; Jazin, Elena



Pharmaco-modulations of induced edema and vascular permeability changes by Vipera lebetina venom: inflammatory mechanisms.  


The inflammatory response induced by Vipera lebetina venom (VLV) in the mice hind paw was evaluated by paw edema value and vascular permeability changes. The edema was produced in a dose- and time-dependent manner. This response was maximal within 2 h and disappeared after 24 h The minimum edema-forming dose was estimated at 0.8 ?g/20 g body weight. Microscopic examination confirmed that VLV also induces skin structure alterations with collagen fiber dissociation and polynuclear infiltration, which is characteristic of edema formation. The induced edema with VLV (1 ?g/paw) could be due to the release of pharmacological active substances at the site of injection. Histamine, serotonine, and arachidonate metabolites may play important roles in the vasoactive and edematic effect of VLV since pretreatment of mice with cromoglycate, cyproheptadine, ibuprofen, loratidine, and indomethacin significantly reduced the edema formation (77, 63, 57, 45, and 43 %, respectively). The obtained results demonstrate that the induced edema and vasodilatation by this venom may be triggered and maintained by different pharmacological mechanisms, since cromoglycate and cyproheptadine were the most active inhibitors of the edema. The relationships between histamine and serotonin release from mast cells and arachidonate metabolites activation could be the main step in edema-forming and the induced vasodilatation by the venom. PMID:23108954

Sebia-Amrane, Fatima; Laraba-Djebari, Fatima



Doxycycline Reduces Mortality and Injury to the Brain and Cochlea in Experimental Pneumococcal Meningitis  

Microsoft Academic Search

Bacterial meningitis is characterized by an inflammatory reaction to the invading pathogens that can ultimately lead to sensorineural hearing loss, permanent brain injury, or death. The matrix metalloproteinases (MMPs) and tumor necrosis factor alpha-converting enzyme (TACE) are key mediators that promote inflam- mation, blood-brain barrier disruption, and brain injury in bacterial meningitis. Doxycycline is a clinically used antibiotic with anti-inflammatory

Damian N. Meli; Roney S. Coimbra; Dominik G. Erhart; Gerard Loquet; Caroline L. Bellac; Martin G. Tauber; Ulf Neumann; Stephen L. Leib



Defective N-acetylaspartate catabolism reduces brain acetate levels and myelin lipid synthesis in Canavan's disease  

PubMed Central

Canavan's disease (CD) is a fatal, hereditary disorder of CNS development that has been linked to mutations in the gene for the enzyme aspartoacylase (ASPA) (EC ASPA acts to hydrolyze N-acetylaspartate (NAA) into l-aspartate and acetate, but the connection between ASPA deficiency and the failure of proper CNS development is unclear. We hypothesize that one function of ASPA is to provide acetate for the increased lipid synthesis that occurs during postnatal CNS myelination. The gene encoding ASPA has been inactivated in the mouse model of CD, and here we show significant decreases in the synthesis of six classes of myelinassociated lipids, as well as reduced acetate levels, in the brains of these mice at the time of peak postnatal CNS myelination. Analysis of the lipid content of white matter from a human CD patient showed decreased cerebroside and sulfatide relative to normal white matter. These results demonstrate that myelin lipid synthesis is significantly compromised in CD and provide direct evidence that defective myelin synthesis, resulting from a deficiency of NAA-derived acetate, is involved in the pathogenesis of CD.

Madhavarao, Chikkathur N.; Arun, Peethambaran; Moffett, John R.; Szucs, Sylvia; Surendran, Sankar; Matalon, Reuben; Garbern, James; Hristova, Diana; Johnson, Anne; Jiang, Wei; Namboodiri, M. A. Aryan



Correction for pulse height variability reduces physiological noise in functional MRI when studying spontaneous brain activity.  


EEG correlated functional MRI (EEG-fMRI) allows the delineation of the areas corresponding to spontaneous brain activity, such as epileptiform spikes or alpha rhythm. A major problem of fMRI analysis in general is that spurious correlations may occur because fMRI signals are not only correlated with the phenomena of interest, but also with physiological processes, like cardiac and respiratory functions. The aim of this study was to reduce the number of falsely detected activated areas by taking the variation in physiological functioning into account in the general linear model (GLM). We used the photoplethysmogram (PPG), since this signal is based on a linear combination of oxy- and deoxyhemoglobin in the arterial blood, which is also the basis of fMRI. We derived a regressor from the variation in pulse height (VIPH) of PPG and added this regressor to the GLM. When this regressor was used as predictor it appeared that VIPH explained a large part of the variance of fMRI signals acquired from five epilepsy patients and thirteen healthy volunteers. As a confounder VIPH reduced the number of activated voxels by 30% for the healthy volunteers, when studying the generators of the alpha rhythm. Although for the patients the number of activated voxels either decreased or increased, the identification of the epileptogenic zone was substantially enhanced in one out of five patients, whereas for the other patients the effects were smaller. In conclusion, applying VIPH as a confounder diminishes physiological noise and allows a more reliable interpretation of fMRI results. PMID:19662656

van Houdt, Petra J; Ossenblok, Pauly P W; Boon, Paul A J M; Leijten, Frans S S; Velis, Demetrios N; Stam, Cornelis J; de Munck, Jan C



Selective and brain-permeable polo-like kinase-2 (Plk-2) inhibitors that reduce ?-synuclein phosphorylation in rat brain.  


Polo-like kinase-2 (Plk-2) has been implicated as the dominant kinase involved in the phosphorylation of ?-synuclein in Lewy bodies, which are one of the hallmarks of Parkinson's disease neuropathology. Potent, selective, brain-penetrant inhibitors of Plk-2 were obtained from a structure-guided drug discovery approach driven by the first reported Plk-2-inhibitor complexes. The best of these compounds showed excellent isoform and kinome-wide selectivity, with physicochemical properties sufficient to interrogate the role of Plk-2 inhibition in?vivo. One such compound significantly decreased phosphorylation of ?-synuclein in rat brain upon oral administration and represents a useful probe for future studies of this therapeutic avenue toward the potential treatment of Parkinson's disease. PMID:23794260

Aubele, Danielle L; Hom, Roy K; Adler, Marc; Galemmo, Robert A; Bowers, Simeon; Truong, Anh P; Pan, Hu; Beroza, Paul; Neitz, R Jeffrey; Yao, Nanhua; Lin, May; Tonn, George; Zhang, Heather; Bova, Michael P; Ren, Zhao; Tam, Danny; Ruslim, Lany; Baker, Jeanne; Diep, Linnea; Fitzgerald, Kent; Hoffman, Jennifer; Motter, Ruth; Fauss, Donald; Tanaka, Pearl; Dappen, Michael; Jagodzinski, Jacek; Chan, Wayman; Konradi, Andrei W; Latimer, Lee; Zhu, Yong L; Sham, Hing L; Anderson, John P; Bergeron, Marcelle; Artis, Dean R



Postinsult treatment with lithium reduces brain damage and facilitates neurological recovery in a rat ischemia\\/reperfusion model  

Microsoft Academic Search

Lithium has long been a primary drug used to treat bipolar mood disorder, even though the drug's therapeutic mechanisms remain obscure. Recent studies demonstrate that lithium has neuroprotective effects against glutamate-induced excitotoxicity in cultured neurons and in vivo. The present study was undertaken to examine whether postinsult treatment with lithium reduces brain damage induced by cerebral ischemia. We found that

Ming Ren; Vladimir V. Senatorov; Ren-Wu Chen; De-Maw Chuang



Increased expression of aquaporin-4 in human traumatic brain injury and brain tumors  

Microsoft Academic Search

Objective: To characterize the expression of aquaporin-4 (AQP4), one of the aquaporins (AQPs), in human brain specimens from patients with traumatic brain injury or brain tumors. Methods: Nineteen human brain specimens were obtained from the patients with traumatic brain injury, brain tumors, benign meningioma or early stage hemorrhagic stroke. MRI or CT imaging was used to assess brain edema. Hematoxylin

HU Hua; YAO Hong-tian; ZHANG Wei-ping; ZHANG Lei; DING Wei; ZHANG Shi-hong; CHEN Zhong; WEI Er-qing



Itraconazole associated quadriparesis and edema: a case report  

PubMed Central

Introduction Itraconazole is an anti-fungal agent widely used to treat various forms of mycosis. It is particularly useful in allergic bronchopulmonary aspergillosis and severe asthma with fungal sensitization. Side effects are uncommon and usually mild. Mild neuropathy is noted to occur very rarely. We present an unusual and, to the best of our knowledge, as yet unreported case of severe neuropathy and peripheral edema due to itraconazole in the absence of a concomitant risk factor. Case presentation A 72-year-old Caucasian man was started on itraconazole following diagnosis of severe asthma with fungal sensitization. One month later he presented with severe bilateral ankle edema with an elevated serum itraconazole level. The itraconazole dose was reduced but his ankle edema persisted and he developed weakness of all four limbs. Itraconazole was completely stopped leading to improvement in his leg edema but he became bed bound due to weakness. He gradually improved with supportive care and neurorehabilitation. On review at six months, our patient was able to mobilize with the aid of two elbow crutches and power had returned to 5/5 in distal extremities and 4+/5 in proximal extremities. The diagnosis was established based on the classical presentation of drug-induced neuropathy and negative investigatory findings for any alternative diagnoses. Conclusion We report the case of a patient presenting with an unusual complication of severe neuropathy and peripheral edema due to itraconazole. Clinicians should be alert to this association when encountered with neuropathy and/or edema in an itraconazole therapy recipient.



Acetate supplementation increases brain phosphocreatine and reduces AMP levels with no effect on mitochondrial biogenesis.  


Acetate supplementation in rats increases plasma acetate and brain acetyl-CoA levels. Although acetate is used as a marker to study glial energy metabolism, the effect that acetate supplementation has on normal brain energy stores has not been quantified. To determine the effect(s) that an increase in acetyl-CoA levels has on brain energy metabolism, we measured brain nucleotide, phosphagen and glycogen levels, and quantified cardiolipin content and mitochondrial number in rats subjected to acetate supplementation. Acetate supplementation was induced with glyceryl triacetate (GTA) by oral gavage (6 g/kg body weight). Rats used for biochemical analysis were euthanized using head-focused microwave irradiation at 2, and 4h following treatment to immediately stop metabolism. We found that acetate did not alter brain ATP, ADP, NAD, GTP levels, or the energy charge ratio [ECR, (ATP+½ ADP)/(ATP+ADP+AMP)] when compared to controls. However, after 4h of treatment brain phosphocreatine levels were significantly elevated with a concomitant reduction in AMP levels with no change in glycogen levels. In parallel studies where rats were treated with GTA for 28 days, we found that acetate did not alter brain glycogen and mitochondrial biogenesis as determined by measuring brain cardiolipin content, the fatty acid composition of cardiolipin and using quantitative ultra-structural analysis to determine mitochondrial density/unit area of cytoplasm in hippocampal CA3 neurons. Collectively, these data suggest that an increase in brain acetyl-CoA levels by acetate supplementation does increase brain energy stores however it has no effect on brain glycogen and neuronal mitochondrial biogenesis. PMID:23321384

Bhatt, Dhaval P; Houdek, Heidi M; Watt, John A; Rosenberger, Thad A



Late onset tongue edema after palatoplasty  

Microsoft Academic Search

Cleft lip palate is a congenital anomaly that requires surgical reconstruction, and patients rarely develop tongue edema after palatoplasty. We describe a 1-year-and-8-month-old boy who underwent palatoplasty for left-sided cleft lip palate accompanied by exudative otitis media. Although previous reports have described that tongue edema usually sets in early after surgery, the symptoms of edema persisted more than 4 hours postoperatively

Mai Mukozawa; Takashi Kono; Shigeki Fujiwara; Ko Takakura



Diabetic Macular Edema: Current and Emerging Therapies  

PubMed Central

Diabetic macular edema is a leading cause of vision impairment among people within the working- age population. This review discusses the pathogenesis of diabetic macular edema and the treatment options currently available for the treatment of diabetic macular edema, including for focal/grid photocoagulation, intravitreal corticosteroids and intravitreal anti-vascular endothelial growth factor agents. The biologic rationale for novel therapeutic agents, many of which are currently being evaluated in clinical trials, also is reviewed.

Wenick, Adam S.; Bressler, Neil M.



Enoxaparin reduces cerebral edemaafter photothrombotic injury in the rat.  


This study investigates the effect of enoxaparin (Lovenox, Klexane), a low-molecular-weight heparin, on edema following a photothrombotic lesion using rose bengal dye in the rat. An area of cerebral ischemia was provoked in the right hemisphere of rats. Edema developed over 24 h after the lesion, as seen comparing water content of a core sample from the right hemisphere to that of a similar sample from the left hemisphere of each rat. Enoxaparin at 0. 5 mg/kg i.v. plus 2 mg/kg s.c. reduced edema 24 h after lesion induction by 32% (p < 0.01) when the treatment was started 2 h after photothrombotic insult, with maintenance doses of 2 mg/kg s.c. enoxaparin at 6 and 18 h. When the same initial treatment with enoxaparin was started 18 h after insult, there was still a significant reduction of 20% (p < 0.01) in cerebral edema. Administration of enoxaparin 18 h after insult reduced cerebral edema in a dose-dependent manner. There was no evidence of intracranial hemorrhages in any of the animal groups and when the hemoglobin content of the brain samples was assayed by the method of Drabkin, no increase in hemoglobin content was seen compared to sham-operated animals. PMID:10087432

Pratt, J; Boudeau, P; Uzan, A; Imperato, A; Stutzmann, J


Short communication Radiotherapy for a solitary brain metastasis during pregnancy: a method for reducing fetal dose  

Microsoft Academic Search

A patient presented during the second half of pregnancy with a solitary brain metastasis from lung cancer. This case shows that, using a new patient position, it is possible to shield the fetus efficiently. This new method consisted of whole brain irradiation with parallel pair treatment by lateral fields with the patient in a supine position with maximal neck extension.



Property-based design of a glucosylceramide synthase inhibitor that reduces glucosylceramide in the brain[S  

PubMed Central

Synthesis inhibition is the basis for the treatment of type 1 Gaucher disease by the glucosylceramide synthase (GCS) inhibitor eliglustat tartrate. However, the extended use of eliglustat and related compounds for the treatment of glycosphingolipid storage diseases with CNS manifestations is limited by the lack of brain penetration of this drug. Property modeling around the D-threo-1-phenyl-2-decanoylamino-3-morpholino-propanol (PDMP) pharmacophore was employed in a search for compounds of comparable activity against the GCS but lacking P-glycoprotein (MDR1) recognition. Modifications of the carboxamide N-acyl group were made to lower total polar surface area and rotatable bond number. Compounds were screened for inhibition of GCS in crude enzyme and whole cell assays and for MDR1 substrate recognition. One analog, 2-(2,3-dihydro-1H-inden-2-yl)-N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)acetamide (CCG-203586), was identified that inhibited GCS at low nanomolar concentrations with little to no apparent recognition by MDR1. Intraperitoneal administration of this compound to mice for 3 days resulted in a significant dose dependent decrease in brain glucosylceramide content, an effect not seen in mice dosed in parallel with eliglustat tartrate.

Larsen, Scott D.; Wilson, Michael W.; Abe, Akira; Shu, Liming; George, Christopher H.; Kirchhoff, Paul; Showalter, H. D. Hollis; Xiang, Jianming; Keep, Richard F.; Shayman, James A.



Glucose administration after traumatic brain injury improves cerebral metabolism and reduces secondary neuronal injury.  


Clinical studies have indicated an association between acute hyperglycemia and poor outcomes in patients with traumatic brain injury (TBI), although optimal blood glucose levels needed to maximize outcomes for these patients' remain under investigation. Previous results from experimental animal models suggest that post-TBI hyperglycemia may be harmful, neutral, or beneficial. The current studies determined the effects of single or multiple episodes of acute hyperglycemia on cerebral glucose metabolism and neuronal injury in a rodent model of unilateral controlled cortical impact (CCI) injury. In Experiment 1, a single episode of hyperglycemia (50% glucose at 2g/kg, i.p.) initiated immediately after CCI was found to significantly attenuate a TBI-induced depression of glucose metabolism in cerebral cortex (4 of 6 regions) and subcortical regions (2 of 7) as well as to significantly reduce the number of dead/dying neurons in cortex and hippocampus at 24h post-CCI. Experiment 2 examined effects of more prolonged and intermittent hyperglycemia induced by glucose administrations (2g/kg, i.p.) at 0, 1, 3 and 6h post-CCI. The latter study also found significantly improved cerebral metabolism (in 3 of 6 cortical and 3 of 7 subcortical regions) and significant neuroprotection in cortex and hippocampus 1 day after CCI and glucose administration. These results indicate that acute episodes of post-TBI hyperglycemia can be beneficial and are consistent with other recent studies showing benefits of providing exogenous energy substrates during periods of increased cerebral metabolic demand. PMID:23994447

Moro, Nobuhiro; Ghavim, Sima; Harris, Neil G; Hovda, David A; Sutton, Richard L



Stimulus features underlying reduced tremor suppression with temporally patterned deep brain stimulation  

PubMed Central

Deep brain stimulation (DBS) provides dramatic tremor relief when delivered at high-stimulation frequencies (more than ?100 Hz), but its mechanisms of action are not well-understood. Previous studies indicate that high-frequency stimulation is less effective when the stimulation train is temporally irregular. The purpose of this study was to determine the specific characteristics of temporally irregular stimulus trains that reduce their effectiveness: long pauses, bursts, or irregularity per se. We isolated these characteristics in stimulus trains and conducted intraoperative measurements of postural tremor in eight volunteers. Tremor varied significantly across stimulus conditions (P < 0.015), and stimulus trains with pauses were significantly less effective than stimulus trains without (P < 0.002). There were no significant differences in tremor between trains with or without bursts or between trains that were irregular or periodic. Thus the decreased effectiveness of temporally irregular DBS trains is due to long pauses in the stimulus trains, not the degree of temporal irregularity alone. We also conducted computer simulations of neuronal responses to the experimental stimulus trains using a biophysical model of the thalamic network. Trains that suppressed tremor in volunteers also suppressed fluctuations in thalamic transmembrane potential at the frequency associated with cerebellar burst-driver inputs. Clinical and computational findings indicate that DBS suppresses tremor by masking burst-driver inputs to the thalamus and that pauses in stimulation prevent such masking. Although stimulation of other anatomic targets may provide tremor suppression, we propose that the most relevant neuronal targets for effective tremor suppression are the afferent cerebellar fibers that terminate in the thalamus.

Birdno, Merrill J.; Kuncel, Alexis M.; Dorval, Alan D.; Turner, Dennis A.; Gross, Robert E.



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

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.



Status Epilepticus Induces Vasogenic Edema via Tumor Necrosis Factor-?/ Endothelin-1-Mediated Two Different Pathways.  


Status epilepticus (SE) induces vasogenic edema in the piriform cortex with disruptions of the blood-brain barrier (BBB). However, the mechanisms of vasogenic edema formation following SE are still unknown. Here we investigated the endothelin B (ETB) receptor-mediated pathway of SE-induced vasogenic edema. Following SE, the release of tumor necrosis factor-? (TNF-?) stimulated endothelin-1 (ET-1) release and expression in neurons and endothelial cells. In addition, TNF-?-induced ET-1 increased BBB permeability via ETB receptor-mediated endothelial nitric oxide synthase (eNOS) activation in endothelial cells. ETB receptor activation also increased intracellular reactive oxygen species by NADPH oxidase production in astrocytes. These findings suggest that SE results in BBB dysfunctions via endothelial-astroglial interactions through the TNF-?-ET-1-eNOS/NADPH oxidase pathway, and that these ETB receptor-mediated interactions may be an effective therapeutic strategy for vasogenic edema in various neurological diseases. PMID:24040253

Kim, Ji-Eun; Ryu, Hea Jin; Kang, Tae-Cheon



Status Epilepticus Induces Vasogenic Edema via Tumor Necrosis Factor-?/ Endothelin-1-Mediated Two Different Pathways  

PubMed Central

Status epilepticus (SE) induces vasogenic edema in the piriform cortex with disruptions of the blood-brain barrier (BBB). However, the mechanisms of vasogenic edema formation following SE are still unknown. Here we investigated the endothelin B (ETB) receptor-mediated pathway of SE-induced vasogenic edema. Following SE, the release of tumor necrosis factor-? (TNF-?) stimulated endothelin-1 (ET-1) release and expression in neurons and endothelial cells. In addition, TNF-?-induced ET-1 increased BBB permeability via ETB receptor-mediated endothelial nitric oxide synthase (eNOS) activation in endothelial cells. ETB receptor activation also increased intracellular reactive oxygen species by NADPH oxidase production in astrocytes. These findings suggest that SE results in BBB dysfunctions via endothelial-astroglial interactions through the TNF-?-ET-1-eNOS/NADPH oxidase pathway, and that these ETB receptor-mediated interactions may be an effective therapeutic strategy for vasogenic edema in various neurological diseases.

Kim, Ji-Eun; Ryu, Hea Jin; Kang, Tae-Cheon



Vasogenic edema and VEGF expression in a rat two-vein occlusion model.  


Vasogenic edema plays an important etiologic role in the pathogenesis of cerebral venous circulation disturbances (CVCDs). Since vascular endothelial growth factor (VEGF) is a major mediator in angiogenesis and vascular permeability, including induction of vasogenic edema, the present study was undertaken to investigate whether it has any relevance to CVCDs. Male Wistar rats (n = 15) were used. Two adjacent cortical veins were occluded photochemically using rose bengal dye and fiberoptic illumination, with evaluation 24 hours thereafter by magnetic resonance imaging (MRI). Each brain was removed from the skull immediately after MRI and processed for hematoxylin-eosin staining (H&E staining) of sections for histopathology and comparison with MRI data. VEGF expression as demonstrated immunohistochemically appeared to coincide with vasogenic edema, diagnosed as high intensity areas on apparent diffusion coefficient of water (ADCw) maps. On the basis of these data, we conclude that VEGF is related to formation of vasogenic edema in the acute stage of CVCD. PMID:14753438

Kimura, R; Nakase, H; Sakaki, T; Taoka, T; Tsuji, T



[Bone marrow edema syndrome (BMES)].  


Bone marrow edema (BME) syndrome represents a pathologic accumulation of interstitial fluid in bone - with a traumatic BME being differentiated from a non-traumatic, often ischemic, and a reactive as well as a mechanical BME. Atraumatic/ischemic BME is inconsistently described as a separate entity or as a reversible preliminary stage of osteonecrosis (ON). However, there is always the risk of transformation of BME into ON and subsequent joint destruction. The most common sites of BME are the hip, knee, and ankle. Magnetic resonance imaging is the diagnostic gold standard. Differential diagnoses of the transient BME as osteonecrosis, osteochondrosis dissecans, and a reflex dystrophy should be considered. Conservative or surgical treatment is considered, depending on the etiology of BME. BME syndrome is generally treated conservatively. Infusion of prostacycline or bisphosphonates is a promising option. Ischemic BME and early stages of ON can be successfully treated by core decompression. A combination of both treatment options may also offer advantages. PMID:23460121

Craiovan, B S; Baier, C; Grifka, J; Götz, J; Schaumburger, J; Beckmann, J



Minocycline reduces lipopolysaccharide-induced neurological dysfunction and brain injury in the neonatal rat.  


Preferential brain white matter injury and hypomyelination induced by intracerebral administration of the endotoxin lipopolysaccharide (LPS) in the neonatal rat brain has been characterized as associated with the activation of microglia. To examine whether inhibition of microglial activation might provide protection against LPS-induced brain injury and behavioral deficits, minocycline (45 mg/kg) was administered intraperitoneally 12 hr before and immediately after an LPS (1 mg/kg) intracerebral injection in postnatal day 5 (P5) Sprague-Dawley rats and then every 24 hr for 3 days. Brain injury and myelination were examined on postnatal day 21 and the tests for neurobehavioral toxicity were carried out from P3 to P21. LPS administration resulted in severe white matter injury, enlarged ventricles, deficits in the hippocampus, loss of oligodendrocytes and tyrosine hydroxylase neurons, damage to axons and dendrites, and impaired myelination as indicated by the decrease in myelin basic protein immunostaining in the P21 rat brain. LPS administration also significantly affected physical development (body weight) and neurobehavioral performance, such as righting reflex, wire hanging maneuver, cliff avoidance, locomotor activity, gait analysis, and responses in the elevated plus-maze and passive avoidance task. Treatment with minocycline significantly attenuated the LPS-induced brain injury and improved neurobehavioral performance. The protective effect of minocycline was associated with its ability to attenuate LPS-induced microglial activation. These results suggest that inhibition of microglial activation by minocycline may have long-term protective effects in the neonatal brain on infection-induced brain injury and associated neurologic dysfunction in the rat. PMID:16118791

Fan, Lir-Wan; Pang, Yi; Lin, Shuying; Tien, Lu-Tai; Ma, Tangeng; Rhodes, Philip G; Cai, Zhengwei



Reduced Ischemic Brain Injury in Interleukin1? Converting Enzyme-Deficient Mice  

Microsoft Academic Search

A variety of recent studies suggest a role for both inflammatory cytokines such as interleukin-1 beta (IL-1?), and apoptosis in ischemic brain injury. Because IL-1? converting enzyme (ICE) is required for the conversion of proIL-1? to its biologically active form, and has homology with proteins that regulate apoptosis in invertebrates, we studied the effect of cerebral ischemia on brain injury

Gerald P Schielke; Guo-Yuan Yang; Brenda D Shivers; A Lorris Betz



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

Microsoft Academic Search

GM1 gangliosidosis is a glycosphingolipid (GSL) lysosomal storage disease caused by a genetic deficiency of acid b-galactosidase (b-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

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



Absence of TLR4 Reduces Neurovascular Unit and Secondary Inflammatory Process after Traumatic Brain Injury in Mice  

PubMed Central

Background Traumatic brain injury (TBI) initiates a neuroinflammatory cascade that contributes to neuronal damage and behavioral impairment. Toll-like receptors (TLRs) are signaling receptors in the innate immune system, although emerging evidence indicates their role in brain injury. We have therefore investigated the role played by TLR4 signaling pathway in the development of mechanisms of secondary inflammatory process in traumatic brain injury (TBI) differ in mice that lack a functional TLR4 signaling pathway. Methods/Principal Findings Controlled cortical impact injury was performed on TLR4 knockout (KO) mice (C57BL/10ScNJ) and wild-type (WT) mice (C57BL/10ScNJ). TBI outcome was evaluated by determination of infarct volume and assessment of neurological scores. Brains were collected at 24 h after TBI. When compared to WT mice, TLR4 KO mice had lower infarct volumes and better outcomes in neurological and behavioral tests (evaluated by EBST and rotarod test). Mice that lacked TLR4 had minor expression of TBI-induced GFAP, Chymase, Tryptase, IL-1?, iNOS, PARP and Nitrotyrosine mediators implicated in brain damage. The translocation of expression of p-JNK, I?B-? and NF-?B pathway were also lower in brains from TLR4 KO mice. When compared to WT mice, resulted in significant augmentation of all the above described parameters. In addition, apoptosis levels in TLR4 KO mice had minor expression of Bax while on the contrary with Bcl-2. Conclusions/Significance Our results clearly demonstrated that absence of TLR4 reduces the development of neuroinflammation, tissues injury events associated with brain trauma and may play a neuroprotective role in TBI in mice.

Campolo, Michela; Genovese, Tiziana; Esposito, Emanuela; Cuzzocrea, Salvatore



Targeted Over-Expression of Glutamate Transporter 1 (GLT-1) Reduces Ischemic Brain Injury in a Rat Model of Stroke  

PubMed Central

Following the onset of an ischemic brain injury, the excitatory neurotransmitter glutamate is released. The excitotoxic effects of glutamate are a major contributor to the pathogenesis of a stroke. The aim of this study was to examine if overexpression of a glutamate transporter (GLT-1) reduces ischemic brain injury in a rat model of stroke. We generated an adeno-associated viral (AAV) vector expressing the rat GLT-1 cDNA (AAV-GLT1). Functional expression of AAV-GLT1 was confirmed by increased glutamate clearance rate in non-stroke rat brain as measured by in vivo amperometry. AAV-GLT1 was injected into future cortical region of infarction 3 weeks prior to 60 min middle cerebral artery occlusion (MCAo). Tissue damage was assessed at one and two days after MCAo using TUNEL and TTC staining, respectively. Behavioral testing was performed at 2, 8 and 14 days post-stroke. Animals receiving AAV-GLT1, compared to AAV-GFP, showed significant decreases in the duration and magnitude of extracellular glutamate, measured by microdialysis, during the 60 minute MCAo. A significant reduction in brain infarction and DNA fragmentation was observed in the region of AAV-GLT1 injection. Animals that received AAV-GLT1 showed significant improvement in behavioral recovery following stroke compared to the AAV-GFP group. We demonstrate that focal overexpression of the glutamate transporter, GLT-1, significantly reduces ischemia-induced glutamate overflow, decreases cell death and improves behavioral recovery. These data further support the role of glutamate in the pathogenesis of ischemic damage in brain and demonstrate that targeted gene delivery to decrease the ischemia-induced glutamate overflow reduces the cellular and behavioral deficits caused by stroke.

Hinzman, Jason; Wires, Emily M.; Chiocco, Matthew J.; Howard, Douglas B.; Shen, Hui; Gerhardt, Greg; Hoffer, Barry J.; Wang, Yun



Mild Hypothermia Reduces Tissue Plasminogen Activator-Related Hemorrhage and Blood Brain Barrier Disruption After Experimental Stroke.  


Therapeutic hypothermia has shown neuroprotective promise, but whether it can be used to improve outcome in stroke has yet to be determined in patients. Recombinant tissue plasminogen activator (rt-PA) is only given to a minority of patients with acute ischemic stroke, and is not without risk, namely significant brain hemorrhage. We explored whether mild hypothermia, in combination with rt-PA, influences the safety of rt-PA. Mice were subjected to middle cerebral artery occlusion (MCAO) using a filament model, followed by 24 hours reperfusion. Two paradigms were studied. In the first paradigm, cooling and rt-PA treatment began at the same time upon reperfusion, whereas in the second paradigm, cooling began soon after ischemia onset, and rt-PA began after re-warming and upon reperfusion. Experimental groups included: tPA treatment at normothermia (37°C), rt-PA treatment at hypothermia (33°C), no rt-PA at normothermia, and no rt-PA treatment at hypothermia. Infarct size, neurological deficit scores, blood brain barrier (BBB) permeability, brain hemorrhage, and expression of endogenous tissue plasminogen activator (tPA) and its inhibitor, plasminogen activator inhibitor (PAI-1) were assessed. For both paradigms, hypothermia reduced infarct size and neurological deficits compared to normothermia, regardless of whether rt-PA was given. rt-PA treatment increased brain hemorrhage and BBB disruption compared to normothermia, and this was prevented by cooling. However, mortality was higher when rt-PA and cooling were administered at the same time, beginning 1-2 hours post MCAO. Endogenous tPA expression was reduced in hypothermic mice, whereas PAI-1 levels were unchanged by cooling. In the setting of rt-PA treatment, hypothermia reduces brain hemorrhage, and BBB disruption, suggesting that combination therapy with mild hypothermia and rt-PA appears safe. PMID:23781399

Tang, Xian Nan; Liu, Liping; Koike, Maya A; Yenari, Midori A



?-Secretase Dependent Production of Intracellular Domains Is Reduced in Adult Compared to Embryonic Rat Brain Membranes  

PubMed Central

Background ?-Secretase is an intramembrane aspartyl protease whose cleavage of the amyloid precursor protein (APP) generates the amyloid ?-peptide (A?) and the APP intracellular domain. A? is widely believed to have a causative role in Alzheimer's disease pathogenesis, and therefore modulation of ?-secretase activity has become a therapeutic goal. Besides APP, more than 50 substrates of ?-secretase with different cellular functions during embryogenesis as well as adulthood have been revealed. Prior to ?-secretase cleavage, substrates are ectodomain shedded, producing membrane bound C-terminal fragments (CTFs). Principal Findings Here, we investigated ?-secretase cleavage of five substrates; APP, Notch1, N-cadherin, ephrinB and p75 neurotrophin receptor (p75-NTR) in membranes isolated from embryonic, young or old adult rat brain by analyzing the release of the corresponding intracellular domains (ICDs) or A?40 by western blot analysis and ELISA respectively. The highest levels of all ICDs and A? were produced by embryonic membranes. In adult rat brain only cleavage of APP and Notch1 could be detected and the A?40 and ICD production from these substrates was similar in young and old adult rat brain. The CTF levels of Notch1, N-cadherin, ephrinB and p75-NTR were also clearly decreased in the adult brain compared to embryonic brain, whereas the APP CTF levels were only slightly decreased. Conclusions In summary our data suggests that ?-secretase dependent ICD production is down-regulated in the adult brain compared to embryonic brain. In addition, the present approach may be useful for evaluating the specificity of ?-secretase inhibitors.

Franberg, Jenny; Karlstrom, Helena; Winblad, Bengt; Tjernberg, Lars O.; Frykman, Susanne



Reduced O-GlcNAcylation links lower brain glucose metabolism and tau pathology in Alzheimer's disease  

PubMed Central

It has been established for a long time that brain glucose metabolism is impaired in Alzheimer's disease. Recent studies have demonstrated that impaired brain glucose metabolism precedes the appearance of clinical symptoms, implying its active role in the development of Alzheimer's disease. However, the molecular mechanism by which this impairment contributes to the disease is not known. In this study, we demonstrated that protein O-GlcNAcylation, a common post-translational modification of nucleocytoplasmic proteins with ?-N-acetyl-glucosamine and a process regulated by glucose metabolism, was markedly decreased in Alzheimer's disease cerebrum. More importantly, the decrease in O-GlcNAc correlated negatively with phosphorylation at most phosphorylation sites of tau protein, which is known to play a crucial role in the neurofibrillary degeneration of Alzheimer's disease. We also found that hyperphosphorylated tau contained 4-fold less O-GlcNAc than non-hyperphosphorylated tau, demonstrating for the first time an inverse relationship between O-GlcNAcylation and phosphorylation of tau in the human brain. Downregulation of O-GlcNAcylation by knockdown of O-GlcNAc transferase with small hairpin RNA led to increased phosphorylation of tau in HEK-293 cells. Inhibition of the hexosamine biosynthesis pathway in rat brain resulted in decreased O-GlcNAcylation and increased phosphorylation of tau, which resembled changes of O-GlcNAcylation and phosphorylation of tau in rodent brains with decreased glucose metabolism induced by fasting, but not those in rat brains when protein phosphatase 2A was inhibited. Comparison of tau phosphorylation patterns under various conditions suggests that abnormal tau hyperphosphorylation in Alzheimer's disease brain may result from downregulation of both O-GlcNAcylation and protein phosphatase 2A. These findings suggest that impaired brain glucose metabolism leads to abnormal hyperphosphorylation of tau and neurofibrillary degeneration via downregulation of tau O-GlcNAcylation in Alzheimer's disease. Thus, restoration of brain tau O-GlcNAcylation and protein phosphatase 2A activity may offer promising therapeutic targets for treating Alzheimer's disease.

Liu, Fei; Shi, Jianhua; Tanimukai, Hitoshi; Gu, Jinhua; Gu, Jianlan; Grundke-Iqbal, Inge; Iqbal, Khalid



Properties of conditioned abducens nerve responses in a highly reduced in vitro brain stem preparation from the turtle.  


Previous work suggested that the cerebellum and red nucleus are not necessary for the acquisition, extinction, and reacquistion of the in vitro classically conditioned abducens nerve response in the turtle. These findings are extended in the present study by obtaining conditioned responses (CRs) in preparations that received a partial ablation of the brain stem circuitry. In addition to removing all tissue rostral to and including the midbrain and cerebellum, a transection was made just caudal to the emergence of the IXth nerve. Such ablations result in a 4-mm-thick section of brain stem tissue that functionally eliminates the sustained component of the unconditioned response (UR) while leaving only a phasic component. We refer to this region of brain stem tissue caudal to the IXth nerve as the "caudal premotor blink region." Neural discharge was recorded from the abducens nerve following a single shock unconditioned stimulus (US) applied to the ipsilateral trigeminal nerve. When the US was paired with a conditioned stimulus (CS) applied to the posterior eighth, or auditory, nerve using a delay conditioning paradigm, a positive slope of CR acquisition was recorded in the abducens nerve, and CR extinction was recorded when the stimuli were alternated. Resumption of paired stimuli resulted in reacquisition. Quantitative analysis of the CRs in preparations in which the caudal premotor blink region had been removed and those with cerebellar/red nucleus lesions showed that both types of preparations had abnormally short latency CR onsets compared with preparations in which these regions were intact. Preparations with brain stem transections had significantly earlier CR offsets as more CRs terminated as short bursts when compared with intact or cerebellar lesioned preparations. These data suggest that a highly reduced in vitro brain stem preparation from the turtle can be classically conditioned. Furthermore, the caudal brain stem is not a site of acquisition in this reduced preparation, but it contributes to the sustained activity of both the UR and CR. Finally, the unusually short CR onset latencies following lesions to the cerebellum are not further exacerbated by removal of the caudal brain stem. These studies suggest that convergence of CS and US synaptic inputs onto the abducens nerve reflex circuitry may underlie acquisition in this reduced preparation, but that mechanisms that control learned CR timing arise from the cerebellorubral system. PMID:10085351

Anderson, C W; Keifer, J



Cystoid macular edema induced by nab-paclitaxel.  


Cystoid macular edema (CME) is a rare complication of taxane-based chemotherapy. We encountered a patient who developed CME during treatment with nab-paclitaxel for metastatic breast cancer. Early detection of this disease enables continuation of appropriate treatment without reducing the quality of life for patients with end-stage disease. Physicians should be aware of this potential adverse effect, and should make changes to the treatment of patients as soon as possible. PMID:22592399

Tanaka, Yuko; Bando, Hiroko; Hara, Hisato; Ito, Yasuaki; Okamoto, Yoshifumi



Single administration of tripeptide ?-MSH(11-13) attenuates brain damage by reduced inflammation and apoptosis after experimental traumatic brain injury in mice.  


Following traumatic brain injury (TBI) neuroinflammatory processes promote neuronal cell loss. Alpha-melanocyte-stimulating hormone (?-MSH) is a neuropeptide with immunomodulatory properties, which may offer neuroprotection. Due to short half-life and pigmentary side-effects of ?-MSH, the C-terminal tripeptide ?-MSH(11-13) may be an anti-inflammatory alternative. The present study investigated the mRNA concentrations of the precursor hormone proopiomelanocortin (POMC) and of melanocortin receptors 1 and 4 (MC1R/MC4R) in naive mice and 15 min, 6, 12, 24, and 48 h after controlled cortical impact (CCI). Regulation of POMC and MC4R expression did not change after trauma, while MC1R levels increased over time with a 3-fold maximum at 12 h compared to naive brain tissue. The effect of ?-MSH(11-13) on secondary lesion volume determined in cresyl violet stained sections (intraperitoneal injection 30 min after insult of 1 mg/kg ?-MSH(11-13) or 0.9% NaCl) showed a considerable smaller trauma in ?-MSH(11-13) injected mice. The expression of the inflammatory markers TNF-? and IL-1? as well as the total amount of Iba-1 positive cells were not reduced. However, cell branch counting of Iba-1 positive cells revealed a reduced activation of microglia. Furthermore, tripeptide injection reduced neuronal apoptosis analyzed by cleaved caspase-3 and NeuN staining. Based on the results single ?-MSH(11-13) administration offers a promising neuroprotective property by modulation of inflammation and prevention of apoptosis after traumatic brain injury. PMID:23940690

Schaible, Eva-Verena; Steinsträßer, Arne; Jahn-Eimermacher, Antje; Luh, Clara; Sebastiani, Anne; Kornes, Frida; Pieter, Dana; Schäfer, Michael K; Engelhard, Kristin; Thal, Serge C



Adaptive decreases in amino acids (taurine in particular), creatine, and electrolytes prevent cerebral edema in chronically hyponatremic mice: Rapid correction (experimental model of central pontine myelinolysis) causes dehydration and shrinkage of brain  

Microsoft Academic Search

The experimental model of central pontine myelinolysis—chronic (4-day) hyponatremia induced by daily injections of hypotonic dextrose solutions and vasopressin followed by rapid correction with saline—was used in young fasted and thirsted mice. In normal controls, chronic fasting and thirsting lowered plasma and brain glucose levels and cerebral glycolytic and tricarboxylic acid cycle metabolic fluxes. The fasting state had little effect

Jean Holowach Thurston; Richard E. Hauhart; James S. Nelson



Reduced brain-derived neurotrophic factor in prefrontal cortex of patients with schizophrenia  

Microsoft Academic Search

Anatomical and molecular abnormalities of excitatory neurons in the dorsolateral prefrontal cortex (DLPFC) are found in schizophrenia. We hypothesized that brain-derived neurotrophic factor (BDNF), a protein capable of increasing pyramidal neuron spine density and augmenting synaptic efficacy of glutamate, may be abnormally expressed in the DLPFC of patients with schizophrenia. Using an RNase protection assay and Western blotting, we detected

C S Weickert; T M Hyde; B K Lipska; M M Herman; D R Weinberger; J E Kleinman



Brain imaging: Reduced sensitivity of RARE-derived techniques to susceptibility effects  

Microsoft Academic Search

Our goal was to evaluate the decreased sensitivity of RARE-derived pulse sequences to susceptibility effects. A variety of RARE-derived T2-weighted fast SE echo (FSE) sequences with echo trains from 6 to 16 were compared with conventional SE (CSE) sequences by means of MRI in phantoms (iron oxides), volunteers (n = 10), and patients (n = 13) with old hemorrhagic brain

P. Reimer; T. Allkemper; G. Schuierer; P. E. Peters



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...


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

ERIC Educational Resources Information Center

|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;…

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



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

SciTech Connect

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.

Schwartz, M.W.; Figlewicz, D.F.; Kahn, S.E.; Baskin, D.G.; Greenwood, M.R.; Porte, D. Jr. (Univ. of Washington, Seattle (USA))



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

ERIC Educational Resources Information Center

|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…

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



Tissue and electrode capacitance reduce neural activation volumes during deep brain stimulation  

Microsoft Academic Search

ObjectiveThe growing clinical acceptance of neurostimulation technology has highlighted the need to accurately predict neural activation as a function of stimulation parameters and electrode design. In this study we evaluate the effects of the tissue and electrode capacitance on the volume of tissue activated (VTA) during deep brain stimulation (DBS).

Christopher R. Butson; Cameron C. McIntyre



Activity Wheel Running Reduces Escape Latency and Alters Brain Monoamine Levels After Footshock  

Microsoft Academic Search

We examined the effects of chronic activity wheel running on brain monoamines and latency to escape foot shock after prior exposure to uncontrollable, inescapable foot shock. Individually housed young (?50 day) female Sprague-Dawley rats were randomly assigned to standard cages (sedentary) or cages with activity wheels. After 9–12 weeks, animals were matched in pairs on body mass. Activity wheel animals

R. K Dishman; K. J Renner; T. G Reigle; B. N Bunnell; K. A Burke; H. S Yoo; E. H Mougey; J. L Meyerhoff



Tau elevations in the brain extracellular space correlate with reduced amyloid-? levels and predict adverse clinical outcomes after severe traumatic brain injury  

PubMed Central

Axonal injury is believed to be a major determinant of adverse outcomes following traumatic brain injury. However, it has been difficult to assess acutely the severity of axonal injury in human traumatic brain injury patients. We hypothesized that microdialysis-based measurements of the brain extracellular fluid levels of tau and neurofilament light chain, two low molecular weight axonal proteins, could be helpful in this regard. To test this hypothesis, 100?kDa cut-off microdialysis catheters were placed in 16 patients with severe traumatic brain injury at two neurological/neurosurgical intensive care units. Tau levels in the microdialysis samples were highest early and fell over time in all patients. Initial tau levels were >3-fold higher in patients with microdialysis catheters placed in pericontusional regions than in patients in whom catheters were placed in normal-appearing right frontal lobe tissue (P?=?0.005). Tau levels and neurofilament light-chain levels were positively correlated (r?=?0.6, P?=?0.013). Neurofilament light-chain levels were also higher in patients with pericontusional catheters (P?=?0.04). Interestingly, initial tau levels were inversely correlated with initial amyloid-? levels measured in the same samples (r?=??0.87, P?=?0.000023). This could be due to reduced synaptic activity in areas with substantial axonal injury, as amyloid-? release is closely coupled with synaptic activity. Importantly, high initial tau levels correlated with worse clinical outcomes, as assessed using the Glasgow Outcome Scale 6 months after injury (r?=??0.6, P?=?0.018). Taken together, our data add support for the hypothesis that axonal injury may be related to long-term impairments following traumatic brain injury. Microdialysis-based measurement of tau levels in the brain extracellular space may be a useful way to assess the severity of axonal injury acutely in the intensive care unit. Further studies with larger numbers of patients will be required to assess the reproducibility of these findings and to determine whether this approach provides added value when combined with clinical and radiological information.

Magnoni, Sandra; Esparza, Thomas J.; Conte, Valeria; Carbonara, Marco; Carrabba, Giorgio; Holtzman, David M.; Zipfel, Greg J.; Stocchetti, Nino



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


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

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



Tacrolimus depresses local immune cell infiltration but fails to reduce cortical contusion volume in brain-injured rats.  


The immunosuppressant drug tacrolimus (FK-506) failed to show an anti-edematous effect despite suppressing pro-inflammatory cytokines in cerebrospinal fluid following focal traumatic brain injury. By questioning the role of the inflammatory response as a pharmacological target, we investigated the effects of FK-506 on immune cell infiltration in brain-injured rats. Following induction of a cortical contusion, male Sprague-Dawley rats received FK-506 or physiological saline intraperitoneally. Brains were removed at 24 h, 72 h or 7 days, respectively. Frozen brain sections (7 microm) were stained immunohistologically for markers of endothelial activation (intercellular adhesion molecule-1--ICAM-1), neutrophil infiltration (His-48), and microglial and macrophage activation (Ox-6; ED-1), respectively. Immunopositive cells were counted microscopically. Contusion volume (CV) was quantified morphometrically 7 days after trauma. Inflammatory response was confined to the ipsilateral cortex and hippocampal formation, predominating in the contusion and pericontusional cortex. Strongest ICAM-1 expression coincided with sustained granulocyte accumulation at 72h which was suppressed by FK-506. Ox-6+ cells prevailing at 72 h were also significantly reduced by FK-506. ED-1+ cells reaching highest intensity at 7 days were significantly attenuated at 72 h. Cortical CV was not influenced. FK-506 significantly decreased post-traumatic local inflammation which, however, was not associated with a reduction in cortical CV. These results question the importance of post-traumatic local immune cell infiltration in the secondary growth of a cortical contusion. PMID:17678714

Thomale, Ulrich W; Bender, Marcel; Casalis, Pablo; Rupprecht, Stefan; Griebenow, Martin; Neumann, Konrad; Woiciechowsky, Christian; Unterberg, Andreas W; Stover, John F



Approach to leg edema of unclear etiology.  


A common challenge for primary care physicians is to determine the cause and find an effective treatment for leg edema of unclear etiology. We were unable to find existing practice guidelines that address this problem in a comprehensive manner. This article provides clinically oriented recommendations for the management of leg edema in adults. We searched on-line resources, textbooks, and MEDLINE (using the MeSH term, "edema") to find clinically relevant articles on leg edema. We then expanded the search by reviewing articles cited in the initial sources. Our goal was to write a brief, focused review that would answer questions about the management of leg edema. We organized the information to make it rapidly accessible to busy clinicians. The most common cause of leg edema in older adults is venous insufficiency. The most common cause in women between menarche and menopause is idiopathic edema, formerly known as "cyclic" edema. A common but under-recognized cause of edema is pulmonary hypertension, which is often associated with sleep apnea. Venous insufficiency is treated with leg elevation, compressive stockings, and sometimes diuretics. The initial treatment of idiopathic edema is spironolactone. Patients who have findings consistent with sleep apnea, such as daytime somnolence, loud [corrected] snoring, or neck circumference >17 inches, should be evaluated for pulmonary hypertension with an echocardiogram. If time is limited, the physician must decide whether the evaluation can be delayed until a later appointment (eg, an asymptomatic patient with chronic bilateral edema) or must be completed at the current visit (eg, a patient with dyspnea or a patient with acute edema [<72 hours]). If the evaluation should be conducted at the current visit, the algorithm shown in Figure 1 could be used as a guide. If the full evaluation could wait for a subsequent visit, the patient should be examined briefly to rule out an obvious systemic cause and basic laboratory tests should be ordered for later review (complete blood count, urinalysis, electrolytes, creatinine, blood sugar, thyroid stimulating hormone, and albumin). PMID:16513903

Ely, John W; Osheroff, Jerome A; Chambliss, M Lee; Ebell, Mark H


Local and systemic treatments for acute edema after burn injury: a systematic review of the literature.  


Burn injury is a complex trauma that results in local and generalized edema. Edema fluid limits the exchange of vital nutrients in healing the burn wound and will compromise vulnerable tissues. Although the importance of edema control in tissue salvage is recognized, treatments targeted at edema control have not been critically reviewed. Thus, the objective was to assess the evidence for the effectiveness of local and systemic treatments for edema management immediately after burn injury. Searches for randomized controlled trials were conducted of online databases, research and thesis registers, and grey literature repositories. Handsearches included journals, bibliographies, and proceedings. Authors were contacted to clarify and submit extra study details. Eight studies were included. Management of acute major burn resuscitation including colloid increases lung edema (mean difference [MD], 0.04 ml/ml alv vol; 95% confidence interval [CI], 0.03-0.04; P < .00001) and mortality (risk ratio, 3.67; 95% CI, 1.16-11.58; P = .03). Continuous administration of vitamin C in acute burn resuscitation reduces local wound edema (MD, -3.50 ml/g; 95% CI, -4.63 to -2.37; P < .00001) and systemic fluid retention (MD, -8.60 kg; 95% CI, -13.47 to -3.73; P = .0005). Local acute hand burn edema is reduced (MD, -29.00 ml; 95% CI, -53.14 to -4.86; P = .02), and active hand motion increased (MD, 10.00°; 95% CI, 4.58-15.42; P = .0003), using electrical stimulation with usual physiotherapy. Each review outcome was based on a small single-facility study. Thus, future research in intervention for acute burn edema must focus on multicentre trials and validation of outcome measures in the burn population. PMID:21252688

Edgar, Dale Wesley; Fish, Joel S; Gomez, Manuel; Wood, Fiona Melanie


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

PubMed Central

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.

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



S-Nitrosoglutathione reduces inflammation and protects brain against focal cerebral ischemia in a rat model of experimental stroke.  


Preservation of endothelial functions with low-dose nitric oxide (NO) and inhibition of excessive production of NO from inducible NO synthase (iNOS) is a potential therapeutic approach for acute stroke. Based on this hypothesis, an NO modulator, S-nitrosoglutathione (GSNO) was used, which provided neuroprotection in a rat model of focal cerebral ischemia. Administration of GSNO after the onset of ischemia reduced infarction and improved cerebral blood flow. To understand the mechanism of protection, the involvement of inflammation in ischemic brain injury was examined. Treatment with GSNO reduced the expression of tumor necrosis factor-alpha, interleukin-1beta, and iNOS; inhibited the activation of microglia/macrophage (ED1, CD11-b); and downregulated the expression of leukocyte function-associated antigen-1 and intercellular adhesion molecule-1 in the ischemic brain. The number of apoptotic cells (including neurons) and the activity of caspase-3 were also decreased after GSNO treatment. Further, the antiinflammatory effect of GSNO on expression of iNOS and activation of NF-kappaB machinery in rat primary astrocytes and in the murine microglial cell line BV2 was tested. Cytokine-mediated expression of iNOS and activation of NF-kappaB were inhibited by GSNO treatment. That GSNO protects the brain against ischemia/reperfusion injury by modulating NO systems, resulting in a reduction in inflammation and neuronal cell death was documented by the results. PMID:15647746

Khan, Mushfiquddin; Sekhon, Bipanjeet; Giri, Shailendra; Jatana, Manu; Gilg, Anne G; Ayasolla, Kamesh; Elango, Chinnasamy; Singh, Avtar K; Singh, Inderjit



Mesencephalic astrocyte-derived neurotrophic factor (MANF) reduces ischemic brain injury and promotes behavioral recovery in rats  

PubMed Central

Mesencephalic astrocyte-derived neurotrophic factor (MANF), also known as Arginine-rich, Mutated in Early Stage of Tumors (ARMET), is a secreted protein which reduces endoplasmic reticulum (ER) stress. Previous studies have shown that MANF mRNA expression and protein levels are increased in the cerebral cortex after brain ischemia, a condition which induces ER stress. The function of MANF during brain ischemia is still not known. The purpose of this study was to examine the protective effect of MANF after ischemic brain injury. Recombinant human MANF was administrated locally to the cerebral cortex before a 60-min middle cerebral artery occlusion (MCAo) in adult rats. Triphenyltetrazolium chloride (TTC) staining indicated that pretreatment with MANF significantly reduced the volume of infarction at two days after MCAo. MANF also attenuated TUNEL labeling, a marker of cell necrosis/apoptosis, in the ischemic cortex. Animals receiving MANF pretreatment demonstrated a decrease in body asymmetry and neurological score as well as an increase in locomotor activity after MCAo. Taken together, these data suggest that MANF has neuroprotective effects against cerebral ischemia, possibly through the inhibition of cell necrosis/apoptosis in cerebral cortex.

Airavaara, Mikko; Shen, Hui; Kuo, Chi-Chung; Peranen, Johan; Saarma, Mart; Hoffer, Barry; Wang, Yun



Caffeic Acid Phenethyl Ester Protects Blood-Brain Barrier Integrity and Reduces Contusion Volume in Rodent Models of Traumatic Brain Injury  

PubMed Central

Abstract A number of studies have established a deleterious role for inflammatory molecules and reactive oxygen species (ROS) in the pathology of traumatic brain injury (TBI). Caffeic acid phenethyl ester (CAPE) has been shown to exert both antioxidant and anti-inflammatory effects. The primary objective of the present study was to examine if CAPE could be used to reduce some of the pathological consequences of TBI using rodent models. Male Sprague-Dawley rats and C57BL/6 mice were subjected to controlled cortical impact (CCI) injury. Blood–brain barrier (BBB) integrity was assessed by examining claudin-5 expression and the extravasation of Evans blue dye. The effect of post-injury CAPE administration on neurobehavioral function was assessed using vestibulomotor, motor, and two hippocampus-dependent learning and memory tasks. We report that post-TBI administration of CAPE reduces Evans blue extravasation both in rats and mice. This improvement was associated with preservation of the levels of the tight junction protein claudin-5. CAPE treatment did not improve performance in either vestibulomotor/motor function (tested using beam balance and foot-fault tests), or in learning and memory function (tested using the Morris water maze and associative fear memory tasks). However, animals treated with CAPE were found to have significantly less cortical tissue loss than vehicle-treated controls. These findings suggest that CAPE may provide benefit in the treatment of vascular compromise following central nervous system injury.

Zhao, Jing; Pati, Shibani; Redell, John B.; Zhang, Min; Moore, Anthony N.



Reduced N400 semantic priming effects in adult survivors of paediatric and adolescent traumatic brain injury.  


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 individuals matched for various demographic variables and behavioural language performance. Participants in the TBI group had a recorded history of paediatric or adolescent TBI involving injury mechanisms associated with diffuse white matter pathology, while participants in the control group never sustained any insult to the brain. A comparison of N400 Mean Amplitudes elicited during three experimental conditions with varying semantic relatedness between the prime and target stimuli (congruent, semantically related, unrelated) revealed a significantly smaller N400 response in the unrelated condition in the TBI group, indicating residual linguistic processing deviations when processing demands required the quick detection of a between-category (unrelated) violation of semantic expectancy. PMID:22819620

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



Effects of photobiostimulation on edema and hemorrhage induced by Bothrops moojeni venom  

Microsoft Academic Search

Antivenom (AV) treatment has been ineffective in neutralizing the severe local fast-developing tissue damage following snake-bite\\u000a envenoming. We studied the effectiveness of low-level laser (LLL) and light-emitting diode (LED) irradiation alone or in combination\\u000a with AV in reducing local edema formation and hemorrhage induced by Bothrops moojeni venom (BmV) in mice. Edema formation was induced by injection of 1 ?g per

Nikele Nadur-Andrade; Ana Maria Barbosa; Fernando Pereira Carlos; Carlos José Lima; José Carlos Cogo; Stella Regina Zamuner


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

SciTech Connect

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.

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.



Serum brain-derived neurotrophic factor is associated with reduced appetite in healthy older adults  

Microsoft Academic Search

Objective: Loss of appetite and body mass are common in older adults and are associated with negative consequences. Research indicates\\u000a that these processes likely involve increases in serum brain-derived neurotrophic factor (BDNF). Animal and human models demonstrate\\u000a that BDNF may serve a regulatory function in food intake, but no study has addressed the possibility that BDNF may be involved\\u000a in

K. Stanek; J. Gunstad; T. Leahey; E. Glickman; T. Alexander; M. B. Spitznagel; J. Juvancic-Heltzel; L. Murray



Transplanted adrenal chromaffin cells in rat brain reduce lesion-induced rotational behaviour  

Microsoft Academic Search

Rats with unilateral lesions of substantia nigra pars compacta (SN), the area of the brain containing most dopamine-containing neurones, are a widely recognized animal model of Parkinson's disease1-4. When given dopamine agonists such as apomorphine, such rats rotate in a direction contralateral to the lesion, presumably because of the development of supersensitive dopamine receptors in the striatum ipsilateral to the

William J. Freed; John M. Morihisa; Eleanor Spoor; Barry J. Hoffer; Lars Olson; Ake Seiger; Richard Jed Wyatt



Reduced serum concentrations of nerve growth factor, but not brain-derived neurotrophic factor, in chronic cannabis abusers.  


Chronic cannabis use produces effects within the central nervous system (CNS) which include deficits in learning and attention tasks and decreased brain volume. Neurotrophins, in particular nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), are proteins that serve as survival factors for CNS neurons. Deficits in the production and utilization of these proteins can lead to CNS dysfunctions including those associated with cannabis abuse. In this study we measured by enzyme-linked immunosorbent assay (ELISA) the NGF and BDNF serum levels in two groups of subjects: cannabis-dependent patients and healthy subjects. We found that NGF serum levels were significantly reduced in cannabis abusers as compared to healthy subjects. These findings indicate that NGF may have a role in the central action of cannabis and potentially in the neurotoxicity induced by this drug. These data also suggest that chronic cannabis consumption may be a risk factor for developing psychosis among drug users. PMID:18774699

Angelucci, Francesco; Ricci, Valerio; Spalletta, Gianfranco; Pomponi, Massimiliano; Tonioni, Federico; Caltagirone, Carlo; Bria, Pietro



ERK1/2 in the brain mediates the effects of central resistin on reducing thermogenesis in brown adipose tissue.  


We investigated the role of ERK1/2 in the brain on the effects of centrally administered resistin on thermogenesis. Resistin (7 ?g) into anaesthetized rats significantly decreased brown adipose tissue temperature by 1.0 ± 0.4 °C (P < 0.005). This response was significantly attenuated by over 60% when ERK1/2 was inhibited by U0126 (7 ?g) (P < 0.05). Resistin reduced uncoupling protein-1 mRNA expression (0.11 ± 0.01 vs 1.24 ± 0.85 resistin vs control respectively) and the expression of peroxisome proliferator-activated receptor gamma co-activator 1-?, but the effects were not statistically significant. The results suggest that ERK1/2 in the brain contributes to resistin's effects on thermogenesis. PMID:24044038

Kosari, Samin; Camera, Donny M; Hawley, John A; Stebbing, Martin; Badoer, Emilio



Impact of edema and seed movement on the dosimetry of prostate seed implants  

PubMed Central

This article summarizes current knowledge concerning the characterization of prostatic edema and intra-prostatic seed movement as these relate to dosimetry of permanent prostate implants, and reports the initial application to clinical data of a new edema model used in calculating pre- and post-implant dose distributions. Published edema magnitude and half-life parameters span a broad range depending on implant technique and measurement uncertainty, hence clinically applicable values should be determined locally. Observed intra-prostatic seed movements appear to be associated with particular aspects of implant technique and could be minimized by technique modification. Using an extended AAPM TG-43 formalism incorporating the new edema model, relative dose error RE associated with neglecting edema was calculated for three I-125 seed implants (18.9 cc, 37.6 cc, 60.2 cc) performed at our center. Pre- and post-plan RE average values and ranges in a 50 × 50 × 50 mm3 calculation volume were similar at ~2% and ~0–3.5%, respectively, for all three implants; however, the spatial distribution of RE varied for different seed configurations. Post-plan values of D90 and V100 for prostate were reduced by ~2% and ~1%, respectively. In cases where RE is not clinically negligible as a consequence of large edema magnitude and / or use of Pd-103 seeds, the dose calculation method demonstrated here can be applied to account for edema explicitly and there by improve the accuracy of clinical dose estimates.

Sloboda, Ron S.; Usmani, N.; Monajemi, T. T.; Liu, D. M-C



Angioneurotic edema from an oral contraceptive.  


To the editor:--A 29-year-old white woman was seen April 17, 1967, with a severe angioneurotic edema of the face which had developed suddenly. She had taken aspirin for the two previous days and ethynodiol diacetate with mestranol (Ovulen) for 15 days. Treatment with epinephrine and dexamethasone administered parenterally and diphenhydramine orally did not benefit. Oral contraceptive thereapy was discontinued, and the edema subsided five days later. On April 25, she was asymptomatic. Aspirin had produced no ill effect, and oral contraceptive therapy was started again. After four days edema of the uvula and soft palate appeared, and again medication did not give relief. The edema subsided after a few days during which the patient abstained from cosmetics, tooth pastes, and all allergenic dietary items. Later she resumed all foods and contactants, but has taken no oral contraceptives, and has remained asymptomatic. PMID:12254853

Wolf, R L



Novel inhibitors of Anthrax edema factor  

PubMed Central

Several pathogenic bacteria produce adenylyl cyclase toxins, such as the edema factor (EF) of Bacillus anthracis. These disturb cellular metabolism by catalyzing production of excessive amounts of the regulatory molecule cAMP. Here, a structure-based method, where a 3D- pharmacophore that fit the active site of EF was constructed from fragments, was used to identify non-nucleotide inhibitors of EF. A library of small molecule fragments was docked to the EF- active site in existing crystal structures and those with the highest HINT scores were assembled into a 3D-pharmacophore. About 10,000 compounds, from over 2.7 million compounds in the ZINC database, had a similar molecular framework. These were ranked according to their docking scores, using methodology that was shown to achieve maximum accuracy (i.e., how well the docked position matched the experimentally determined site for ATP analogues in crystal structures of the complex). Finally, 19 diverse compounds with the best AutoDock binding/docking scores were assayed in a cell based assay for their ability to reduce cAMP secretion induced by EF. Four of the test compounds, from different structural groups, inhibited in the low micromolar range. One of these has a core structure common to phosphatase inhibitors previously identified by high-throughput assays of a diversity library. Thus, the fragment based pharmacophore identified a small number of diverse compounds for assay, and greatly enhanced the selection process of advanced lead compounds for combinatorial design.

Chen, Deliang; Misra, Milind; Sower, Laurie; Peterson, Johnny W.; Kellogg, Glen E.; Schein, Catherine H.



Keyhole and zero-padding approaches for reduced-encoding diffusion tensor imaging of the mouse brains?  

PubMed Central

Keyhole diffusion tensor imaging (keyhole DTI) was previously proposed in cardiac imaging to reconstruct DTI maps from the reduced phase-encoding images. To evaluate the feasibility of keyhole DTI in brain imaging, keyhole and zero-padding DTI algorithms were employed on in vivo mouse brain. The reduced phase-encoding portion, also termed as the sharing rate, was varied from 50% to 90% of the full k-space. Our data showed that zero-padding DTI resulted in decreased fractional anisotropy (FA) and decreased mean apparent diffusion coefficient (mean ADC) in white matter (WM) regions. Keyhole DTI showed a better edge preservation on mean ADC maps but not on FA maps as compared to the zero-padding DTI. When increasing the sharing rate in keyhole approach, an underestimation of FA and an over- or underestimation of mean ADC were measured in WM depending on the selected reference image. The inconsistency of keyhole DTI may add a challenge for the wide use of this modality. However, with a carefully selected directive diffusion-weighted image to serve as the reference image in the keyhole approach, this study demonstrated that one may obtain DTI indices of reduced-encoding images with high consistency to those derived with full k-space DTI.

Sun, Shu-Wei; Chen, Yu-Jen; Chou, Kun-Hsien; Chu, Woei-Chyn



Specific blood flow reducing effects of hyperoxaemia on high flow capillaries in the pig brain.  


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

Sjöberg, F; Gustafsson, U; Eintrei, C



Cyanamide reduces brain catalase and ethanol-induced locomotor activity: is there a functional link?  

Microsoft Academic Search

The present study was designed in an attempt to assess a previously suggested role of brain catalase activity in ethanol-induced\\u000a behaviour by examining ethanol-induced locomotor activity in cyanamide-treated mice. Mice were pretreated with IP injections\\u000a of the catalase inhibitor cyanamide (3.75, 7.5, 15, 30 or 45?mg\\/kg) or saline. Following this treatment, animals in each group\\u000a received IP injections of ethanol

Carles Sanchis-Segura; Marta Miquel; Mercè Correa; Carlos M. G. Aragon



L-alpha-aminoadipate reduces glutamate release from brain tissue exposed to combined oxygen and glucose deprivation.  


The effect of the glutamate analogue L-alpha-aminoadipate (alpha AA) on the release of glutamate and gamma-aminobutyric acid (GABA) from rat hippocampal slices was investigated in vitro. Oxygen/glucose deprivation caused a large release of glutamate and GABA. alpha AA added during energy deprivation reduced the glutamate release in a dose-dependent manner (56% reduction at 5 mM), whereas GABA release was unchanged. We speculate that ischemic glutamate release from the brain is mediated by a low affinity transport mechanism that is blocked by alpha AA. PMID:9183295

Haugstad, T S; Langmoen, I A



Reduced Matrix Metalloproteinase-9 Activity and Cell Death After Global Ischemia in the Brain Preconditioned with Hyperbaric Oxygen  

Microsoft Academic Search

\\u000a Matrix metalloproteinase-9 (MMP-9) plays a deleterious role in cell death after global cerebral ischemia. Preconditioning\\u000a with hyperbaric oxygen (HBO-PC) reduces neuronal damage in the post-ischemic brain; however, its effect on ischemia-induced\\u000a increase in MMP-9 activity and expression remains unexplored.\\u000a \\u000a \\u000a We investigated effects of HBO-PC on alterations in MMP-9 activity\\/tissue expression accompanying neuronal death after transient\\u000a global cerebral ischemia.\\u000a \\u000a \\u000a \\u000a Male SD

Robert P. Ostrowski; Vikram Jadhav; Wanqiu Chen; John H. Zhang


CDC grand rounds: reducing severe traumatic brain injury in the United States.  


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



Calorie restriction reduces the influence of glucoregulatory dysfunction on regional brain volume in aged rhesus monkeys.  


Insulin signaling dysregulation is related to neural atrophy in hippocampus and other areas affected by neurovascular and neurodegenerative disorders. It is not known if long-term calorie restriction (CR) can ameliorate this relationship through improved insulin signaling or if such an effect might influence task learning and performance. To model this hypothesis, magnetic resonance imaging was conducted on 27 CR and 17 control rhesus monkeys aged 19-31 years from a longitudinal study. Voxel-based regression analyses were used to associate insulin sensitivity with brain volume and microstructure cross-sectionally. Monkey motor assessment panel (mMAP) performance was used as a measure of task performance. CR improved glucoregulation parameters and related indices. Higher insulin sensitivity predicted more gray matter in parietal and frontal cortices across groups. An insulin sensitivity × dietary condition interaction indicated that CR animals had more gray matter in hippocampus and other areas per unit increase relative to controls, suggesting a beneficial effect. Finally, bilateral hippocampal volume adjusted by insulin sensitivity, but not volume itself, was significantly associated with mMAP learning and performance. These results suggest that CR improves glucose regulation and may positively influence specific brain regions and at least motor task performance. Additional studies are warranted to validate these relationships. PMID:22415875

Willette, Auriel A; Bendlin, Barbara B; Colman, Ricki J; Kastman, Erik K; Field, Aaron S; Alexander, Andrew L; Sridharan, Aadhavi; Allison, David B; Anderson, Rozalyn; Voytko, Mary-Lou; Kemnitz, Joseph W; Weindruch, Richard H; Johnson, Sterling C



Repeated 4-aminopyridine seizures reduce parvalbumin content in the medial mammillary nucleus of the rat brain.  


Parvalbumin (Pv) containing fast spiking neurons play a crucial role in synchronizing the activity of excitatory neuronal circuits in the brain. Alterations of parvalbumin content in these neurons can affect their spike characteristics and, ultimately, may increase the susceptibility of neuronal circuits to epileptic seizures. In the present study, we examined whether repeated 4-aminopyridine (4-AP)-induced seizures modify the regional parvalbumin contents in the rat brain. 4-Aminopyridine was injected intraperitoneally in adult rats, controls received the solvent. Animals were sacrificed at 3 h after a single acute treatment, or following repeated, daily treatments of 12 days. In situ hybridization (ISH) indicated significantly decreased parvalbumin mRNA level in the medial mammillary nucleus (MM) at 12 days. Western blotting revealed 20.1% significant decrease of parvalbumin content in the medial mammillary area, while parvalbumin immunohistochemistry indicated no change of the number of immunoreactive cells in the medial mammillary nucleus. The results reveal the downregulation of the transcription of the parvalbumin gene and the decrease of parvalbumin synthesis in medial mammillary nucleus neurons in response to experimental seizures. PMID:15530659

Vizi, Sándor; Bagosi, Andrea; Krisztin-Péva, Beáta; Gulya, Károly; Mihály, András



Calorie Restriction Reduces the Influence of Glucoregulatory Dysfunction on Regional Brain Volume in Aged Rhesus Monkeys  

PubMed Central

Insulin signaling dysregulation is related to neural atrophy in hippocampus and other areas affected by neurovascular and neurodegenerative disorders. It is not known if long-term calorie restriction (CR) can ameliorate this relationship through improved insulin signaling or if such an effect might influence task learning and performance. To model this hypothesis, magnetic resonance imaging was conducted on 27 CR and 17 control rhesus monkeys aged 19–31 years from a longitudinal study. Voxel-based regression analyses were used to associate insulin sensitivity with brain volume and microstructure cross-sectionally. Monkey motor assessment panel (mMAP) performance was used as a measure of task performance. CR improved glucoregulation parameters and related indices. Higher insulin sensitivity predicted more gray matter in parietal and frontal cortices across groups. An insulin sensitivity × dietary condition interaction indicated that CR animals had more gray matter in hippocampus and other areas per unit increase relative to controls, suggesting a beneficial effect. Finally, bilateral hippocampal volume adjusted by insulin sensitivity, but not volume itself, was significantly associated with mMAP learning and performance. These results suggest that CR improves glucose regulation and may positively influence specific brain regions and at least motor task performance. Additional studies are warranted to validate these relationships.

Willette, Auriel A.; Bendlin, Barbara B.; Colman, Ricki J.; Kastman, Erik K.; Field, Aaron S.; Alexander, Andrew L.; Sridharan, Aadhavi; Allison, David B.; Anderson, Rozalyn; Voytko, Mary-Lou; Kemnitz, Joseph W.; Weindruch, Richard H.; Johnson, Sterling C.



Brain injury-induced proteolysis is reduced in a novel calpastatin-overexpressing transgenic mouse.  


The calpain family of calcium-dependent proteases has been implicated in a variety of diseases and neurodegenerative pathologies. Prolonged activation of calpains results in proteolysis of numerous cellular substrates including cytoskeletal components and membrane receptors, contributing to cell demise despite coincident expression of calpastatin, the specific inhibitor of calpains. Pharmacological and gene-knockout strategies have targeted calpains to determine their contribution to neurodegenerative pathology; however, limitations associated with treatment paradigms, drug specificity, and genetic disruptions have produced inconsistent results and complicated interpretation. Specific, targeted calpain inhibition achieved by enhancing endogenous calpastatin levels offers unique advantages in studying pathological calpain activation. We have characterized a novel calpastatin-overexpressing transgenic mouse model, demonstrating a substantial increase in calpastatin expression within nervous system and peripheral tissues and associated reduction in protease activity. Experimental activation of calpains via traumatic brain injury resulted in cleavage of ?-spectrin, collapsin response mediator protein-2, and voltage-gated sodium channel, critical proteins for the maintenance of neuronal structure and function. Calpastatin overexpression significantly attenuated calpain-mediated proteolysis of these selected substrates acutely following severe controlled cortical impact injury, but with no effect on acute hippocampal neurodegeneration. Augmenting calpastatin levels may be an effective method for calpain inhibition in traumatic brain injury and neurodegenerative disorders. PMID:23305291

Schoch, Kathleen M; von Reyn, Catherine R; Bian, Jifeng; Telling, Glenn C; Meaney, David F; Saatman, Kathryn E



Demyelination reduces brain parenchymal stiffness quantified in vivo by magnetic resonance elastography  

PubMed Central

The detection of pathological tissue alterations by manual palpation is a simple but essential diagnostic tool, which has been applied by physicians since the beginnings of medicine. Recently, the virtual “palpation” of the brain has become feasible using magnetic resonance elastography, which quantifies biomechanical properties of the brain parenchyma by analyzing the propagation of externally elicited shear waves. However, the precise molecular and cellular patterns underlying changes of viscoelasticity measured by magnetic resonance elastography have not been investigated up to date. We assessed changes of viscoelasticity in a murine model of multiple sclerosis, inducing reversible demyelination by feeding the copper chelator cuprizone, and correlated our results with detailed histological analyses, comprising myelination, extracellular matrix alterations, immune cell infiltration and axonal damage. We show firstly that the magnitude of the complex shear modulus decreases with progressive demyelination and global extracellular matrix degradation, secondly that the loss modulus decreases faster than the dynamic modulus during the destruction of the corpus callosum, and finally that those processes are reversible after remyelination.

Schregel, Katharina; Wuerfel nee Tysiak, Eva; Garteiser, Philippe; Gemeinhardt, Ines; Prozorovski, Timour; Aktas, Orhan; Merz, Hartmut; Petersen, Dirk; Wuerfel, Jens; Sinkus, Ralph



HIF-1alpha inhibition ameliorates neonatal brain injury in a rat pup hypoxic-ischemic model.  


Hypoxia-inducible factor-1alpha (HIF-1alpha) 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-1alpha 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 2 h of hypoxia (8% O2 at 37 degrees C). HIF-1alpha 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-1alpha upregulation by DMOG increased the permeability of the BBB and brain edema compared with HI group. 2ME2 attenuated the increase in HIF-1alpha 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-1alpha 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

Chen, Wanqiu; Jadhav, Vikram; Tang, Jiping; Zhang, John H



Chronic hypertension aggravates heat stress-induced brain damage: possible neuroprotection by cerebrolysin.  


Whole body hyperthermia (WBH) aggravates brain edema formation and cell damage in chronic hypertensive rats compared with normotensive animals. In this investigation, we examined the influence of cerebrolysin on WBH-induced edema formation and brain pathology in hypertensive and normotensive rats. Rats subjected to 4 h WBH at 38 degrees C in a biological oxygen demand (BOD) incubator showed breakdown of the blood-brain barrier (BBB), reduced cerebral blood flow (CBF), edema formation and cell injuries in several parts of the brain. These effects were further aggravated in chronic hypertensive rats (two-kidney one clip model (2K1C), for 4 weeks) subjected to WBH. Pretreatment with cerebrolysin (5 mL/kg, 24 h and 30 min before heat stress) markedly attenuated the BBB dysfunction and brain pathology in normal animals. However, in hypertensive animals, a high dose of cerebrolysin (10 mL/kg, 24 h and 30 min before heat stress) was needed to attenuate WBH-induced BBB dysfunction and brain pathology. These observations indicate that heat stress could affect differently in normal and hypertensive conditions. Furthermore, our results suggest that patients suffering from various chronic cardiovascular diseases may respond differently to hyperthermia and to neuroprotective drugs, e.g., cerebrolysin not reported earlier. PMID:19812973

Muresanu, Dafin Fior; Zimmermann-Meinzingen, Sibilla; Sharma, Hari Shanker



Activation of liver X receptor reduces global ischemic brain injury by reduction of nuclear factor-kappaB.  


Recent studies have found that liver X receptors (LXRs) agonists decrease brain inflammation and exert neuroprotective effect. The aim of this study was to examine the mechanisms of action of liver X receptor agonist GW3965 against brain injury following global cerebral ischemia in the rat. The 48 male SD (Sprague-Dawley) rats were randomly partitioned into three groups: sham, global ischemia (4-vessel occlusion for 15 min; 4VO) treated with vehicle and global ischemia treated with GW3965 (20 mg/kg, via i.p. injection at 10 min after reperfusion). The functional outcome was determined by neurological evaluation at 24 h 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 h 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 kappaB (p-IkappaBalpha), nuclear factor-kappaB (NF-kappaB) subunit p65, and cyclo-oxygenase-2 (COX-2) were analyzed with Western blot at 12 h after reperfusion. GW3965 tended to reduce 72 h 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-kappaB activation and the subsequent suppression of COX-2 in the post ischemic brain. PMID:20096333

Cheng, O; Ostrowski, R P; Liu, W; Zhang, J H



Benzodiazepines: Anxiety-Reducing Activity by Reduction of Serotonin Turnover in the Brain  

Microsoft Academic Search

The anxiety-reducing effects of minor tranquilizers in the rat conflict test were mimicked by serotonin antagonists and by p-chlorophenylalanine, an inhibitor of serotonin synthesis; the depressant effects of the minor tranquilizers were mimicked by norepinephrine antagonists. Intraventricular injections of serotonin led to a suppression of behavior, and also antagonized the anxiety-reducing action of benzodiazeprines. Intraventricular injections of norepinephrine led to

C. David Wise; Barry D. Berger; Larry Stein



HDAC inhibitor increases histone H3 acetylation and reduces microglia inflammatory response following traumatic brain injury in rats  

PubMed Central

Traumatic brain injury (TBI) produces a rapid and robust inflammatory response in the brain characterized in part by activation of microglia. A novel histone deacetylase (HDAC) inhibitor, 4-dimethylamino-N-[5-(2-mercaptoacetylamino)pentyl]benzamide (DMA-PB), was administered (0, 0.25, 2.5, 25 mg/kg) systemically immediately after lateral fluid percussion TBI in rats. Hippocampal CA2/3 tissue was processed for acetyl-histone H3 immunolocalization, OX-42 immunolocalization (for microglia), and Fluoro-Jade B histofluorescence (for degenerating neurons) at 24 h after injury. Vehicle-treated TBI rats exhibited a significant reduction in acetyl-histone H3 immunostaining in the ipsilateral CA2/3 hippocampus compared to the sham TBI group (p<0.05). The reduction in acetyl-histone H3 immunostaining was attenuated by each of the DMA-PB dosage treatment groups. Vehicle-treated TBI rats exhibited a high density of phagocytic microglia in the ipsilateral CA2/3 hippocampus compared to sham TBI in which none were observed. All doses of DMA-PB significantly reduced the density of phagocytic microglia (p<0.05). There was a trend for DMA-PB to reduce the number of degenerating neurons in the ipsilateral CA2/3 hippocampus (p = 0.076). We conclude that the HDAC inhibitor DMA-PB is a potential novel therapeutic for inhibiting neuroinflammation associated with TBI.

Zhang, Bin; West, Eric J.; Van, Ken C.; Gurkoff, Gene G.; Zhou, Jia; Zhang, Xiu-Mei; Kozikowski, Alan P.; Lyeth, Bruce G.



Contribution of reduced and oxidized glutathione to signals detected by magnetic resonance spectroscopy as indicators of local brain redox state.  


The reduced form of glutathione (GSH; gamma-glutamyl cysteinyl glycine) is supposedly the most powerful reducing battery in the central nervous system against oxidative stress. We evaluated the contribution of GSH and GSSG to MEGA-PRESS (a frequency-selective refocusing technique) signals assessed by magnetic resonance spectroscopy (MRS). GSH gave a single positive signal (2.95 ppm) by the MEGA-PRESS. In contrast, GSSG gave a multiplet of reversed signals (3.03, 3.23, and 3.34 ppm). A phantom solution mimicking the normal in vivo condition (GSH:GSSG=100:1) gave a single positive peak. Even when the ratio was changed to 10:1, corresponding to toxic oxidative stress, GSH was prominent and GSSG signals were minimal. Thus, GSSG signals could be negligible. In the phantom solution (creatine:GSH:aspartate:gamma-aminobutyric acid=7:3:1:1), the creatine signal overshadowed the other signals. Through the MEGA-PRESS, a single peak of GSH stood out over other signals. In vivo, the brains of healthy volunteers gave similar signals as the in vitro phantom solution, indicating that the signal originated from GSH. The estimated concentration of GSH in the human brain was 1.9+/-0.37 mM (mean+/-S.D., n=4). In conclusion, MEGA-PRESS allowed us to assess GSH levels in vivo non-invasively. PMID:16503064

Satoh, Takumi; Yoshioka, Yoshichika



Inhaled Nitric Oxide Reduces Endothelial Activation and Parasite Accumulation in the Brain, and Enhances Survival in Experimental Cerebral Malaria  

PubMed Central

The host immune response contributes to the onset and progression of severe malaria syndromes, such as cerebral malaria. Adjunctive immunomodulatory strategies for severe malaria may improve clinical outcome beyond that achievable with artemisinin-based therapy alone. Here, we report that prophylaxis with inhaled nitric oxide significantly reduced systemic inflammation (lower TNF, IFN? and MCP-1 in peripheral blood) and endothelial activation (decreased sICAM-1 and vWF, and increased angiopoeitin-1 levels in peripheral blood) in an experimental cerebral malaria model. Mice that received inhaled nitric oxide starting prior to infection had reduced parasitized erythrocyte accumulation in the brain, decreased brain expression of ICAM-1, and preserved vascular integrity compared to control mice. Inhaled nitric oxide administered in combination with artesunate, starting as late as 5.5 days post-infection, improved survival over treatment with artesunate alone (70% survival in the artesunate only vs. 100% survival in the artesunate plus iNO group, p?=?0.03). These data support the clinical investigation of inhaled nitric oxide as a novel adjunctive therapy in patients with severe malaria.

Lu, Ziyue; Kain, Dylan C.; Miller, Chris; Francis, Roland C.; Liles, W. Conrad; Zapol, Warren M.; Kain, Kevin C.



Acetate supplementation reduces microglia activation and brain interleukin-1? levels in a rat model of Lyme neuroborreliosis  

PubMed Central

Background We have found that acetate supplementation significantly reduces neuroglia activation and pro-inflammatory cytokine release in a rat model of neuroinflammation induced with lipopolysaccharide. To test if the anti-inflammatory effect of acetate supplementation is specific to a TLR4-mediated injury, we measured markers of neuroglia activation in rats subjected to B. burgdorferi-induced neuroborreliosis that is mediated in large part by a TLR2-type mechanism. Methods In this study, rats were subjected to Lyme neuroborreliosis following an intravenous infusion of B. burgdorferi (B31-MI-16). Acetate supplementation was induced using glyceryl triacetate (6g/kg) by oral gavage. Immunohistochemistry, qPCR, and western blot analyses were used to measure bacterial invasion into the brain, neuroglial activation, and brain and circulating levels of interleukin 1?. Statistical analysis was performed using one-way analysis of variance (ANOVA) followed by a Tukey’s post hoc tests or using a Student’s t test assuming unequal variances when appropriate. Results We found that acetate supplementation significantly reduced microglia activation by 2-fold as determined by immunohistochemical and western blot analysis. Further, acetate supplementation also reduced the expression of the pro-inflammatory cytokine IL-1? by 2-fold as compared to controls. On the other hand, the inoculation of rats with B. burgdorferi had no effect on astroglial activation as determined by immunocytochemistry and western blot analysis despite significant increases in circulation levels of antigen toward B. burgdorferi and presence of the bacteria in the central nervous system. Conclusions These results suggest that microglial activation is an essential component to neuroborreliosis and that acetate supplementation may be an effective treatment to reduce injury phenotype and possibly injury progression in Lyme neuroborreliosis.



Reduced muscle activation during exercise related to brain oxygenation and metabolism in humans.  


Maximal exercise may be limited by central fatigue defined as an inability of the central nervous system to fully recruit the involved muscles. This study evaluated whether a reduction in the cerebral oxygen-to-carbohydrate index (OCI) and in the cerebral mitochondrial oxygen tension relate to the ability to generate a maximal voluntary contraction and to the transcranial magnetic stimulated force generation. To determine the role of a reduced OCI and in central fatigue, 16 males performed low intensity, maximal intensity and hypoxic cycling exercise. Exercise fatigue was evaluated by ratings of perceived exertion (RPE), arm maximal voluntary force (MVC), and voluntary activation of elbow flexor muscles assessed with transcranial magnetic stimulation. Low intensity exercise did not produce any indication of central fatigue or marked cerebral metabolic deviations. Exercise in hypoxia (0.10) reduced cerebral oxygen delivery 25% and decreased 11+/-4 mmHg (P<0.001) together with OCI (6.2+/-0.7 to 4.8+/-0.5, P<0.001). RPE increased while MVC and voluntary activation were reduced (P<0.05). During maximal exercise declined 8+/-4 mmHg (P<0.05) and OCI to 3.8+/-0.5 (P<0.001). RPE was 18.5, and MVC and voluntary activation were reduced (P<0.05). We observed no signs of muscular fatigue in the elbow flexors and all control MVCs were similar to resting values. Exhaustive exercise provoked cerebral deoxygenation, metabolic changes and indices of fatigue similar to those observed during exercise in hypoxia indicating that reduced cerebral oxygenation may play a role in the development of central fatigue and may be an exercise capacity limiting factor. PMID:20403976

Rasmussen, P; Nielsen, J; Overgaard, M; Krogh-Madsen, R; Gjedde, A; Secher, N H; Petersen, N C



EEG data space adaptation to reduce intersession nonstationarity in brain-computer interface.  


A major challenge in EEG-based brain-computer interfaces (BCIs) is the intersession nonstationarity in the EEG data that often leads to deteriorated BCI performances. To address this issue, this letter proposes a novel data space adaptation technique, EEG data space adaptation (EEG-DSA), to linearly transform the EEG data from the target space (evaluation session), such that the distribution difference to the source space (training session) is minimized. Using the Kullback-Leibler (KL) divergence criterion, we propose two versions of the EEG-DSA algorithm: the supervised version, when labeled data are available in the evaluation session, and the unsupervised version, when labeled data are not available. The performance of the proposed EEG-DSA algorithm is evaluated on the publicly available BCI Competition IV data set IIa and a data set recorded from 16 subjects performing motor imagery tasks on different days. The results show that the proposed EEG-DSA algorithm in both the supervised and unsupervised versions significantly outperforms the results without adaptation in terms of classification accuracy. The results also show that for subjects with poor BCI performances when no adaptation is applied, the proposed EEG-DSA algorithm in both the supervised and unsupervised versions significantly outperforms the unsupervised bias adaptation algorithm (PMean). PMID:23663147

Arvaneh, Mahnaz; Guan, Cuntai; Ang, Kai Keng; Quek, Chai



Primary treatment of diabetic macular edema  

PubMed Central

Diabetic macular edema (DME) is a leading cause of vision loss in older Americans. Thermal laser treatment remains the mainstay of treatment for DME. Recently, alternative primary treatments for DME have been evaluated. These treatments include intravitreal injections of steroids as well as pharmaceuticals containing antibodies against vascular endothelial growth factor (VEGF). Surgical treatment has been shown to be appropriate in selected cases. We review the evidence and scientific rationale for various primary treatment options in patients with DME. Regular and timely ophthalmologic evaluation remains crucial to recognition and treatment of macular edema in diabetic patients.

Ranchod, Tushar M; Fine, Stuart L



Are oscillatory brain responses generally reduced in schizophrenia during long sustained attentional processing?  

Microsoft Academic Search

Deficits in sustained attention and vigilance were assessed for oscillatory delta, theta, alpha, and gamma EEG activity during an auditory continuous performance task in patients with schizophrenia and healthy controls by quantifying peak-to-peak amplitudes of averaged and single-trial data. Averaged data indicated significantly reduced amplitudes in schizophrenia patients in all analyzed frequency bands, mainly at anterior locations. Single-trial analysis suggested

Canan Basar-Eroglu; Christina Schmiedt-Fehr; Birgit Mathes; Jörg Zimmermann; Andreas Brand



Reduced activity of monoamine oxidase in the rat brain following repeated nandrolone decanoate administration  

Microsoft Academic Search

Anabolic androgenic steroids (AAS) are known as doping agents within sports and body-building, but are currently also abused by other groups in society in order to promote increased courage and aggression. We previously showed that 14 days of daily intramuscular injections of the AAS nandrolone decanoate (15 mg\\/kg) reduced the extracellular levels of the dopaminergic metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid

Carolina Birgner; Anna M. S. Kindlundh-Högberg; Lars Oreland; Johan Alsiö; Jonas Lindblom; Helgi B. Schiöth; Lena Bergström



A3 Adenosine Receptor Agonist Reduces Brain Ischemic Injury and Inhibits Inflammatory Cell Migration in Rats  

PubMed Central

A3 adenosine receptor (A3AR) is recognized as a novel therapeutic target for ischemic injury; however, the mechanism underlying anti-ischemic protection by the A3AR agonist remains unclear. Here, we report that 2-chloro-N6-(3-iodobenzyl)-5?-N-methylcarbamoyl-4?-thioadenosine (LJ529), a selective A3AR agonist, reduces inflammatory responses that may contribute to ischemic cerebral injury. Postischemic treatment with LJ529 markedly reduced cerebral ischemic injury caused by 1.5-hour middle cerebral artery occlusion, followed by 24-hour reperfusion in rats. This effect was abolished by the simultaneous administration of the A3AR antagonist MRS1523, but not the A2AAR antagonist SCH58261. LJ529 prevented the infiltration/migration of microglia and monocytes occurring after middle cerebral artery occlusion and reperfusion, and also after injection of lipopolysaccharides into the corpus callosum. The reduced migration of microglia by LJ529 could be related with direct inhibition of chemotaxis and down-regulation of spatiotemporal expression of Rho GTPases (including Rac, Cdc42, and Rho), rather than by biologically relevant inhibition of inflammatory cytokine/chemokine release (eg, IL-1?, TNF-?, and MCP-1) or by direct inhibition of excitotoxicity/oxidative stress (not affected by LJ529). The present findings indicate that postischemic activation of A3AR and the resultant reduction of inflammatory response should provide a promising therapeutic strategy for the treatment of ischemic stroke.

Choi, In-Young; Lee, Jae-Chul; Ju, Chung; Hwang, Sunyoung; Cho, Geum-Sil; Lee, Hyuk Woo; Choi, Won Jun; Jeong, Lak Shin; Kim, Won-Ki



Autofluorescence Imaging for Diagnosis and Follow-up of Cystoid Macular Edema  

PubMed Central

Lipofuscin results from digestion of photoreceptor outer segments by the retinal pigment epithelium (RPE) and is the principal compound that causes RPE fluorescence during autofluorescence imaging. Absorption of the 488-nanometer blue light by macular pigments, especially by the carotenoids lutein and zeaxanthin, causes normal macular hypo-autofluorescence. Fundus autofluorescence imaging is being increasingly employed in ophthalmic practice to diagnose and monitor patients with a variety of retinal disorders. In macular edema for example, areas of hyper-autofluorescence are usually present which are postulated to be due to dispersion of macular pigments by pockets of intraretinal fluid. For this reason, the masking effect of macular pigments is reduced and the natural autofluorescence of lipofuscin can be observed without interference. In cystic types of macular edema, e.g. cystoid macular edema due to retinal vein occlusion, diabetic macular edema and post cataract surgery, hyper-autofluorescent regions corresponding to cystic spaces of fluid accumulation can be identified. In addition, the amount of hyper-autofluorescence seems to correspond to the severity of edema. Hence, autofluorescence imaging, as a noninvasive technique, can provide valuable information on cystoid macular edema in terms of diagnosis, follow-up and efficacy of treatment.

Ebrahimiadib, Nazanin; Riazi-Esfahani, Mohammad



Reduced matrix metalloproteinase-9 activity and cell death after global ischemia in the brain preconditioned with hyperbaric oxygen.  


Matrix metalloproteinase-9 (MMP-9) plays a deleterious role in cell death after global cerebral ischemia. Preconditioning with hyperbaric oxygen (HBO-PC) reduces neuronal damage in the post-ischemic brain; however, its effect on ischemia-induced increase in MMP-9 activity and expression remains unexplored.We investigated effects of HBO-PC on alterations in MMP-9 activity/tissue expression accompanying neuronal death after transient global cerebral ischemia.Male SD rats (300-350 g), were allocated either to non-ischemic (naive control or sham-operated) or ischemic (four-vessel occlusion, 4VO; 10 min) groups that were HBO-preconditioned (2.5 ATA, 1 h daily for 5 days; the last session 24 h before ischemia) or not. Neurobehavioral deficits were assessed prior to collection of brain tissue for gel zymography (MMP-9) and histology (MMP-9 immunofluorescence, TUNEL) at 0 (without ischemia), 6, 24, 72 h and 7 days after 4VO.Both, MMP-9 levels and cell death increased in the hippocampus at 72 h after 4VO. HBO-PC suppressed postischemic MMP-9 activity and CA1 cell damage, and improved functional performance. The increase in MMP-9 immunoreactivity in the brain was also detected after HBO-PC alone. HBO-PC suppresses MMP-9 activity and expression in the postischemic hippocampus. The mechanism of HBO preconditioning may depend on the induction of MMP-9 in the preischemic phase and may be in part mediated by exhaustion of MMP-9 stores in cerebral tissues. PMID:19812919

Ostrowski, Robert P; Jadhav, Vikram; Chen, Wanqiu; Zhang, John H



Combination therapy of olmesartan and azelnidipine inhibits sympathetic activity associated with reducing oxidative stress in the brain of hypertensive rats.  


It has been demonstrated that the antihypertensive drugs with the antioxidant action on the brainstem inhibit the sympathetic activity and consequently decrease blood pressure and heart rate (HR) in hypertensive rats. Combination drugs of the angiotensin receptor blocker and calcium channel blocker, such as olmesartan (OLM)/azelnidipine (AZ) and candesartan (CAN)/amlodipine (AM), are widely used for treating hypertension in Japan. In this study, it was investigated whether there are differences in the antioxidant effect in the brain and the sympathoinhibitory effect between OLM/AZ and CAN/AM combination therapies in stroke-prone spontaneously hypertensive rats (SHRSP). OLM/AZ (10/8 mg kg(-1) day(-1)), CAN/AM (4/2.5 mg kg(-1) day(-1)), or vehicle was orally administered for 30 days to SHRSP. OLM/AZ and CAN/AM markedly decreased systolic blood pressure to the same extent. OLM/AZ decreased HR to a greater extent than CAN/AM. Urinary norepinephrine excretion as a marker of sympathetic activity was unchanged in the CAN/AM group, but reduced in the OLM/AZ group. Oxidative stress in the whole brain assessed using the in vivo electron spin resonance method was similarly decreased in both OLM/AZ and CAN/AM groups. Importantly, thiobarbituric acid reactive substance levels in the brainstem were significantly lower in the OLM/AZ group, but not in the CAN/AM group, than in the vehicle group. These results suggest that combination therapy of either OLM/AZ or CAN/AM does not induce reflex-mediated sympathetic activation despite the marked blood pressure reduction, which is associated with an antioxidant effect in the brain regions affecting the sympathetic activity. Furthermore, the antioxidant effect in the brainstem and the sympathoinhibitory effect of OLM/AZ combination may be greater than those of CAN/AM combination treatment. PMID:22471901

Shinohara, Keisuke; Hirooka, Yoshitaka; Ogawa, Kiyohiro; Kishi, Takuya; Yasukawa, Keiji; Utsumi, Hideo; Sunagawa, Kenji



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)

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 ?/? 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.

(Jay Chen, Zhe; Roberts, Kenneth; Decker, Roy; Pathare, Pradip; Rockwell, Sara; Nath, Ravinder



Activation of adenosine A3 receptors reduces ischemic brain injury in rodents.  


Adenosine A3 receptor (A3R) agonists have been shown to reduce cardiac and lung injury, but the protective roles of A3R agonists in the CNS are not well characterized. The protective effect of selective A3R agonist chloro-N(6)-(3-iodo-benzyl)-adenosine-5'-N-methyluronamide (Cl-IB-MECA) was first examined in primary cortical cultures. In cortical culture, Cl-IB-MECA pretreatment antagonized the hypoxia-mediated decrease in cell viability. In vivo, Cl-IB-MECA or vehicle was given intracerebroventricularly or intravenously to anesthetized rats. Animals were subjected to focal cerebral ischemia induced by transient middle cerebral artery (MCA) ligation. Intracerebroventricular or repeated intravenous administration (i.e., at 165 min and 15 min before MCA ligation) of Cl-IB-MECA did not alter blood pressure during ischemia but increased locomotor activity and decreased cerebral infarction 2 days after. In these animals, Cl-IB-MECA also reduced the density of TUNEL labeling in the lesioned cortex. The possibility of endogeneous neuroprotection was further examined in A3R knockout mice. After MCA ligation, an increase in cerebral infarction was found in the A3R knockouts compared with the A3R wild-type controls, suggesting that A3Rs are tonically activated during ischemia. Additionally, intracerebroventricular pretreatment with Cl-IB-MECA decreased the size of infarction in the wild-type controls, but not in the A3R knockout animals, suggesting that Cl-IB-MECA-induced protection was mediated through the A3 receptors. Collectively, these data suggest that Cl-IB-MECA reduced cerebral infarction through the activation of A3Rs and suppression of apoptosis. PMID:17016854

Chen, Guann-Juh; Harvey, Brandon K; Shen, Hui; Chou, Jenny; Victor, Adrienne; Wang, Yun



Establishment and evaluation of an experimental animal model of high altitude cerebral edema.  


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

Guo, Ping; Luo, Han; Fan, Yong; Luo, Yongjun; Zhou, Qiquan



Cannabidiol reduces lipopolysaccharide-induced vascular changes and inflammation in the mouse brain: an intravital microscopy study  

PubMed Central

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.



Steroids and the Management of Macular Edema  

Microsoft Academic Search

Macular edema (ME) is a condition which is usually secondary to an underlying disease process. It is most commonly seen following venous occlusive disease, diabetic retinopathy and posterior segment inflammatory disease. The treatment of ME varies, depending upon the underlying etiology, and has led to varying degrees of success. Traditionally, the main treatment options have included topical and systemic steroids,

Shani Golan; Anat Loewenstein



Current status in diabetic macular edema treatments  

PubMed Central

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.

Romero-Aroca, Pedro



Clinical management of hydrogel-induced edema.  


Clinical techniques and guidelines are discussed to manage manifestations of edema induced by hydrogels. Emphasis is on the pathogenesis of folds in Descemet's membrane (striate keratopathy) accompanying vertical striae that have been found to occur horizontally as well as vertically. PMID:984176

Kame, R T



Effects of sabiporide, a specific Na +\\/H + exchanger inhibitor, on neuronal cell death and brain ischemia  

Microsoft Academic Search

We investigated the effects of an Na+\\/H+ exchanger inhibitor, sabiporide, on excitotoxicity in cultured neuronal cells and in vivo. Sabiporide attenuated glutamate- or NMDA (N-methyl-d-aspartic acid)-induced neuronal cell death. Sabiporide also reduced glutamate or NMDA-induced increase in [Ca2+]i. In in vivo brain ischemia model, sabiporide produced protective effects, decreasing the infarct size and edema volume. Our results suggest that sabiporide

Hye-Seong Park; Bo Kyung Lee; Sok Park; Seung U. Kim; Soo Hwan Lee; Eun Joo Baik; Sunkyung Lee; Kyu Yang Yi; Sung Eun Yoo; Chang-Hyun Moon; Yi-Sook Jung



Periorbital edema as initial manifestation of chronic cutaneous lupus erythematosus  

PubMed Central

Periorbital edema occurs frequently in dermatomyositis, but it has rarely been noted in systemic systemic lupus erythematosus. We describe a patient who developed bilateral periorbital edema and erythema as the sole manifestation of systemic lupus erythematosus.

Erras, Samar; Benjilali, Laila; Essaadouni, Lamiaa



Cerebrolysin attenuates blood-brain barrier and brain pathology following whole body hyperthermia in the rat.  


The possibility that Cerebrolysin, a mixture of several neurotrophic factors, has some neuroprotective effects on whole body hyperthermia (WBH) induced breakdown of the blood-brain barrier (BBB), blood-CSF barrier (BCSFB), brain edema formation and neuropathology were examined in a rat model. Rats subjected to a 4 h heat stress at 38 degrees C in a biological oxygen demand (BOD) incubator exhibited profound increases in BBB and BCSFB permeability to Evans blue and radioiodine tracers compared to controls. Hippocampus, caudate nucleus, thalamus and hypothalamus exhibited pronounced increase in water content and brain pathology following 4 h heat stress. Pretreatment with Cerebrolysin (1, 2 or 5 mL/kg i.v.) 24 h before WBH significantly attenuated breakdown of the BBB or BCSFB and brain edema formation. This effect was dose dependent. Interestingly, the cell and tissue injury following WBH in cerebrolysin-treated groups were also considerably reduced. These novel observations suggest that cerebrolysin can attenuate WBH induced BBB and BCSFB damage resulting in neuroprotection. PMID:19812972

Sharma, Hari Shanker; Zimmermann-Meinzingen, Sibilla; Sharma, Aruna; Johanson, Conrad E



Tumefactive perivascular spaces mimicking cerebral edema in a patient with diabetic hyperglycemic hyperosmolar syndrome: a case report  

PubMed Central

Introduction Acute cerebral edema is a significant cause of death in patients treated for diabetic ketoacidosis and hyperglycemic hyperosmolar syndrome. Case presentation We present the case of a 44-year-old African American woman admitted with acute severe headache and diagnosed with diabetic hyperglycemic hyperosmolar syndrome. Computed tomography of the head showed diffuse leukoencephalopathy, but sparing of the cortex. We were concerned for acute cerebral edema secondary to hyperglycemic hyperosmolar syndrome. Magnetic resonance imaging of the brain showed numerous collections of cystic spaces in the white matter of both hemispheres representing tumefactive perivascular spaces. Her headache improved with correction of the hyperglycemic hyperosmolar state. Conclusion Although the clinical presentation and head computed tomography were concerning for cerebral edema, the distinctive features on brain magnetic resonance imaging helped to clarify the diagnosis and differentiate it from other processes.



Aging and infection reduce expression of specific brain-derived neurotrophic factor mRNAs in hippocampus.  


Aging increases the likelihood of cognitive decline after negative life events such as infection or injury. We have modeled this increased vulnerability in aged (24-month-old), but otherwise unimpaired F344xBN rats. In these animals, but not in younger (3-month-old) counterparts, a single intraperitoneal injection of E. coli leads to specific deficits in long-term memory and long-lasting synaptic plasticity in hippocampal area CA1-processes strongly dependent on brain-derived neurotrophic factor (BDNF). Here we have investigated the effects of age and infection on basal and fear-conditioning-stimulated expression of Bdnf in hippocampus. We performed in situ hybridization with 6 probes recognizing: total (pan-)BDNF mRNA, the 4 predominant 5' exon-specific transcripts (I, II, IV, and VI), and BDNF mRNAs with a long 3' untranslated region (3' UTR). In CA1, aging reduced basal levels and fear-conditioning-induced expression of total BDNF mRNA, exon IV-specific transcripts, and transcripts with long 3' UTRs; effects of infection were similar and sometimes compounded the effects of aging. In CA3, aging reduced all of the transcripts to some degree; infection had no effect. Effects in dentate were minimal. Northern blot analysis confirmed an aging-associated loss of total BDNF mRNA in areas CA1 and CA3, and revealed a parallel, preferential loss of BDNF mRNA transcripts with long 3' UTRs. PMID:21907460

Chapman, Timothy R; Barrientos, Ruth M; Ahrendsen, Jared T; Hoover, Jennifer M; Maier, Steven F; Patterson, Susan L



Hypercapnic cerebral edema presenting in a woman with asthma: a case report  

Microsoft Academic Search

Introduction  Common causes of non-traumatic acute cerebral edema include malignant hypertension, hyponatremia, anoxia, and cerebral vascular\\u000a accident. The computed tomographic images and data obtained during care of the patient described in this case report provide\\u000a evidence that hypercarbia can cause increased intracranial pressure and coma without permanent brain injury. Partial pressure\\u000a of carbon dioxide evaluation for coma is essential to provide

Ryan R Joyce; William T McGee



5-HT1 agonists reduce 5-hydroxytryptamine release in rat hippocampus in vivo as determined by brain microdialysis.  

PubMed Central

1. An intracerebral perfusion method, brain microdialysis, was used to assess changes of 5-hydroxytryptamine (5-HT) release in the ventral hippocampus of the chloral hydrate-anaesthetized rat in response to systemic administration of a variety of 5-HT1 receptor agonists. 2. A stable output of reliably detectable endogenous 5-HT was measured in dialysates collected from ventral hippocampus with the 5-HT reuptake inhibitor, citalopram, present in the perfusion medium. 3. Under these conditions the putative 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) caused a dose-dependent (5-250 micrograms kg-1, s.c.) reduction of 5-HT in hippocampal dialysates. 4. Similarly, the putative 5-HT1A agonists gepirone (5 mg kg-1, s.c.), ipsapirone (5 mg kg-1, s.c.) and buspirone (5 mg kg-1, s.c.) markedly reduced levels of 5-HT in hippocampal perfusates whereas their common metabolite 1-(2-pyrimidinyl) piperazine (5 mg kg-1, s.c.), which does not bind to central 5-HT1A recognition sites, had no effect. 5. 5-Methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (RU 24969), a drug with reported high affinity for brain 5-HT1B binding sites, also produced a dose-dependent (0.25-5 mg kg-1, s.c.) decrease of hippocampal 5-HT output. 6. These data are direct biochemical evidence that systemically administered putative 5-HT1A and 5-HT1B agonists markedly inhibit 5-HT release in rat ventral hippocampus in vivo.

Sharp, T.; Bramwell, S. R.; Grahame-Smith, D. G.



Intravitreal Cortisone Injection for Refractory Diffuse Diabetic Macular Edema  

Microsoft Academic Search

Purpose: The purpose of this study was to evaluate the safety and efficacy of intravitreal triamcinolone acetonide injection in patients with diffuse diabetic macular edema. We also compared the effect of intravitreal triamcinolone with macular grid laser photocoagulation in macular edema. Patients and Methods: Thirty patients with diabetic diffuse macular edema unresponsive to grid laser photocoagulation for at least 4

Hamdi Er



Localization of dermal edema in lipodermatosclerosis, lymphedema, and cardiac insufficiency  

Microsoft Academic Search

Background: Chronic edema in venous insufficiency is associated with leg ulceration, whereas in lymphedema skin ulceration is less frequent and edema from cardiac failure does not cause major skin changes. The reason for these differences is unclear.Objective: Our purpose was to investigate, by means of ultrasound, the distribution of intradermal fluid in patients with edema associated with lipodermatosclerosis, lymphedema, or

Monika Gniadecka



Oral treatment with laquinimod augments regulatory T-cells and brain-derived neurotrophic factor expression and reduces injury in the CNS of mice with experimental autoimmune encephalomyelitis.  


Laquinimod is an orally active molecule that showed efficacy in clinical trials in multiple sclerosis. We studied its effects in the CNS, when administered by therapeutic regimen to mice inflicted with experimental autoimmune encephalomyelitis (EAE). Laquinimod reduced clinical and inflammatory manifestations and elevated the prevalence of T-regulatory cells in the brain. In untreated mice, in the chronic disease stage, brain derived neurotrophic factor (BDNF) expression was impaired. Laquinimod treatment restored BDNF expression to its level in healthy controls. Furthermore, CNS injury, manifested by astrogliosis, demyelination and axonal damages, was significantly reduced following laquinimod treatment, indicating its immunomodulatory and neuroprotective activity. PMID:22749337

Aharoni, Rina; Saada, Ravit; Eilam, Raya; Hayardeny, Liat; Sela, Michael; Arnon, Ruth



Characterization and quantification of cerebral edema induced by synchrotron x-ray microbeam radiation therapy  

NASA Astrophysics Data System (ADS)

Cerebral edema is one of the main acute complications arising after irradiation of brain tumors. Microbeam radiation therapy (MRT), an innovative experimental radiotherapy technique using spatially fractionated synchrotron x-rays, has been shown to spare radiosensitive tissues such as mammal brains. The aim of this study was to determine if cerebral edema occurs after MRT using diffusion-weighted MRI and microgravimetry. Prone Swiss nude mice's heads were positioned horizontally in the synchrotron x-ray beam and the upper part of the left hemisphere was irradiated in the antero-posterior direction by an array of 18 planar microbeams (25 mm wide, on-center spacing 211 mm, height 4 mm, entrance dose 312 Gy or 1000 Gy). An apparent diffusion coefficient (ADC) was measured at 7 T 1, 7, 14, 21 and 28 days after irradiation. Eventually, the cerebral water content (CWC) was determined by microgravimetry. The ADC and CWC in the irradiated (312 Gy or 1000 Gy) and in the contralateral non-irradiated hemispheres were not significantly different at all measurement times, with two exceptions: (1) a 9% ADC decrease (p < 0.05) was observed in the irradiated cortex 1 day after exposure to 312 Gy, (2) a 0.7% increase (p < 0.05) in the CWC was measured in the irradiated hemispheres 1 day after exposure to 1000 Gy. The results demonstrate the presence of a minor and transient cellular edema (ADC decrease) at 1 day after a 312 Gy exposure, without a significant CWC increase. One day after a 1000 Gy exposure, the CWC increased, while the ADC remained unchanged and may reflect the simultaneous presence of cellular and vasogenic edema. Both types of edema disappear within a week after microbeam exposure which may confirm the normal tissue sparing effect of MRT. For more information on this article, see

Serduc, Raphaël; van de Looij, Yohan; Francony, Gilles; Verdonck, Olivier; van der Sanden, Boudewijn; Laissue, Jean; Farion, Régine; Bräuer-Krisch, Elke; Siegbahn, Erik Albert; Bravin, Alberto; Prezado, Yolanda; Segebarth, Christoph; Rémy, Chantal; Lahrech, Hana



Characterization and quantification of cerebral edema induced by synchrotron x-ray microbeam radiation therapy.  


Cerebral edema is one of the main acute complications arising after irradiation of brain tumors. Microbeam radiation therapy (MRT), an innovative experimental radiotherapy technique using spatially fractionated synchrotron x-rays, has been shown to spare radiosensitive tissues such as mammal brains. The aim of this study was to determine if cerebral edema occurs after MRT using diffusion-weighted MRI and microgravimetry. Prone Swiss nude mice's heads were positioned horizontally in the synchrotron x-ray beam and the upper part of the left hemisphere was irradiated in the antero-posterior direction by an array of 18 planar microbeams (25 mm wide, on-center spacing 211 mm, height 4 mm, entrance dose 312 Gy or 1000 Gy). An apparent diffusion coefficient (ADC) was measured at 7 T 1, 7, 14, 21 and 28 days after irradiation. Eventually, the cerebral water content (CWC) was determined by microgravimetry. The ADC and CWC in the irradiated (312 Gy or 1000 Gy) and in the contralateral non-irradiated hemispheres were not significantly different at all measurement times, with two exceptions: (1) a 9% ADC decrease (p < 0.05) was observed in the irradiated cortex 1 day after exposure to 312 Gy, (2) a 0.7% increase (p < 0.05) in the CWC was measured in the irradiated hemispheres 1 day after exposure to 1000 Gy. The results demonstrate the presence of a minor and transient cellular edema (ADC decrease) at 1 day after a 312 Gy exposure, without a significant CWC increase. One day after a 1000 Gy exposure, the CWC increased, while the ADC remained unchanged and may reflect the simultaneous presence of cellular and vasogenic edema. Both types of edema disappear within a week after microbeam exposure which may confirm the normal tissue sparing effect of MRT. PMID:18296755

Serduc, Raphaël; van de Looij, Yohan; Francony, Gilles; Verdonck, Olivier; van der Sanden, Boudewijn; Laissue, Jean; Farion, Régine; Bräuer-Krisch, Elke; Siegbahn, Erik Albert; Bravin, Alberto; Prezado, Yolanda; Segebarth, Christoph; Rémy, Chantal; Lahrech, Hana



Optical Coherence Tomographic Findings in Berlin's Edema  

PubMed Central

Purpose To describe optical coherence tomography (OCT) findings in a patient with Berlin’s edema following blunt ocular trauma. Case Report A 26-year-old man presented with acute loss of vision in his left eye following blunt trauma. He underwent a complete ophthalmologic examination and OCT. Fundus examination revealed abnormal yellow discoloration in the macula. OCT disclosed thickening of outer retinal structures and increased reflectivity in the area of photoreceptor outer segments with preservation of inner retinal architecture. Re-examination was conducted one month later at the time which OCT changes resolved leading to a surprisingly normal appearance. Conclusion OCT can be a useful tool in the diagnosis and follow-up of eyes with Berlin’s edema and may reveal ultrastructural macular changes.

El Matri, Leila; Chebil, Ahmed; Kort, Fedra; Bouraoui, Rym; Largueche, Leila; Mghaieth, Fatma



Cerebral edema induced in mice by a convulsive dose of soman. Evaluation through diffusion-weighted magnetic resonance imaging and histology  

SciTech Connect

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.

Testylier, Guy [Centre de Recherches du Service Sante des Armees, Departement de Toxicologie, BP87, F-38702 La Tronche cedex (France)]. E-mail:; Lahrech, Hana [Inserm, UMR-S 836-Grenoble Institut des Neurosciences, Grenoble, F-38043 (France); Universite Joseph Fourier, Grenoble, F-38043 (France); Montigon, Olivier [Inserm, UMR-S 836-Grenoble Institut des Neurosciences, Grenoble, F-38043 (France); Universite Joseph Fourier, Grenoble, F-38043 (France); Foquin, Annie [Centre de Recherches du Service Sante des Armees, Departement de Toxicologie, BP87, F-38702 La Tronche cedex (France); Delacour, Claire [Centre de Recherches du Service Sante des Armees, Departement de Toxicologie, BP87, F-38702 La Tronche cedex (France); Bernabe, Denis [Centre de Recherches du Service Sante des Armees, Departement de Toxicologie, BP87, F-38702 La Tronche cedex (France); Segebarth, Christoph [Inserm, UMR-S 836-Grenoble Institut des Neurosciences, Grenoble, F-38043 (France); Universite Joseph Fourier, Grenoble, F-38043 (France); Dorandeu, Frederic [Centre de Recherches du Service Sante des Armees, Departement de Toxicologie, BP87, F-38702 La Tronche cedex (France); Carpentier, Pierre [Centre de Recherches du Service Sante des Armees, Departement de Toxicologie, BP87, F-38702 La Tronche cedex (France)



Matrix metalloproteinase-9 mediates hypoxia-induced vascular leakage in the brain via tight junction rearrangement  

PubMed Central

Blood–brain barrier (BBB) disruption, resulting from loss of tight junctions (TJ) and activation of matrix metalloproteinases (MMPs), is associated with edema formation in ischemic stroke. Cerebral edema develops in a phasic manner and consists of both vasogenic and cytotoxic components. Although it is contingent on several independent mechanisms, involving hypoxic and inflammatory responses, the single effect of prolonged hypoxia on BBB integrity in vivo was not addressed so far. Exposing mice to normobaric hypoxia (8% oxygen for 48?h) led to a significant increase in vascular permeability associated with diminished expression of the TJ protein occludin. Immunofluorescence studies revealed that hypoxia resulted in disrupted continuity of occludin and zonula occludens-1 (Zo-1) staining with significant gap formation. Hypoxia increased gelatinolytic activity specifically in vascular structures and gel zymography identified MMP-9 as enzymatic source. Treatment with an MMP inhibitor reduced vascular leakage and attenuated disorganization of TJ. Inhibition of vascular endothelial growth factor (VEGF) attenuated vascular leakage and MMP-9 activation induced by hypoxia. In conclusion, our data suggest that hypoxia-induced edema formation is mediated by MMP-9-dependent TJ rearrangement by a mechanism involving VEGF. Therefore, inhibition of MMP-9 might provide the basis for therapeutic strategies to treat brain edema.

Bauer, Alexander T; Burgers, Heinrich F; Rabie, Tamer; Marti, Hugo H



Reduced Levels of DEAD-Box Proteins DBP-RB and p72 in Fetal Down Syndrome Brains  

Microsoft Academic Search

Down syndrome (DS) is characterized by abnormal brain morphology and neurological and behavioral functions. The pivotal role of helicases in brain development, growth, and differentiation made us evaluate three DEAD BOX proteins, DEAD-box protein 1 (DBP-RB), DEAD-box protein 3 (HLP2), DEAD-box protein 72 (P72), and the RuvB-like DNA helicase (TIP49b), in fetal brain of controls and DS subjects, using two-dimensional

Susanne G. Kircher; Seong Hwan Kim; Michael Fountoulakis; Gert Lubec



Antioxidant and iron-binding properties of curcumin, capsaicin, and S-allylcysteine reduce oxidative stress in rat brain homogenate.  


Research demonstrates that antioxidants and metal chelators may be of beneficial use in the treatment of neurodegenerative diseases, such as Alzheimer's disease (AD). This study investigated the antioxidant and metal-binding properties of curcumin, capsaicin, and S-allylcysteine, which are major components found in commonly used dietary spice ingredients turmeric, chilli, and garlic, respectively. The DPPH assay demonstrates that these compounds readily scavenge free radicals. These compounds significantly curtail iron- (Fe2+) and quinolinic acid (QA)-induced lipid peroxidation and potently scavenge the superoxide anion generated by 1 mM cyanide in rat brain homogenate. The ferrozine assay was used to measure the extent of Fe2+ chelation, and electrochemistry was employed to measure the Fe3+ binding activity of curcumin, capsaicin, and S-allylcysteine. Both assays demonstrate that these compounds bind Fe2+ and Fe3+ and prevent the redox cycling of iron, suggesting that this may be an additional method through which these agents reduce Fe2+-induced lipid peroxidation. This study demonstrates the antioxidant and metal-binding properties of these spice ingredients, and it is hereby postulate that these compounds have important implications in the prevention or treatment of neurodegenerative diseases such as AD. PMID:18422331

Dairam, Amichand; Fogel, Ronen; Daya, Santy; Limson, Janice L



Towards reducing impact-induced brain injury: lessons from a computational study of army and football helmet pads.  


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

Moss, William C; King, Michael J; Blackman, Eric G



Rhodiola crenulata Extract Alleviates Hypoxic Pulmonary Edema in Rats  

PubMed Central

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-1?) 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.

Li, Min-Hui; Shi, Li-Shian; Ho, Cheng-Wen



Effect of ethanol and/or reduced caloric intake during pregnancy on brain weight and synaptic membranes of mothers and their newborn  

SciTech Connect

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.

Breen, M.; Weinsxein, H.G.



Dicyclomine, an M1 Muscarinic Antagonist, Reduces Biomarker Levels, But Not Neuronal Degeneration, in Fluid Percussion Brain Injury  

PubMed Central

Abstract Recent studies indicate that ?II-spectrin breakdown products (SBDPs) have utility as biological markers of traumatic brain injury (TBI). However, the utility of SBDP biomarkers for detecting effects of therapeutic interventions has not been explored. Acetylcholine plays a role in pathological neuronal excitation and TBI-induced muscarinic cholinergic receptor activation may contribute to excitotoxic processes. In experiment I, regional and temporal changes in calpain-mediated ?-spectrin degradation were evaluated at 3, 12, 24, and 48?h using immunostaining for 145-kDa SBDP. Immunostaining of SBDP-145 was only evident in the hemisphere ipsilateral to TBI and was generally limited to the cortex except at 24?h when immunostaining was also prominent in the dentate gyrus and striatum. In Experiment II, cerebral spinal fluid (CSF) samples were analyzed for various SBDPs 24?h after moderate lateral fluid percussion TBI. Rats were administered either dicyclomine (5?mg/kg i.p.) or saline vehicle (n?=?8 per group) 5?min prior to injury. Injury produced significant increases (p?1000% in SBDP-150,??145, and ?120, respectively in vehicle-treated rats compared to sham. Dicyclomine treatment produced decreases of 38% (p?=?0.077), 37% (p?=?0.028), and 63% (p?=?0.051) in SBDP-150,??145, and ?120, respectively, compared to vehicle-treated injury. Following CSF extraction, coronal brain sections were processed for detecting degenerating neurons using Fluoro-Jade histofluorescence. Stereological techniques were used to quantify neuronal degeneration in the dorsal hippocampus CA2/3 region and in the parietal cortex. No significant differences were detected in numbers of degenerating neurons in the dorsal CA2/3 hippocampus or the parietal cortex between saline and dicyclomine treatment groups. The percent weight loss following TBI was significantly reduced by dicyclomine treatment. These data provide additional evidence that, as TBI biomarkers, SBDPs are able to detect a therapeutic intervention even in the absence of changes in neuronal cell degeneration measured by Fluoro-jade.

Cox, Christopher D.; West, Eric J.; Liu, Ming Cheng; Wang, Kevin K.W.; Hayes, Ronald L.



Lithium reduced neural progenitor apoptosis in the hippocampus and ameliorated functional deficits after irradiation to the immature mouse brain.  


Lithium was recently shown to inhibit apoptosis and promote survival of neural progenitor cells after hypoxia-ischemia in the immature rat brain. Our aim was to evaluate the effects of lithium on cell death and proliferation in the hippocampus after irradiation (IR) to the immature brain. Male mice were injected with 2 mmol/kg lithium chloride i.p. on postnatal day 9 (P9) and additional lithium injections, 1 mmol/kg, were administered at 24 h intervals for up to 7 days. BrdU was injected 4 h after lithium injections on P9 and P10. The left hemisphere received a single dose of 8 Gy (MV photons) on P11. The animals were euthanized 6 h or 7 weeks after IR. The number of BrdU-labeled cells in the subgranular zone (SGZ) of the granule cell layer (GCL) 6h after IR was 24% higher in the lithium-treated mice. The number of proliferating, phospho-histone H3-positive cells in the SGZ 7 weeks after IR was 59% higher in the lithium group, so the effect was long-lasting. The number of apoptotic cells in the SGZ 6 h after IR was lower in the lithium group, as judged by 3 different parameters, pyknosis, staining for active caspase-3 and TUNEL. Newly formed cells (BrdU-labeled 1 or 2 days before IR) showed the greatest degree of protection, as judged by 50% fewer TUNEL-positive cells, whereas non-BrdU-labeled cells showed 38% fewer TUNEL-positive cells 6 h after IR. Consequently, the growth retardation of the GCL was less pronounced in the lithium group. The number and size of microglia in the DG were also lower in the lithium group, indicating reduced inflammation. Learning was facilitated after lithium treatment, as judged by improved context-dependent fear conditioning, and improved place learning, as judged by assessment in the IntelliCage platform. In summary, lithium administration could decrease IR-induced neural progenitor cell apoptosis in the GCL of the hippocampus and ameliorate learning impairments. It remains to be shown if lithium can be used to prevent the debilitating cognitive late effects seen in children treated with cranial radiotherapy. PMID:22800605

Huo, Kaiming; Sun, Yanyan; Li, Hongfu; Du, Xiaonan; Wang, Xiaoyang; Karlsson, Niklas; Zhu, Changlian; Blomgren, Klas



Retrograde, transneuronal spread of pseudorabies virus in defined neuronal circuitry of the rat brain is facilitated by gE mutations that reduce virulence.  


The pseudorabies virus (PRV) gE gene encodes a multifunctional membrane protein found in infected cell membranes and in the virion envelope. Deletion of the gE gene results in marked attenuation of the virus in almost every animal species tested that is permissive for PRV. A common inference is that gE mutants are less virulent because they have reduced ability to spread from cell to cell; e.g., gE mutants infect fewer cells and, accordingly, animals live longer. In this report, we demonstrate that this inference does not hold in a rat experimental model for virus invasion of the brain. We find that animals infected with gE mutants live longer despite extensive retrograde, transneuronal spread of virus in the rat brain. In this model of brain infection, virus is injected into the stomach musculature and virions spread to the brain in long axons of brain stem neurons that give rise to the tenth cranial nerve (the vagus). The infection then spreads from neuron to neuron in well-defined, and physically separated, areas of the brain involved in autonomic regulation of the viscera. We examined the progression of infection of five PRV strains in this circuitry: the wild-type PRV-Becker strain, the attenuated PRV-Bartha vaccine strain, and three gE mutants isogenic with the PRV-Becker strain. By 60 to 67 h after infection, all PRV-Becker-infected animals were dead. Analysis of Becker-infected rats killed prior to virus-induced death demonstrated that the virus had established an infection only in the primary vagal neurons connected directly to the stomach and synaptically linked neurons in the immediate vicinity of the caudal brain stem. There was little spread to other neurons in the vagus circuitry. In contrast, rats infected with PRV-Bartha or PRV-Becker gE mutants survived to at least 96 h and exhibited few overt signs of disease. Despite this long survival and the lack of symptoms, brains of animals sacrificed at this time revealed extensive transsynaptic infection not only of the brain stem but also of areas of the forebrain synaptically linked to neurons in the brain stem. This finding provides evidence that the gE protein plays a role in promoting symptoms of infection and death in animals that is independent of neuron-to-neuron spread during brain infection. When this early virulence function is not active, animals live longer, resulting in more extensive spread of virus in the brain. PMID:10196333

Yang, M; Card, J P; Tirabassi, R S; Miselis, R R; Enquist, L W



Cardiac MRI of Edema in Acute Myocardial Infarction using Cine Balanced SSFP: A Translational Study  

PubMed Central

Objective To investigate the capabilities of balanced steady-state-free-precession (bSSFP) MRI as a novel cine imaging approach for characterizing myocardial edema in animals and patients following reperfused myocardial infarction. Background Current MRI methods require two separate scans for assessment of myocardial edema and cardiac function. Methods Mini-pigs (n=13) with experimentally induced reperfused myocardial infarction and patients with reperfused STEMI (n=26) underwent MR scans on days 2–4 post reperfusion. Cine bSSFP, T2-STIR, and late-gadolinium enhancement (LGE) were performed at 1.5T. Cine bSSFP and T2-STIR images were acquired with body coil to mitigate surface coil bias. Signal, contrast and the area of edema were compared. Additional patients (n=10) were analyzed for the effect of microvascular obstruction on bSSFP. A receiver-operator-characteristic analysis was performed to assess the accuracy of edema detection. Results An area of hyperintense bSSFP signal consistent with edema was observed in the infarction zone (contrast-to-noise ratio (CNR) 37±13) in all animals and correlated well with the area of LGE (R=0.83, p<0.01). In all patients, T2-STIR and bSSFP images showed regional hyperintensity in the infarction zone. Normalized CNR were not different between T2-STIR and bSSFP. On a slice-basis, the volumes of hyperintensity on T2-STIR and bSSFP images correlated well (R=0.86, p<0.001), and their means were not different. When compared with T2-STIR, bSSFP was positive for edema in 25/26 patients (sensitivity of 96%) and was negative in all controls (specificity 100%). All patients with MVO showed a significant reduction of signal in the subendocardial infarction zone, compared to infarcted epicardial tissue without MVO (p<0.05). Conclusion Myocardial edema from STEMI can be detected using cine bSSFP imaging with image contrast similar to T2-STIR. This new imaging approach allows for evaluating cardiac function and edema simultaneously, thereby reducing patient scan time and increasing efficiency. Further work is necessary to optimize edema contrast in bSSFP images.

Kumar, Andreas; Beohar, Nirat; Arumana, Jain Mangalathu; Larose, Eric; Li, Debiao; Friedrich, Matthias G; Dharmakumar, Rohan



Reperfusion of cerebral artery thrombosis by the GPIb-VWF blockade with the Nanobody ALX-0081 reduces brain infarct size in guinea pigs.  


Thrombolytic therapy is the cornerstone of treatment of acute atherothrombotic ischemic stroke but is associated with brain hemorrhage; antiplatelet therapy has limited efficacy and is still associated with intracranial bleeding. Therefore, new antithrombotic approaches with a better efficacy/safety ratio are required. We have assessed the effect of ALX-0081, a Nanobody against the A1 domain of von Willebrand factor (VWF) that blocks VWF binding to GPIb, of the thrombolytic agent recombinant tissue plasminogen activator (rtPA), and of the GPIIb/IIIa antagonist tirofiban, in a middle cerebral artery (MCA) thrombosis model in guinea pigs. Drugs were administered before, immediately after, or 15 or 60 minutes after the total occlusion of the MCA. ALX-0081 prevented MCA thrombosis and induced reperfusion when given immediately after and 15 minutes after complete occlusion and reduced brain damage without inducing hemorrhage, whereas tirofiban prevented thrombosis but did not induce reperfusion and induced striking brain hemorrhage. rtPA also induced reperfusion when given 60 minutes after occlusion but provoked brain hemorrhage. Skin bleeding time was not modified or was moderately prolonged by ALX-0081, whereas tirofiban and rtPA prolonged it. The inhibition of the GPIb-VWF axis in guinea pigs prevents cerebral artery thrombosis and induces early reperfusion without provoking intracerebral bleeding thus reducing brain infarct area. PMID:23589671

Momi, Stefania; Tantucci, Michela; Van Roy, Maarten; Ulrichts, Hans; Ricci, Giovanni; Gresele, Paolo



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

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.

Epelbaum, J.; Dussaillant, M.; Enjalbert, A.; Kordon, C.; Rostene, W.



Acquired Brain Pathology  

Microsoft Academic Search

\\u000a Acute brain injury is rarely seen, but salient features include acute hemorrhage, thrombosis, and localized or general edema.\\u000a Findings are rarely specific with regard to etiology. In addition to maternal disease, risk factors for acquired brain lesions\\u000a include disorders of the placenta and\\/or umbilical cord, exposure to toxic agents, metabolic disease, iatrogenic hazards,\\u000a fetal cardiovascular disease, and space-occupying lesions. Most

Daniela Prayer; Ulrika Asenbaum; Peter C. Brugger; Gregor Kasprian


Activation of liver X receptor reduces global ischemic brain injury by reduction of nuclear factor-?B  

Microsoft Academic Search

Recent studies have found that liver X receptors (LXRs) agonists decrease brain inflammation and exert neuroprotective effect. The aim of this study was to examine the mechanisms of action of liver X receptor agonist GW3965 against brain injury following global cerebral ischemia in the rat. The 48 male SD (Sprague–Dawley) rats were randomly partitioned into three groups: sham, global ischemia

O. Cheng; R. P. Ostrowski; W. Liu; J. H. Zhang



Grid photocoagulation combined with intravitreal bevacizumab for recurrent macular edema associated with retinal vein occlusion  

PubMed Central

Purpose: To report the efficacy of grid photocoagulation combined with intravitreal bevacizumab (IVB) for macular edema recurring after previous IVBs associated with retinal vein occlusion (RVO). Methods: This retrospective study consisted of 19 eyes with branch retinal vein occlusion (BRVO) and nine eyes with central retinal vein occlusion (CRVO), which were treated with grid photocoagulation combined with IVB for recurrent macular edema after previous IVBs. The mean duration of total follow-up was 29.3 ± 5.8 months. Results: After this combination therapy, foveal thickness was reduced, significant with slight improvement in visual acuity (VA). At 1 month after treatment, although 25 of the 28 eyes showed complete resolution of the cystoid space, the macular edema recurred to some extent in 19 eyes. Compared with initial values, final foveal thickness was reduced significantly in both BRVO and CRVO groups (P < 0.001), but improvement in VA was significant only for eyes with BRVO (P = 0.012). The total number of IVB was 2.8 ± 0.7 for eyes with either BRVO or CRVO. Conclusion: Grid photocoagulation combined with IVB has a substantial effect on reducing recurrent macular edema associated with RVO, but the effect on visual acuity is limited.

Ogino, Ken; Tsujikawa, Akitaka; Murakami, Tomoaki; Muraoka, Yuki; Kurashige, Yumiko; Yoshimura, Nagahisa



Transcranial Doppler sonography and intracranial pressure monitoring in children and juveniles with acute brain injuries or hydrocephalus  

Microsoft Academic Search

Transcranial Doppler sonography is a noninvasive method of obtaining information about changes in cerebral hemodynamics and intracranial pressure. After severe head injuries the development of brain swelling and brain edema can be assessed and the efficacy of treatment monitored. Development of severe brain edema accompanied by a rapid increase in intracranial pressure can be recognized by a decrease in blood

P. Sanker; K. E. Richard; H. C. Weigl; N. Klug; K. van Leyen



Improved perioperative neurological monitoring of coronary artery bypass graft patients reduces the incidence of postoperative delirium: the Haga Brain Care Strategy  

PubMed Central

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.

Palmbergen, Wijnand A.C.; van Sonderen, Agnes; Keyhan-Falsafi, Ali M.; Keunen, Ruud W.M.; Wolterbeek, Ron



Lymphoscintigraphy in the evaluation of limb edema.  


Lymphedema is a chronic condition caused by ineffective lymphatic transport that results in edema and skin damage. Distinguishing lymphedema from other causes can be difficult. Lymphoscintigraphy is a simple and noninvasive functional test for the evaluation of the lymphatic system. Technetium-labeled sulfur colloid is injected intradermally at the interdigital web spaces of the upper/lower limbs. Once injected, the radiolabeled colloid particles travel through the superficial lymphatic channels. Thus, their lymphatic transport is monitored with dual-head gamma camera. The typical patterns of upper and lower limb lymphedema on lymphoscintigraphy are summarized in this section. PMID:24089069

Sundaram, P Shanmuga; Subramanyam, Padma



Reduced brain corticotropin-releasing factor receptor activation is required for adequate maternal care and maternal aggression in lactating rats.  


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

Klampfl, Stefanie M; Neumann, Inga D; Bosch, Oliver J



Hemorrhagic stroke associated with pulmonary edema and catastrophic cardiac failure.  


Cerebral arteriovenous fistula (AVF) is a vascular malformation that is rare in the pediatric population. Older children with cerebral AVF tend to present with neurologic problems related to intracranial venous hypertension or intracranial hemorrhage. Cardiac and pulmonary complications following acute neurologic injury such as subarachnoid hemorrhage are common in adults, but are rarely reported in children. However, complications have been reported in cases of enterovirus 71 rhombencephalitis in infants and children and can cause high morbidity and mortality. Here, we report a 14-year-old boy who presented with cardiac failure associated with pulmonary edema following cerebral hemorrhagic stroke due to AVF. After aggressive investigation and management, we intervened before significant hypoxia and hypotension developed, potentially reducing the risk of long-term adverse neurologic consequences in this patient. PMID:18947007

Lee, Jiun-Chang; Lin, Jainn-Jim; Lin, Kuang-Lin; Hsia, Shao-Hsuan; Wu, Chang-Teng; Wong, Alex Mun-Ching



Treatment of macular edema due to retinal vein occlusions  

PubMed Central

Retinal vein occlusion (RVO) is a prevalent retinal vascular disease, second only to diabetic retinopathy. Previously there was no treatment for central retinal vein occlusion (CRVO) and patients were simply observed for the development of severe complications, generally resulting in poor visual outcomes. The only treatment for branch vein occlusion (BRVO) was grid laser photocoagulation, which reduces edema very slowly and provides benefit in some, but not all patients. Within the past year, clinical trials have demonstrated the effects of three new pharmacologic treatments, ranibizumab, triamcinolone acetonide, and dexamethasone implants. The benefit/risk ratio is best for intraocular injections of ranibizumab, making this first-line therapy for most patients with CRVO or BRVO, while intraocular steroids are likely to play adjunctive roles. Standard care for patients with RVO has changed and will continue to evolve as results with other new agents are revealed.

Channa, Roomasa; Smith, Michael; Campochiaro, Peter A



Treatment of macular edema due to retinal vein occlusions.  


Retinal vein occlusion (RVO) is a prevalent retinal vascular disease, second only to diabetic retinopathy. Previously there was no treatment for central retinal vein occlusion (CRVO) and patients were simply observed for the development of severe complications, generally resulting in poor visual outcomes. The only treatment for branch vein occlusion (BRVO) was grid laser photocoagulation, which reduces edema very slowly and provides benefit in some, but not all patients. Within the past year, clinical trials have demonstrated the effects of three new pharmacologic treatments, ranibizumab, triamcinolone acetonide, and dexamethasone implants. The benefit/risk ratio is best for intraocular injections of ranibizumab, making this first-line therapy for most patients with CRVO or BRVO, while intraocular steroids are likely to play adjunctive roles. Standard care for patients with RVO has changed and will continue to evolve as results with other new agents are revealed. PMID:21629578

Channa, Roomasa; Smith, Michael; Campochiaro, Peter A



The Gut Hormones PYY3-36 and GLP-17-36 amide Reduce Food Intake and Modulate Brain Activity in Appetite Centers in Humans  

PubMed Central

Summary Obesity is a major public health issue worldwide. Understanding how the brain controls appetite offers promising inroads toward new therapies for obesity. Peptide YY (PYY) and glucagon-like peptide 1 (GLP-1) are coreleased postprandially and reduce appetite and inhibit food intake when administered to humans. However, the effects of GLP-1 and the ways in which PYY and GLP-1 act together to modulate brain activity in humans are unknown. Here, we have used functional MRI to determine these effects in healthy, normal-weight human subjects and compared them to those seen physiologically following a meal. We provide a demonstration that the combined administration of PYY3-36 and GLP-17-36 amide to fasted human subjects leads to similar reductions in subsequent energy intake and brain activity, as observed physiologically following feeding.

De Silva, Akila; Salem, Victoria; Long, Christopher J.; Makwana, Aidan; Newbould, Rexford D.; Rabiner, Eugenii A.; Ghatei, Mohammad A.; Bloom, Stephen R.; Matthews, Paul M.; Beaver, John D.; Dhillo, Waljit S.



Laser Photocoagulation Combined with Intravitreal Triamcinolone Acetonide Injection in Proliferative Diabetic Retinopathy with Macular Edema  

PubMed Central

Purpose To evaluate therapeutic effects and usefulness of a combination treatment of intravitreal injection of triamcinolone acetonide (IVTA) and panretinal photocoagulation (PRP) in patients with clinically significant macular edema secondary to proliferative diabetic retinopathy (PDR). Methods Visual acuity test, fundoscopy, fluorescein angiography, and optical coherence tomography (OCT) were taken in 20 patients (20 eyes) of macular edema and PDR. A combination of intravitreal injection of triamcinolone acetonide and PRP was performed in 10 patients (10 eyes) and a combination of focal or grid laser photocoaqulation and PRP in the remaining 10 eyes. The postoperative outcomes were compared between the two combination treatments by best corrected visual acuity (BCVA), tonometry, fluorescein angiography, and OCT at 2 weeks, 1, 2, and 3 months. Results Average BCVA (log MAR) significantly improved from preoperative 0.56±0.20 to 0.43±0.08 at 1 month (P=0.042) and it was maintained until 3 months after a combination of IVTA and PRP in 10 eyes (P=0.007). The thickness of fovea decreased from average 433.3±114.9 µm to average 279.5±34.1 µm at 2 weeks after combined treatment of IVTA and PRP (P=0.005), which was significantly maintained until 3 months, but there was a transient visual disturbance and no significant difference in thickness of the fovea before and after treatment in the groups with PRP and focal or grid laser photocoagulation. Conclusions A combination of IVTA and PRP might be an effective treatment modality in the treatment of macular edema and PDR and prevent the subsequent PRP-induced macular edema result in visual dysfunction. In combination with PRP, IVTA might be more effective than focal or grid laser photocoagulation and PRP for reducing diabetic macular edema and preventing aggravation of macular edema without transient visual disturbance in patients requiring immediate PRP.

Chung, JK; Lim, Sang Hyun



Impaired brain development and reduced astrocyte response to injury in transgenic mice expressing IGF binding protein-1  

Microsoft Academic Search

Numerous reports indicate that insulin-like growth factor-I (IGF-I) has a critical role in brain development, that it contributes to neuronal survival and that its activity is regulated by a family of IGF binding proteins (IGFBPs). In the present study, brain development was investigated in transgenic (Tg) mice that overexpress rat IGFBP-1 under the control of phosphoglycerate kinase promoter. Adult Tg

W Ni; K Rajkumar; J. I Nagy; L. J Murphy



Reduced Expression of Brain-Enriched microRNAs in Glioblastomas Permits Targeted Regulation of a Cell Death Gene  

Microsoft Academic Search

Glioblastoma is a highly aggressive malignant tumor involving glial cells in the human brain. We used high-throughput sequencing to comprehensively profile the small RNAs expressed in glioblastoma and non-tumor brain tissues. MicroRNAs (miRNAs) made up the large majority of small RNAs, and we identified over 400 different cellular pre-miRNAs. No known viral miRNAs were detected in any of the samples

Rebecca L. Skalsky; Bryan R. Cullen



Spinal Morphine Administration Reduces the Fatty Acid Contents in Spinal Cord and Brain by Increasing Oxidative Stress  

Microsoft Academic Search

It is well known that oxidative stress damages bimolecules such as DNA and lipids. No study is available on the morphine-induced\\u000a oxidative damage and fatty acids changes in brain and spinal tissues. The aim of this work was to determine the effects of\\u000a morphine on the concentrations and compositions of fatty acid in spinal cord segments and brain tissues in

?smail Özmen; Mustafa Naz?ro?lu; H. Ahmet Alici; Fikrettin ?ahin; Mustafa Cengiz; ?brahim Eren



New Compton densitometer for measuring pulmonary edema  

SciTech Connect

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.

Loo, B.W.; Goulding, F.S.; Simon, D.S.



Vasogenic edema with intraparenchymatous expanding mass lesions: a theory on its pathophysiology and mode of action of hyperventilation and corticosteroids.  


Vasogenic edema with expanding mass brain lesions is hypothesized to be due to an increased intracapillary pressure. The latter may be due to preferential occlusion of the venous system by the growth of the lesion but endothelila proliferation and biogenic amines may also play a part. Endocytosis appears to be a mechanical response to the increased intraluminal pressure. This is a poorly selective process which can explain the proteinaceous nature of vasogenic edema. Steroids may act by forming hydrophobic bonds in the endothelial cell membrane and making it more difficult for any membrane fission to occur. Hyperventilation can be of use in vasogenic edema by decreasing intracranial pressure, providing better oxygenation and also by diminishing the capillary head pressure. PMID:6427564

Casanova, M F



Vitamin E reduces amyloidosis and improves cognitive function in Tg2576 mice following repetitive concussive brain injury.  


Traumatic brain injury is a well-recognized environmental risk factor for developing Alzheimer's disease. Repetitive concussive brain injury (RCBI) exacerbates brain lipid peroxidation, accelerates amyloid (Abeta) formation and deposition, as well as cognitive impairments in Tg2576 mice. This study evaluated the effects of vitamin E on these four parameters in Tg2576 mice following RCBI. Eleven-month-old mice were randomized to receive either regular chow or chow-supplemented with vitamin E for 4 weeks, and subjected to RCBI (two injuries, 24 h apart) using a modified controlled cortical impact model of closed head injury. The same dietary regimens were maintained up to 8 weeks post-injury, when the animals were killed for biochemical and immunohistochemical analyses after behavioral evaluation. Vitamin E-treated animals showed a significant increase in brain vitamin E levels and a significant decrease in brain lipid peroxidation levels. After RBCI, compared with the group on regular chow, animals receiving vitamin E did not show the increase in Abeta peptides, and had a significant attenuation of learning deficits. This study suggests that the exacerbation of brain oxidative stress following RCBI plays a mechanistic role in accelerating Alphabeta accumulation and behavioral impairments in the Tg2576 mice. PMID:15255955

Conte, Valeria; Uryu, Kunihiro; Fujimoto, Scott; Yao, Yuemang; Rokach, Joshua; Longhi, Luca; Trojanowski, John Q; Lee, Virginia M-Y; McIntosh, Tracy K; Praticò, Domenico



CAPS1 Deficiency Perturbs Dense-Core Vesicle Trafficking and Golgi Structure and Reduces Presynaptic Release Probability in the Mouse Brain.  


Ca(2+)-dependent activator protein for secretion 1 (CAPS1) plays a regulatory role in the dense-core vesicle (DCV) exocytosis pathway, but its functions at the cellular and synaptic levels in the brain are essentially unknown because of neonatal death soon after birth in Caps1 knock-out mice. To clarify the functions of the protein in the brain, we generated two conditional knock-out (cKO) mouse lines: 1) one lacking Caps1 in the forebrain; and 2) the other lacking Caps1 in the cerebellum. Both cKO mouse lines were born normally and grew to adulthood, although they showed subcellular and synaptic abnormalities. Forebrain-specific Caps1 cKO mice showed reduced immunoreactivity for the DCV marker secretogranin II (SgII) and the trans-Golgi network (TGN) marker syntaxin 6, a reduced number of presynaptic DCVs, and dilated trans-Golgi cisternae in the CA3 region. Cerebellum-specific Caps1 cKO mice had decreased immunoreactivity for SgII and brain-derived neurotrophic factor (BDNF) along the climbing fibers. At climbing fiber-Purkinje cell synapses, the number of DCVs was markedly lower and the number of synaptic vesicles was also reduced. Correspondingly, the mean amplitude of EPSCs was decreased, whereas paired-pulse depression was significantly increased. Our results suggest that loss of CAPS1 disrupts the TGN-DCV pathway, which possibly impairs synaptic transmission by reducing the presynaptic release probability. PMID:24174665

Sadakata, Tetsushi; Kakegawa, Wataru; Shinoda, Yo; Hosono, Mayu; Katoh-Semba, Ritsuko; Sekine, Yukiko; Sato, Yumi; Tanaka, Mika; Iwasato, Takuji; Itohara, Shigeyoshi; Furuyama, Kenichiro; Kawaguchi, Yoshiya; Ishizaki, Yasuki; Yuzaki, Michisuke; Furuichi, Teiichi



Cerebral edema associated with Gliadel wafers: Two case studies  

PubMed Central

While the introduction of carmustine wafers (Gliadel wafers) into the tumor resection cavity has been shown to be a beneficial therapy for malignant glioma, it is recognized that clinically significant cerebral edema is a potential adverse effect. Following are two clinical case reports demonstrating profound cerebral edema associated with implantation of Gliadel wafers. As a result, one of these individuals had premature death. A brief literature review is provided to assist in explaining the mechanisms by which clinically significant cerebral edema may develop.

Weber, Emil L.; Goebel, Eric A.



Mice Deficient for Testis-Brain RNA-Binding Protein Exhibit a Coordinate Loss of TRAX, Reduced Fertility, Altered Gene Expression in the Brain, and Behavioral Changes  

Microsoft Academic Search

Testis-brain RNA-binding protein (TB-RBP), the mouse orthologue of the human protein Translin, is a widely expressed and highly conserved protein with proposed functions in chromosomal translocations, mitotic cell division, and mRNA transport and storage. To better define the biological roles of TB-RBP, we generated mice lacking TB-RBP. Matings between heterozygotes gave rise to viable, apparently normal homozygous mutant mice at

Vargheese Chennathukuzhi; Joel M. Stein; Ted Abel; Stacy Donlon; Shicheng Yang; Juli P. Miller; David M. Allman; Rebecca A. Simmons; Norman B. Hecht



Effects of vasodilators on fibrin-induced pulmonary edema, so-called neurogenic pulmonary edema, in the rat  

Microsoft Academic Search

The present study was undertaken to evaluate the effects of vasodilators on the development of neurogenic pulmonary edema.\\u000a Pulmonary edema was induced by injecting fibrinogen and thrombin into the cisterna magna of vagotomized rats (fibrin-induced\\u000a pulmonary edema). Before the intrathecal injections, rats were pretreated with intravenous injection of one of the following\\u000a vasodilators: phentolamine, isoproterenol, nifedipine, diltiazem, isosorbide dinitrate, or

Kimitoshi Nishiwaki; Akiko Hirabayashi; Yasuhiro Shimada; Naohisa Ishikawa



Osteopontin reduced hypoxia-ischemia neonatal brain injury by suppression of apoptosis in a rat pup model  

PubMed Central

Background and Purpose Osteopontin (OPN) is neuroprotective in ischemic brain injuries in adult experimental models, therefore, we hypothesized that OPN would provide neuroprotection and improve long term neurological function in the immature brain after hypoxic-ischemic (HI) injury. Methods HI was induced by unilateral ligation of the right carotid artery followed by hypoxia (8% O2 for 2h) in postnatal day 7 rats. OPN (0.03 µg or 0.1 µg) was injected intracerebroventricularly at 1h post HI. Temporal expression of endogenous OPN was evaluated in the normal rat brain at the age of day 0, 4, 7, 11, 14, and 21, and in the ipsilateral hemisphere following HI. The effects of OPN were evaluated using TTC staining, apoptotic cell death assay, and cleaved caspase-3 expression. Neurological function was assessed by Morris water maze test. Results Endogenous OPN expression in the brain was the highest at the age of day 0, with continuous reduction till the age of day 21 during development. After HI injury, endogenous OPN expression was increased and peaked at 48h. Exogenous OPN decreased infarct volume and improved neurological outcomes 7 weeks after HI injury. OPN-induced neuroprotection was blocked by an integrin antagonist. Conclusions OPN-induced neuroprotection was associated with cleaved-caspase-3 inhibition and antiapoptotic cell death. OPN treatment improved long-term neurological function against neonatal HI brain injury.

Chen, Wanqiu; Ma, Qingyi; Suzuki, Hidenori; Hartman, Richard; Tang, Jiping; Zhang, John H.



Hypercapnic cerebral edema presenting in a woman with asthma: a case report  

PubMed Central

Introduction Common causes of non-traumatic acute cerebral edema include malignant hypertension, hyponatremia, anoxia, and cerebral vascular accident. The computed tomographic images and data obtained during care of the patient described in this case report provide evidence that hypercarbia can cause increased intracranial pressure and coma without permanent brain injury. Partial pressure of carbon dioxide evaluation for coma is essential to provide faster diagnosis and therapeutic correction in certain common critical disease states. We present the case of a patient in a coma associated with cerebral edema during a typical asthma exacerbation with hypercapnic respiratory failure. Case presentation An obese 63-year-old African American woman with asthma presented to our hospital with facial swelling and shortness of breath. Immediately following intubation for hypercapnic respiratory failure, she was noted to have a dilated, unresponsive right pupil. An emergent computed tomographic head scan revealed that she had increased intracranial pressure. A neurosurgeon agreed with the computed tomography interpretation and recommended no surgical intervention. The patient's respiratory acidosis was corrected with ventilatory management over several hours in the intensive care unit. Nine and one-half hours later a follow-up head computed tomographic scan was read as normal without cerebral edema. At 12 hours, the patient's right pupil was 5 mm in diameter and reactive. By 24 hours, her pupils were symmetrically equal and reactive. Her symptoms had improved, and she was extubated. A brain magnetic resonance imaging scan revealed no abnormalities. Conclusion Alteration of consciousness related to hypercapnia during respiratory failure is not generally thought to be related to cerebral edema. Respiratory acidosis resulting from hypercarbia is known to produce carbon dioxide narcosis and coma, but no current treatment algorithm suggests that rapid hypercapnia correction can be critical to neurologic outcome. To the best of our knowledge, our case is a unique example of the physiological changes that may occur in relation to arterial carbon dioxide concentration in the normal brain in the setting of typical hypercapnic respiratory failure. Correction of respiratory acidosis reversed the neurologic symptoms and physiology causing cerebral edema and coma in our patient. Rare similar cases have been sporadically reported in the medical literature, typically in children. Our case is also unusual in that rapid deterioration and clinical status were directly observed on simultaneous computed tomographic scans. Had this patient been found unresponsive, or had she had brief respiratory or cardiac arrest, the scan could have been interpreted as global anoxic injury leading to a different therapeutic course.



Chronic l-deprenyl treatment alters brain monoamine levels and reduces impulsiveness in an animal model of Attention-Deficit\\/Hyperactivity Disorder  

Microsoft Academic Search

Effects of chronic l-deprenyl administration on hyperactive behaviour and brain monoamine levels were studied in spontaneously hypertensive rats (SHR) and Wistar–Kyoto (WKY) rats. SHR were hyperactive, impulsive and had impaired sustained attention when tested with a multiple 2-min fixed interval (FI) 5-min extinction (EXT) schedule of reinforcement. Even low, 0.25 mg\\/kg, doses of chronically-administered l-deprenyl reduced the impulsiveness (bursts of

Fernando Boix; Shuo-wang Qiao; Tone Kolpus; Terje Sagvolden



Anorexia nervosa is linked to reduced brain structure in reward and somatosensory regions: a meta-analysis of VBM studies  

PubMed Central

Background Structural imaging studies demonstrate brain tissue abnormalities in eating disorders, yet a quantitative analysis has not been done. Methods In global and regional meta-analyses of 9 voxel-based morphometry (VBM) studies, with a total of 228 eating disorder participants (currently ill with anorexia nervosa), and 240 age-matched healthy controls, we compare brain volumes using global and regional analyses. Results Anorexia nervosa (AN) patients have global reductions in gray (effect size?=??0.66) and white matter (effect size?=??0.74) and increased cerebrospinal fluid (effect size?=?0.98) and have regional decreases in left hypothalamus, left inferior parietal lobe, right lentiform nucleus and right caudate, and no significant increases. No significant difference in hemispheric lateralization was found. Conclusions Global and regional meta-analyses suggest that excessive restrained eating as found in those with anorexia nervosa coincides with structural brain changes analogous to clinical symptoms.



Dietary omega-3 fatty acids normalize BDNF levels, reduce oxidative damage, and counteract learning disability after traumatic brain injury in rats.  


Omega-3 fatty acids (i.e., docosahexaenoic acid; DHA) regulate signal transduction and gene expression, and protect neurons from death. In this study we examined the capacity of dietary omega3 fatty acids supplementation to help the brain to cope with the effects of traumatic injury. Rats were fed a regular diet or an experimental diet supplemented with omega-3 fatty acids, for 4 weeks before a mild fluid percussion injury (FPI) was performed. FPI increased oxidative stress, and impaired learning ability in the Morris water maze. This type of lesion also reduced levels of brain-derived neurotrophic factor (BDNF), synapsin I, and cAMP responsive element-binding protein (CREB). It is known that BDNF facilitates synaptic transmission and learning ability by modulating synapsin I and CREB. Supplementation of omega-3 fatty acids in the diet counteracted all of the studied effects of FPI, that is, normalized levels of BDNF and associated synapsin I and CREB, reduced oxidative damage, and counteracted learning disability. The reduction of oxidative stress indicates a benevolent effect of this diet on mechanisms that maintain neuronal function and plasticity. These results imply that omega-3 enriched dietary supplements can provide protection against reduced plasticity and impaired learning ability after traumatic brain injury. PMID:15672635

Wu, Aiguo; Ying, Zhe; Gomez-Pinilla, Fernando



Dietary Virgin Olive Oil Reduces Oxidative Stress and Cellular Damage in Rat Brain Slices Subjected to Hypoxia–Reoxygenation  

Microsoft Academic Search

We investigated how virgin olive oil (VOO) affected platelet and hypoxic brain damage in rats. Rats were given VOO orally\\u000a for 30 days at 0.25 or 0.5 mL kg?1 per day (doses A and B, respectively). Platelet aggregation, thromboxane B2, 6-keto-PGF1?, and nitrites + nitrates were measured, and hypoxic damage was evaluated in a hypoxia–reoxygenation assay with fresh brain\\u000a slices. Oxidative stress, prostaglandin E\\u000a 2,

J. A. González-Correa; J. Muñoz-Marín; M. M. Arrebola; A. Guerrero; F. Narbona; J. A. López-Villodres; J. P. De La Cruz



Smoke aldehyde component influences pulmonary edema  

SciTech Connect

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)

Hales, C.A.; Musto, S.W.; Janssens, S.; Jung, W.; Quinn, D.A.; Witten, M. (Department of Medicine (Pulmonary/Critical Care Unit), Massachusetts General Hospital, Boston (United States))



Oxygen-deficient metabolism and corneal edema.  


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

Leung, B K; Bonanno, J A; Radke, C J



Anthrax Edema Toxin Impairs Clearance in Mice  

PubMed Central

The anthrax edema toxin (ET) of Bacillus anthracis is composed of the receptor-binding component protective antigen (PA) and of the adenylyl cyclase catalytic moiety, edema factor (EF). Uptake of ET into cells raises intracellular concentrations of the secondary messenger cyclic AMP, thereby impairing or activating host cell functions. We report here on a new consequence of ET action in vivo. We show that in mouse models of toxemia and infection, serum PA concentrations were significantly higher in the presence of enzymatically active EF. These higher concentrations were not caused by ET-induced inhibition of PA endocytosis; on the contrary, ET induced increased PA binding and uptake of the PA oligomer in vitro and in vivo through upregulation of the PA receptors TEM8 and CMG2 in both myeloid and nonmyeloid cells. ET effects on protein clearance from circulation appeared to be global and were not limited to PA. ET also impaired the clearance of ovalbumin, green fluorescent protein, and EF itself, as well as the small molecule biotin when these molecules were coinjected with the toxin. Effects on injected protein levels were not a result of general increase in protein concentrations due to fluid loss. Functional markers for liver and kidney were altered in response to ET. Concomitantly, ET caused phosphorylation and activation of the aquaporin-2 water channel present in the principal cells of the collecting ducts of the kidneys that are responsible for fluid homeostasis. Our data suggest that in vivo, ET alters circulatory protein and small molecule pharmacokinetics by an as-yet-undefined mechanism, thereby potentially allowing a prolonged circulation of anthrax virulence factors such as EF during infection.

Sastalla, Inka; Tang, Shixing; Crown, Devorah; Liu, Shihui; Eckhaus, Michael A.; Hewlett, Indira K.; Leppla, Stephen H.



The inhibitory effect of S-nitrosoglutathione on blood-brain barrier disruption and peroxynitrite formation in a rat model of experimental stroke  

PubMed Central

The hallmark of stroke injury is endothelial dysfunction leading to blood brain barrier (BBB) leakage and edema. Among the causative factors of BBB disruption are accelerating peroxynitrite formation and the resultant decreased bioavailability of nitric oxide (NO). S-nitrosoglutathione (GSNO), an S-nitrosylating agent, was found not only to reduce the levels of peroxynitrite but also to protect the integrity of BBB in a rat model of cerebral ischemia and reperfusion (IR). A treatment with GSNO (3 ?mol/kg) after IR reduced 3-nitrotyrosine levels in and around vessels and maintained NO levels in brain. This mechanism protected endothelial function by reducing BBB leakage, increasing the expression of Zonula occludens-1 (ZO-1), decreasing edema, and reducing the expression of MMP-9 and E-selectin in the neurovascular unit. An administration of the peroxynitrite-forming agent 3-morpholino sydnonimine (3 ?mol/kg) at reperfusion increased BBB leakage and decreased the expression of ZO-1, supporting the involvement of peroxynitrite in BBB disruption and edema. Mechanistically, the endothelium-protecting action of GSNO was invoked by reducing the activity of NF-?B and increasing the expression of S-nitrosylated proteins. Taken together, the results support the ability of GSNO to improve endothelial function by reducing nitroxidative stress in stroke.

Khan, Mushfiquddin; Dhammu, Tajinder S; Sakakima, Harutoshi; Shunmugavel, Anadakumar; Gilg, Anne G; Singh, Avtar K.; Singh, Inderjit



Fast Resolution of Recurrent Pronounced Macular Edema following Intravitreal Injection of Dexamethasone 0.7 mg  

PubMed Central

Purpose To report the fast resolution of recurrent pronounced macular edema due to central retinal vein occlusion (CRVO) within 72 h following intravitreal injection of dexamethasone 0.7 mg (Ozurdex®). Methods An interventional case report with optical coherence tomography scans and fluorescein angiographic pictures. Results A 69-year-old Caucasian man underwent intravitreal injection of dexamethasone 0.7 mg due to incomplete CRVO. He had previously undergone 6 intravitreal injections of bevacizumab 1.25 mg (Avastin®) and a C-grid laser photocoagulation over an interval of 16 months. After repeated recurrences of macular edema, the injection of dexamethasone reduced the macular edema from 570 ?m preoperatively to 246 ?m postoperatively within 72 h following the injection. Best-corrected visual acuity improved from 0.1 to 0.6 within the same interval. Conclusion Dexamethasone can lead to a very fast reduction of macular edema in patients with vision loss due to CRVO and may facilitate an immediate visual rehabilitation. Retinal anatomy and visual acuity may be restored even in long-standing, recurrent cases.

Meyer, Linda M.; Schonfeld, Carl-Ludwig



A brain tumor segmentation framework based on outlier detection  

Microsoft Academic Search

This paper describes a framework for automatic brain tumor segmentation from MR images. The detection of edema is done simultaneously with tumor segmentation, as the knowledge of the extent of edema is important for diagnosis, planning, and treatment. Whereas many other tumor segmentation methods rely on the intensity enhancement produced by the gadolinium contrast agent in the T1-weighted image, the

Marcel Prastawa; Elizabeth Bullitt; Sean Ho; Guido Gerig



Is upregulation of benzodiazepine receptors a compensatory reaction to reduced GABAergic tone in the brain of stressed mice?  

Microsoft Academic Search

Effects of various forms of stress on the GABAA receptor-chloride ionophore complex in the brain of NMRI mice were investigated. Male albino mice were subjected to stress by placing them on small platforms (SP; 3.5 cm diameter) surrounded by water for 24 h. This experimental model contains several stress factors like rapid eye movement (REM) sleep deprivation, isolation, immobilization, falling

P. Pokk; T. Kivastik; D. Sobol; Sture Liljequist; A. Zharkovsky



Action expertise reduces brain activity for audiovisual matching actions: An fMRI study with expert drummers  

Microsoft Academic Search

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

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



Current-controlled deep brain stimulation reduces in vivo voltage fluctuations observed during voltage-controlled stimulation  

PubMed Central

Objective Clinical deep brain stimulation (DBS) systems typically utilize voltage-controlled stimulation and thus the voltage distribution generated in the brain can be affected by electrode impedance fluctuations. The goal of this study was to experimentally evaluate the theoretical advantages of using current-controlled pulse generators for DBS applications. Methods Time-dependent changes in the voltage distribution generated in the brain during voltage-controlled and current-controlled DBS were monitored with in vivo experimental recordings performed in non-human primates implanted with scaled-down clinical DBS electrodes. Results In the days following DBS lead implantation, electrode impedance progressively increased. Application of continuous stimulation through the DBS electrode produced a decrease in the electrode impedance in a time dependent manner, with the largest changes occurring within the first hour of stimulation. Over that time period, voltage-controlled stimuli exhibited an increase in the voltage magnitudes generated in the tissue near the DBS electrode, while current-controlled DBS showed minimal changes. Conclusion Large electrode impedance changes occur during DBS. During voltage-controlled stimulation, these impedance changes were significantly correlated with changes in the voltage distribution generated in the brain. However, these effects can be minimized with current-controlled stimulation. Significance The use of current-controlled DBS may help minimize time-dependent changes in therapeutic efficacy that can complicate patient programming when using voltage-controlled DBS.

Lempka, Scott F.; Johnson, Matthew D.; Miocinovic, Svjetlana; Vitek, Jerrold L.; McIntyre, Cameron C.



Excellent Tolerance to Cilnidipine in Hypertensives with Amlodipine - Induced Edema  

PubMed Central

Background: Ankle edema is a common adverse effect of amlodipine, an L-type calcium channel blocker (CCB). Cilnidipine is a newer L/N-type CCB, approved for treatment of essential hypertension. Aim: This study was designed to determine whether cilnidipine can produce resolution of amlodipine-induced edema while maintaining adequate control of hypertension. Materials and Methods: A prospective study was performed on 27 patients with essential hypertension with amlodipine-induced edema. Concomitant nephropathy, cardiac failure, hepatic cirrhosis, or other causes of edema, and secondary hypertension were excluded by appropriate tests. Amlodipine therapy was substituted in all the cases with an efficacy-equivalent dose of cilnidipine. Clinical assessment of ankle edema and measurement of bilateral ankle circumference, body weight, blood pressure, and pulse rate were performed at onset of the study and after 4 weeks of cilnidipine therapy. Results: At completion of the study, edema had resolved in all the patients. There was a significant decrease in bilateral ankle circumference and body weight (P < 0.001). There was no significant change in mean arterial blood pressure and pulse rate. Conclusions: Therapy with cilnidipine resulted in complete resolution of amlodipine-induced edema in all the cases without significant worsening of hypertension or tachycardia. Cilnidipine is an acceptable alternative antihypertensive for patients with amlodipine-induced edema.

Shetty, Ranjan; Vivek, G; Naha, Kushal; Tumkur, Anil; Raj, Abhinav; Bairy, K L



Fumonisin-induced pulmonary edema and hydrothorax in swine  

Microsoft Academic Search

Pulmonary edema and hydrothorax were observed in mature swine that died approximately 5 days after consuming corn screenings. These postmortem observations were reproduced in younger pigs that died within 1 week when fed the corn screenings under experimental conditions. Additionally, pulmonary edema and hydrothorax were induced in a pig that died after receiving 4 daily intravenous injections of fumonisin B1,

Bill M. Colvin; Lenn R. Harrison



Stem cell factor and granulocyte colony-stimulating factor reduce ?-amyloid deposits in the brains of APP/PS1 transgenic mice  

PubMed Central

Introduction Alzheimer's disease (AD) is widely recognized as a serious public health problem and heavy financial burden. Currently, there is no treatment that can delay or stop the progressive brain damage in AD. Recently, we demonstrated that stem cell factor (SCF) in combination with granulocyte colony-stimulating factor (G-CSF) (SCF+G-CSF) has therapeutic effects on chronic stroke. The purpose of the present study is to determine whether SCF+G-CSF can reduce the burden of ?-amyloid deposits in a mouse model of AD. Methods APP/PS1 transgenic mice were used as the model of AD. To track bone marrow-derived cells in the brain, the bone marrow of the APP/PS1 mice was replaced with the bone marrow from mice expressing green fluorescent protein (GFP). Six weeks after bone marrow transplantation, mice were randomly divided into a saline control group and a SCF+G-CSF-treated group. SCF in combination with G-CSF was administered subcutaneously for 12 days. Circulating bone marrow stem cells (CD117+ cells) were quantified 1 day after the final injection. Nine months after treatment, at the age of 18 months, mice were sacrificed. Brain sections were processed for immunohistochemistry to identify ?-amyloid deposits and GFP expressing bone marrow-derived microglia in the brain. Results Systemic administration of SCF+G-CSF to APP/PS1 transgenic mice leads to long-term reduction of ?-amyloid deposition in the brain. In addition, we have also observed that the SCF+G-CSF treatment increases circulating bone marrow stem cells and augments bone marrow-derived microglial cells in the brains of APP/PS1 mice. Moreover, SCF+G-CSF treatment results in enhancement of the co-localization of bone marrow-derived microglia and ?-amyloid deposits in the brain. Conclusions These data suggest that bone marrow-derived microglia play a role in SCF+G-CSF-induced long-term effects to reduce ?-amyloid deposits. This study provides insights into the contribution of the hematopoeitic growth factors, SCF and G-CSF, to limit ?-amyloid accumulation in AD and may offer a new therapeutic approach for AD.



Mechanisms of perianeurysmal edema following endovascular embolization of aneurysms.  


Summary: After coil embolization for an aneurysm, edema surrounding the aneurysm revealed by magnetic resonance imaging (MRI) is rarely seen and is usually associated with neurological symptoms. Perianeurysmal edema was found by postoperative MRI in three out of 182 patients with cerebral aneurysm, which was treated with Guglielmi Detachable Coil (GDC), and neurological symptoms developed simultaneously. In cases where neurological symptoms improved with conservative medical treatment, a temporary increase in the volume of an aneurysm, due to coil and thrombus formation, may result in edema. In cases where symptoms were not alleviated with conservative medical treatment, persistent water-hammer effect against the residual lumen of the aneurysm as well as an increase in the volume of aneurysm by hemorrhage in the aneurysmal wall may contribute to the development of perianeurysmal edema. Consideration of the mechanism of edema development by neurological symptoms, MRI findings, and angiographic findings is needed in order to select appropriate treatment. PMID:20566093

Tomokiyo, M; Kazekawa, K; Onizuka, M; Aikawa, H; Tsutsumi, M; Ikoh, M; Kodama, T; Nii, K; Matsubara, S; Tanaka, A



Mechanisms of Perianeurysmal Edema Following Endovascular Embolization of Aneurysms  

PubMed Central

Summary After coil embolization for an aneurysm, edema surrounding the aneurysm revealed by magnetic resonance imaging (MRI) is rarely seen and is usually associated with neurological symptoms. Perianeurysmal edema was found by postoperative MRI in three out of 182 patients with cerebral aneurysm, which was treated with Guglielmi Detachable Coil (GDC), and neurological symptoms developed simultaneously. In cases where neurological symptoms improved with conservative medical treatment, a temporary increase in the volume of an aneurysm, due to coil and thrombus formation, may result in edema. In cases where symptoms were not alleviated with conservative medical treatment, persistent water-hammer effect against the residual lumen of the aneurysm as well as an increase in the volume of aneurysm by hemorrhage in the aneurysmal wall may contribute to the development of perianeurysmal edema. Consideration of the mechanism of edema development by neurological symptoms, MRI findings, and angiographic findings is needed in order to select appropriate treatment.

Tomokiyo, M.; K., Kazekawa; Onizuka, M.; Aikawa, H.; Tsutsumi, M.; Ikoh, M.; Kodama, T.; Nii, K.; Matsubara, S.; Tanaka, A.



Decreased expression of nardilysin in SH-SY5Y cells under ethanol stress and reduced density of nardilysin-expressing neurons in brains of alcoholics.  


There is evidence for a genetic link between the metalloendopeptidase nardilysin and alcohol dependence, but the functional implication of the enzyme in alcoholism is unknown. Interestingly, some of the enzyme's substrates and interaction partners are altered in neural and non-neural tissues under the influence of ethanol consumption. To learn more about putative roles of nardilysin in alcohol dependence we studied the expression of the enzyme protein in human neuroblastoma cells under chronic ethanol exposure as well as in four brain regions of alcoholics and matched controls. Cultured SH-SY5Y cells were exposed for 96 h to two different concentrations of ethanol (50 and 200 mM). Nardilysin expression was determined using Western blotting with densitometric analysis. Furthermore, we morphometrically studied the cellular expression of nardilysin in postmortem brains of eight chronic alcoholics and nine controls by counting the number of nardilysin-immunopositive neurons in left frontal limbic area, Nuc. basalis of Meynert, paraventricular and supraoptic hypothalamic nuclei and calculating numerical cell densities. Nardilysin expression was significantly reduced after 96 h of SH-SY5Y cells exposure to 200 mM ethanol. In human brains nardilysin protein was localized to multiple neurons. In heavy drinkers there was a significantly reduced density of nardilysin immunoreactive neurons in Nuc. basalis of Meynert, paraventricular, and supraoptic nuclei. The alcohol-dependent reduction of nardilysin in cell culture and nervous tissue points to an implication of the enzyme in the pathophysiology of alcoholism. PMID:23219461

Bernstein, Hans-Gert; Stricker, Rolf; Zschiebsch, Katja; Müller, Susan; Dobrowolny, Henrik; Steiner, Johann; Bogerts, Bernhard; Reiser, Georg



Reduced permeation of /sup 14/C-sucrose, /sup 3/H-mannitol and /sup 3/H-inulin across blood-brain barrier in nephrectomized rats  

SciTech Connect

Experiments were carried out to determine if changes in the concentration-time profile of a blood-borne radiotracer such as /sup 14/C-sucrose would spuriously alter measurements of its permeation across the blood-brain barrier (permeability-area product, PA) based on a 2-compartment (plasma/brain) simple diffusion model. Anesthetized rats which were bilaterally nephrectomized and given a standard intravenous bolus injection of /sup 14/C-sucrose, /sup 3/H-mannitol or /sup 3/H-inulin exhibited an elevated plasma tracer concentration compared to control animals. However, tracer concentration measured in brain parenchyma after 30 min was not proportionally elevated, and PA calculated from the ratio, parenchymal tracer concentration: plasma concentration-time integral, was significantly reduced below control values. In control rats, distortion and elevation of the plasma /sup 14/C-sucrose profile by continuous intravenous infusion did not result in lowered PA values. This suggested that the lowering of PA by nephrectomy reflected reduced cerebrovascular permeability or area or other cerebral influence rather than a deficiency in the 2-compartment model for PA measurement.

Preston, E.; Haas, N.; Allen, M.



Reduced function of ?-aminobutyric acid A receptors in tottering mouse brain: Role of cAMP-dependent protein kinase  

Microsoft Academic Search

The single-locus mutant mouse tottering (tg) displays spontaneous seizures that resemble those in human petit-mal epilepsy. In order to examine alterations in GABAA receptor function which could arise as a result of this mutation, the influx of 36C1? was determined using microsacs (membrane vesicles) isolated from the brain of tg\\/tg and coisogenic C57BL\\/6J ( + \\/ + ) control mice.

Mohammad H. Jalilian Tehrani; Eugene M. Barnes



Reduced N-acetylaspartate content in the frontal part of the brain in patients with probable Alzheimer's disease  

Microsoft Academic Search

The fully relaxed water signal was used as an internal standard in a STEAM experiment to calculate the concentrations of the metabolites: N-acetylasparfate (NAA), creatine + phosphocreatine [Cr + PCr], and choline-containing metabolites (Cho) in the frontal part of the brain in 12 patients with probable Alzheimer's disease. Eight age-matched healthy volunteers served as controls. Furthermore, T1 and T2 relaxation

P. Christiansen; A. Schlosser; O. Henriksen



ZnT3 mRNA levels are reduced in Alzheimer's disease post-mortem brain  

Microsoft Academic Search

BACKGROUND: ZnT3 is a membrane Zn2+ transporter that is responsible for concentrating Zn2+ into neuronal presynaptic vesicles. Zn2+ homeostasis in the brain is relevant to Alzheimer's disease (AD) because Zn2+ released during neurotransmission may bind to A? peptides, accelerating the assembly of A? into oligomers which have been shown to impair synaptic function. RESULTS: We quantified ZnT3 mRNA levels in

Nancy Beyer; David TR Coulson; Shirley Heggarty; Rivka Ravid; G Brent Irvine; Jan Hellemans; Janet A Johnston



Reduced susceptibility to ischemic brain injury and N-methyl-D-aspartate-mediated neurotoxicity in cyclooxygenase-2-deficient mice  

Microsoft Academic Search

Cyclooxygenase-2 (COX-2), a prostanoid-synthesizing enzyme that contributes to the toxicity associated with inflammation, has recently emerged as a promising therapeutic target for several illnesses, ranging from osteoarthritis to Alzheimer's disease. Although COX-2 has also been linked to ischemic stroke, its role in the mechanisms of ischemic brain injury remains controversial. We demonstrate that COX-2-deficient mice have a significant reduction in

Costantino Iadecola; Kiyoshi Niwa; Shigeru Nogawa; Xueren Zhao; Masao Nagayama; Eiichi Araki; Scott Morham; M. Elizabeth Ross



Cerebellar Purkinje Cells are Reduced in a Subpopulation of Autistic Brains: A Stereological Experiment Using Calbindin-D28k  

Microsoft Academic Search

Although a decreased number of cerebellar Purkinje cells (PCs) in the autistic brain has been widely reported with a variety\\u000a of qualitative and quantitative methods, the more accurate method of cell counting with modern stereology has not yet been\\u000a employed. An additional possible problem with prior reports is the use of Nissl staining to identify the PCs, as this can

Elizabeth R. Whitney; Thomas L. Kemper; Margaret L. Bauman; Douglas L. Rosene; Gene J. Blatt



Reduced concentrations and increased metabolism of biogenic amines in a single case of Rett-syndrome: a postmortem brain study  

Microsoft Academic Search

Summary Preliminary data of a postmortem brain study in a single case with Rett-syndrome compared to a single control case show a severe reduction of dopamine (DA), noradrenaline (NA), and serotonin (5-HT) in most regions studied and in two regions of adrenaline (A). A marked increase in the 3,4-dihydroxyphenyl acetic acid (DOPAC)\\/DA, homovanillic acid (HVA)\\/ DA, and the 5-hydroxyindole acetic

T. Briicke; E. Sofic; W. Killian; A. Rett; P. Riederer



Overexpression of mitochondrial Hsp70\\/Hsp75 in rat brain protects mitochondria, reduces oxidative stress, and protects from focal ischemia  

Microsoft Academic Search

Mitochondria are known to be central to the cell's response to ischemia, because of their role in energy generation, in free radical generation, and in the regulation of apoptosis. Heat shock protein 75 (Hsp75\\/Grp75\\/mortalin\\/TRAP1) is a member of the HSP70 chaperone family, which is targeted to mitochondria. Overexpression of Hsp75 was achieved in rat brain by DNA transfection, and expression

Lijun Xu; Ludmila A Voloboueva; YiBing Ouyang; John F Emery; Rona G Giffard



1H MRS-detectable metabolic brain changes and reduced impulsive behavior in adult rats exposed to methylphenidate during adolescence  

Microsoft Academic Search

Administration of methylphenidate (MPH, Ritalin®) to children affected by attention deficit hyperactivity disorder (ADHD) is an elective therapy, which however raises concerns for public health, due to possible persistent neuro-behavioral alterations. We investigated potential long-term consequences at adulthood of MPH exposure during adolescence, by means of behavioral and brain MRS assessment in drug-free state. Wistar adolescent rats (30- to 44-day-old)

W. Adriani; R. Canese; F. Podo; G. Laviola



A CD11d monoclonal antibody treatment reduces tissue injury and improves neurological outcome after fluid percussion brain injury in rats.  


Traumatic brain injury (TBI) is an international health concern often resulting in chronic neurological abnormalities, including cognitive deficits, emotional disturbances, and motor impairments. An anti-CD11d monoclonal antibody that blocks the CD11d/CD18 integrin and vascular cell adhesion molecule (VCAM)-1 interaction following experimental spinal cord injury improves functional recovery, while reducing the intraspinal number of neutrophils and macrophages, oxidative activity, and tissue damage. Since the mechanisms of secondary injury in the brain and spinal cord are similar, we designed a study to evaluate fully the effects of anti-CD11d treatment after a moderate lateral fluid percussion TBI in the rat. Rats were treated at 2?h after TBI with either the anti-CD11d antibody or an isotype-matched control antibody 1B7, and both short (24- to 72-h) and long (4-week) recovery periods were examined. The anti-CD11d integrin treatment reduced neutrophil and macrophage levels in the injured brain, with concomitant reductions in lipid peroxidation, astrocyte activation, amyloid precursor protein accumulation, and neuronal loss. The reduced neuroinflammation seen in anti-CD11d-treated rats correlated with improved performance on a number of behavioral tests. At 24?h, the anti-CD11d group performed significantly better than the 1B7 controls on several water maze measures of spatial cognition. At 4 weeks post-injury the anti-CD11d-treated rats had better sensorimotor function as assessed by the beam task, and reduced anxiety-like behaviors, as evidenced by elevated-plus maze testing, compared to 1B7 controls. These findings suggest that neuroinflammation is associated with behavioral deficits after TBI, and that anti-CD11d antibody treatment is a viable strategy to improve neurological outcomes after TBI. PMID:22676851

Bao, Feng; Shultz, Sandy R; Hepburn, Jeff D; Omana, Vanessa; Weaver, Lynne C; Cain, Donald P; Brown, Arthur



Corncob Bedding Alters the Effects of Estrogens on Aggressive Behavior and Reduces Estrogen Receptor-? Expression in the Brain  

PubMed Central

There is growing appreciation that estrogen signaling pathways can be modulated by naturally occurring environmental compounds such as phytoestrogens and the more recently discovered xenoestrogens. Many researchers studying the effects of estrogens on brain function or behavior in animal models choose to use phytoestrogen-free food for this reason. Corncob bedding is commonly used in animal facilities across the United States and has been shown to inhibit estrogen-dependent reproductive behavior in rats. The mechanism for this effect was unclear, because the components of corncob bedding mediating this effect did not bind estrogen receptors. Here, we show in the California mouse (Peromyscus californicus) that estrogens decrease aggression when cardboard-based bedding is used but that this effect is absent when corncob bedding is used. California mice housed on corncob bedding also had fewer estrogen receptor-?-positive cells in the bed nucleus of the stria terminalis and ventromedial hypothalamus compared with mice housed on cardboard-based bedding. In addition, corncob bedding suppressed the expression of phosphorylated ERK in these brain regions as well as in the medial amygdala and medial preoptic area. Previous reports of the effects of corncob bedding on reproductive behavior are not widely appreciated. Our observations on the effects of corncob bedding on behavior and brain function should draw attention to the importance that cage bedding can exert on neuroendocrine research.

Landeros, Rosalina Villalon; Morisseau, Christophe; Yoo, Hyun Ju; Fu, Samuel H.; Hammock, Bruce D.



Corncob bedding alters the effects of estrogens on aggressive behavior and reduces estrogen receptor-? expression in the brain.  


There is growing appreciation that estrogen signaling pathways can be modulated by naturally occurring environmental compounds such as phytoestrogens and the more recently discovered xenoestrogens. Many researchers studying the effects of estrogens on brain function or behavior in animal models choose to use phytoestrogen-free food for this reason. Corncob bedding is commonly used in animal facilities across the United States and has been shown to inhibit estrogen-dependent reproductive behavior in rats. The mechanism for this effect was unclear, because the components of corncob bedding mediating this effect did not bind estrogen receptors. Here, we show in the California mouse (Peromyscus californicus) that estrogens decrease aggression when cardboard-based bedding is used but that this effect is absent when corncob bedding is used. California mice housed on corncob bedding also had fewer estrogen receptor-?-positive cells in the bed nucleus of the stria terminalis and ventromedial hypothalamus compared with mice housed on cardboard-based bedding. In addition, corncob bedding suppressed the expression of phosphorylated ERK in these brain regions as well as in the medial amygdala and medial preoptic area. Previous reports of the effects of corncob bedding on reproductive behavior are not widely appreciated. Our observations on the effects of corncob bedding on behavior and brain function should draw attention to the importance that cage bedding can exert on neuroendocrine research. PMID:22186416

Villalon Landeros, Rosalina; Morisseau, Christophe; Yoo, Hyun Ju; Fu, Samuel H; Hammock, Bruce D; Trainor, Brian C



Role of TRPV1 in nociception and edema induced by monosodium urate crystals in rats.  


Gout is characterized by the deposition of monosodium urate (MSU) crystals. Despite being one of the most painful forms of arthritis, gout and the mechanisms responsible for its acute attacks are poorly understood. In the present study, we found that MSU caused dose-related nociception (ED(50) [ie, the necessary dose of MSU to elicit 50% of the response relative to the control value]=0.04 [95% confidence interval 0.01-0.11]mg/paw) and edema (ED(50)=0.08 [95% confidence interval 0.04-0.16]mg/paw) when injected into the hind paw of rats. Treatment with the selective TRPV1 receptor (also known as capsaicin receptor and vanilloid receptor-1) antagonists SB366791 or AMG9810 largely prevented nociceptive and edematogenic responses to MSU. Moreover, the desensitization of capsaicin-sensitive afferent fibers as well as pretreatment with the tachykinin NK(1) receptor antagonist RP 67580 also significantly prevented MSU-induced nociception and edema. Once MSU was found to induce mast cell stimulation, we investigated the participation of these cells on MSU effects. Prior degranulation of mast cells by repeated treatment with the compound 48/80 decreased MSU-induced nociception and edema or histamine and serotonin levels in the injected tissue. Moreover, pretreatment with the mast cell membrane stabilizer cromolyn effectively prevented nociceptive and edematogenic responses to MSU. MSU induced a release of histamine, serotonin, and tryptase in the injected tissue, confirming mast cell degranulation. Furthermore, the antagonism of histaminergic H1 and serotoninergic receptors decreased the edema, but not the nociception of MSU. Finally, the prevention of the tryptase activity was capable of largely reducing both MSU-induced nociception and edema. Collectively, the present findings demonstrate that MSU produces nociceptive and edematogenic responses mediated by TRPV1 receptor activation and mast cell degranulation. PMID:21550723

Hoffmeister, Carin; Trevisan, Gabriela; Rossato, Mateus Fortes; de Oliveira, Sara Marchesan; Gomez, Marcus Vinícius; Ferreira, Juliano



Effects of indole-3-acetic acid on croton oil- and arachidonic acid-induced mouse ear edema  

Microsoft Academic Search

The indole-3-acetic acid (IAA) is a plant growth hormone (auxin) being considered as a tryptophan metabolite in animals. The main purpose of this work was to verify IAA's topical anti-inflammatory action using croton oil- or arachidonic acid-induced mouse ear edema, in comparison to known anti-inflammatory agents. IAA antioxidant activity was also verified by measuring the inhibition of brain homogenate lipid

L. H. Jones; D. S. P. Abdalla; J. C. Freitas



Scutellaria baicalensis attenuates blood-brain barrier disruption after intracerebral hemorrhage in rats.  


Disruption of the blood-brain barrier (BBB) contributes to the inflammatory response and edema formation in the brain, exacerbating brain damage. The present study evaluated the effects of Scutellaria baicalensis (SR) water extracts on BBB disruption after intracerebral hemorrhage (ICH) in rats. ICH was induced by stereotaxic intrastriatal injection of bacterial type VII collagenase, and SR was administrated orally three times (50 mg/ml/kg) during the 48 h after ICH onset. SR treatment significantly reduced the degree of (1) hemorrhage volume and edema percentage of the ipsilateral hemisphere, (2) brain water content, (3) MPO-positive neutrophil infiltration in the peri-hematoma, and (4) BBB permeability measured by Evans blue leakage. In addition, expression of matrix metalloproteinase (MMP)-9, MMP-12, and tissue inhibitor of MMPs (TIMP)-1 were investigated with immunohistochemistry. SR treatment reduced MMP-9 and MMP-12 expression in the peri-hematoma after ICH. These results indicate that SR attenuates the BBB disruption through anti-inflammatory effects and suppression of MMP expression. These findings provide a pharmacological basis for the use of SR in the treatment of the BBB disruption following stroke and trauma. PMID:22298450

Shin, Jung-Won; Kang, Ho-Chang; Shim, Jaewon; Sohn, Nak-Won



Effect of Vascular Normalization by Antiangiogenic Therapy on Interstitial Hypertension, Peritumor Edema, and Lymphatic Metastasis: Insights from a Mathematical Model  

PubMed Central

Preclinical and clinical evidence shows that antiangiogenic agents can decrease tumor vessel permeability and interstitial fluid pressure (IFP) in a process of vessel “normalization.” The resulting normalized vasculature has more efficient perfusion, but little is known about how tumor IFP and interstitial fluid velocity (IFV) are affected by changes in transport properties of the vessels and interstitium that are associated with antiangiogenic therapy. By using a mathematical model to simulate IFP and IFV profiles in tumors, we show here that antiangiogenic therapy can decrease IFP by decreasing the tumor size, vascular hydraulic permeability, and/or the surface area per unit tissue volume of tumor vessels. Within a certain window of antiangiogenic effects, interstitial convection within the tumor can increase dramatically, whereas fluid convection out of the tumor margin decreases. This would result in increased drug convection within the tumor and decreased convection of drugs, growth factors, or metastatic cancer cells from the tumor margin into the peritumor fluid or tissue. Decreased convection of growth factors, such as vascular endothelial growth factor-C (VEGF-C), would limit peritumor hyperplasia, and decreased VEGF-A would limit angiogenesis in sentinel lymph nodes. Both of these effects would reduce the probability of lymphatic metastasis. Finally, decreased fluid convection into the peritumor tissue would decrease peritumor edema associated with brain tumors and ascites accumulation in the peritoneal or pleural cavity, a major complication with a number of malignancies.

Jain, Rakesh K.; Tong, Ricky T.; Munn, Lance L.



NTCP Modeling of Subacute/Late Laryngeal Edema Scored by Fiberoptic Examination  

SciTech Connect

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.

Rancati, Tiziana [Prostate Program, Istituto Nazionale dei Tumori, Milano (Italy); Fiorino, Claudio, E-mail: fiorino.claudio@hsr.i [Medical Physics, San Raffaele Scientific Institute, Milano (Italy); Sanguineti, Giuseppe [Radiation Oncology, University of Texas Medical Branch, Galveston, TX (United States)



Medical management of patients with brain tumors  

Microsoft Academic Search

The most common medical problems in brain tumor patients include the management of seizures, peritumoral edema, medication side effects, venous thromboembolism (VTE), fatigue and cognitive dysfunction. Despite their importance, there are relatively few studies specifically addressing these issues. There is increasing evidence that brain tumor patients who have not had a seizure do not benefit from prophylactic antiepileptic medications. Patients

Patrick Y. Wen; David Schiff; Santosh Kesari; Jan Drappatz; Debra C. Gigas; Lisa Doherty



Robust Estimation for Brain Tumor Segmentation  

Microsoft Academic Search

Given models for healthy brains, tumor segmentation can be seen as a process of detecting abnormalities or outliers that are present with certain image intensity and geometric properties. In this paper, we propose a method that segments brain tumor and edema in two stages. We first detect intensity outliers using robust estimation of the location and dispersion of the normal

Marcel Prastawa; Elizabeth Bullitt; Sean Ho; Guido Gerig



Brain Weight and Sudden Infant Death Syndrome  

Microsoft Academic Search

Increased brain weights have been reported in the literature to occur among infants who have died from sudden infant death syndrome, suggesting that cerebral edema might play a role in the cause of death among these children. We have compared brain weights from children between the ages of 1 week and 1 year, autopsied between 1980 and 1992. One group

Geir Falck; Jovan Rajs



Economic Considerations of Macular Edema Therapies  

PubMed Central

Purpose To relate costs and treatment benefits for macular edema due to diabetes (DME) and branch and central retinal vein occlusion (BRVO, CRVO). Design A model of resource utilization, outcomes, and cost effectiveness and utility. Participants none Methods Results from published clinical trials (index studies) of laser, intravitreal corticosteroids, intravitreal anti-vascular endothelial growth factor (VEGF) agents, and vitrectomy trials were used to ascertain visual benefit and clinical protocols. Calculations followed from the costs of one year of treatment for each treatment modality and the visual benefits as ascertained. Main Outcome measures Visual acuity (VA) saved, cost of therapy, cost per line saved, cost per line-year saved, and costs per quality adjusted life years (QALYs). Results The lines saved for DME (0.26 to 2.02), BRVO (0.74 to 4.92), and CRVO (1.2 to 3.75) yielded calculations of costs/line of saved VA for DME ($1329 to 11609), BRVO ($494 to 13039), and CRVO ($704 to 7611), costs/line-year for DME ($60 to 561), BRVO ($25 to 754), and CRVO ($45 to 473), and costs/QALY of $824 to $25566. Conclusion Relative costs and benefits should be considered in perspective when applying and developing treatment strategies.

Smiddy, William E.



Subacute hemorrhage and resolution of edema in Rose Bengal stroke model in rats coincides with improved sensorimotor functions.  


The Rose Bengal model in rats is widely used to study brain plasticity, functional recovery and restorative therapies. The present study evaluated temporal profiles of hemorrhage and edema by magnetic resonance imaging (MRI) in rats in relation to sensorimotor impairment after photochemically induced cortical infarct. Adult, male Wistar rats were injected with Rose Bengal dye followed by illumination to produce a lesion over the sensorimotor cortex. Brain damage including infarct volume, edema, and bleeding was determined from postoperative days 1 to 10 by using MRI. Prussian blue staining was used to confirm hemorrhage in perfused brain sections. Functional outcome was assessed by limb-placing test during the follow-up. A consistent cortical lesion was detected in T(2) weighted MRI 24h after cortical photothrombosis without any signs of blood in T(2)(*) weighted images. However, from postoperative days 3 to 8, hemorrhage was indicated by almost complete signal void in T(2)(*) weighted gradient echo images and confirmed by Perls' Prussian blue staining on postoperative day 10 for presence of iron in corresponding lesion areas. The subacute appearance of hemorrhage on postoperative days 3-8 and resolution of edema coincides with improved performance in the limb-placing test. The results suggest that bleeding around cortical infarct is part of the wound healing process and may not impair functional outcome. PMID:17954010

Jolkkonen, Jukka; Jokivarsi, Kimmo; Laitinen, Teemu; Gröhn, Olli



Bevacizumab in Reducing CNS Side Effects in Patients Who Have Undergone Radiation Therapy to the Brain for Primary Brain Tumor, Meningioma, or Head and Neck Cancer

Adult Anaplastic Astrocytoma; Adult Anaplastic Ependymoma; Adult Anaplastic Meningioma; Adult Anaplastic Oligodendroglioma; Adult Brain Stem Glioma; Adult Central Nervous System Germ Cell Tumor; Adult Choroid Plexus Tumor; Adult Diffuse Astrocytoma; Adult Ependymoma; Adult Grade II Meningioma; Adult Grade III Meningioma; Adult Malignant Hemangiopericytoma; Adult Mixed Glioma; Adult Oligodendroglioma; Adult Papillary Meningioma; Adult Pineocytoma; Malignant Neoplasm; Meningeal Melanocytoma; Radiation Toxicity; Recurrent Adenoid Cystic Carcinoma of the Oral Cavity; Recurrent Adult Brain Tumor; Recurrent Basal Cell Carcinoma of the Lip; Recurrent Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Recurrent Inverted Papilloma of the Paranasal Sinus and Nasal Cavity; Recurrent Lymphoepithelioma of the Nasopharynx; Recurrent Lymphoepithelioma of the Oropharynx; Recurrent Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity; Recurrent Mucoepidermoid Carcinoma of the Oral Cavity; Recurrent Salivary Gland Cancer; Recurrent Squamous Cell Carcinoma of the Hypopharynx; Recurrent Squamous Cell Carcinoma of the Larynx; Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity; Recurrent Squamous Cell Carcinoma of the Nasopharynx; Recurrent Squamous Cell Carcinoma of the Oropharynx; Recurrent Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Recurrent Verrucous Carcinoma of the Larynx; Recurrent Verrucous Carcinoma of the Oral Cavity; Stage I Adenoid Cystic Carcinoma of the Oral Cavity; Stage I Basal Cell Carcinoma of the Lip; Stage I Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Stage I Inverted Papilloma of the Paranasal Sinus and Nasal Cavity; Stage I Lymphoepithelioma of the Nasopharynx; Stage I Lymphoepithelioma of the Oropharynx; Stage I Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity; Stage I Mucoepidermoid Carcinoma of the Oral Cavity; Stage I Salivary Gland Cancer; Stage I Squamous Cell Carcinoma of the Hypopharynx; Stage I Squamous Cell Carcinoma of the Larynx; Stage I Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage I Squamous Cell Carcinoma of the Nasopharynx; Stage I Squamous Cell Carcinoma of the Oropharynx; Stage I Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage I Verrucous Carcinoma of the Larynx; Stage I Verrucous Carcinoma of the Oral Cavity; Stage III Adenoid Cystic Carcinoma of the Oral Cavity; Stage III Basal Cell Carcinoma of the Lip; Stage III Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Stage III Inverted Papilloma of the Paranasal Sinus and Nasal Cavity; Stage III Lymphoepithelioma of the Nasopharynx; Stage III Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity; Stage III Mucoepidermoid Carcinoma of the Oral Cavity; Stage III Salivary Gland Cancer; Stage III Squamous Cell Carcinoma of the Hypopharynx; Stage III Squamous Cell Carcinoma of the Larynx; Stage III Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage III Squamous Cell Carcinoma of the Nasopharynx; Stage III Squamous Cell Carcinoma of the Oropharynx; Stage III Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage III Verrucous Carcinoma of the Larynx; Stage III Verrucous Carcinoma of the Oral Cavity; Stage IV Adenoid Cystic Carcinoma of the Oral Cavity; Stage IV Basal Cell Carcinoma of the Lip; Stage IV Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Stage IV Inverted Papilloma of the Paranasal Sinus and Nasal Cavity; Stage IV Lymphoepithelioma of the Nasopharynx; Stage IV Lymphoepithelioma of the Oropharynx; Stage IV Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity; Stage IV Mucoepidermoid Carcinoma of the Oral Cavity; Stage IV Salivary Gland Cancer; Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IV Squamous Cell Carcinoma of the Larynx; Stage IV Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IV Squamous Cell Carcinoma of the Nasopharynx; Stage IV Squamous Cell Carcinoma of the Oropharynx; Stage IV Squamous Cell Carcinoma of the Paranasal



Amiloride-Sensitive Sodium Channels and Pulmonary Edema  

PubMed Central

The development of pulmonary edema can be considered as a combination of alveolar flooding via increased fluid filtration, impaired alveolar-capillary barrier integrity, and disturbed resolution due to decreased alveolar fluid clearance. An important mechanism regulating alveolar fluid clearance is sodium transport across the alveolar epithelium. Transepithelial sodium transport is largely dependent on the activity of sodium channels in alveolar epithelial cells. This paper describes how sodium channels contribute to alveolar fluid clearance under physiological conditions and how deregulation of sodium channel activity might contribute to the pathogenesis of lung diseases associated with pulmonary edema. Furthermore, sodium channels as putative molecular targets for the treatment of pulmonary edema are discussed.

Althaus, Mike; Clauss, Wolfgang G.; Fronius, Martin



Ginkgo biloba leaf extract (EGb761) combined with neuroprotective agents reduces the infarct volumes of gerbil ischemic brain.  


Ginkgo biloba exerts many pharmacological actions. It possesses antioxidant properties, the ability of neurotransmitter/receptor modulation and antiplatelet activation factor. This research is designed to investigate the neuroprotective effects of long-term treatment with EGb761 (a standard form of the extract of Ginkgo biloba leaf) in combination with MgSO(4), FK506, or MK-801 on the infarct volume of male gerbils' brain induced by unilateral middle cerebral artery occlusion (MCAO). Thirty-five gerbils fed a standard diet were intragastrically given water or EGb761 (100 mg/kg/day) for one week. Five randomized groups were established: control (n = 7), EGb761 (n = 8), EGb761 + MgSO(4) (n = 7), EGb761 + FK506 (n = 7), and EGb761 + MK-801 (n = 6). The three drug-combination groups were injected with MgSO(4) (90 mg/kg), FK506 (0.5 mg/kg), or MK-801 (1 mg/kg), respectively 30 min before MCAO. Gerbils were anesthetized and craniectomized to expose the right middle cerebral artery (MCA). The right MCA was constricted with an 8-0 suture to produce a permanent ligation for 24 hours. Postmortem infarct volumes were determined by quantitative image analysis of 2,3,5-triphenyltetrazolium chloride (TTC)-stained brain sections. Results showed that the total infarct volumes of the four treated groups either EGb761 alone or in combination with drugs were lower than the control group by 36.1% (EGb761 alone), 40.3% (EGb761 + MgSO(4)), 35.3% (EGb761 + FK506), and 56.4% (EGb761 + MK-801), respectively (p < 0.01). The main affected areas of the brain in the four treated groups were significantly focused between 4 and 6 mm from the frontal pole, when compared to the control group (p < 0.01). All animals in the five groups had infarctions in both cortex and subcortex. These results indicate that long-term pre-treatment of EGb761 administered either alone or in combination with drugs significantly effective neuroprotection on infarct volume in gerbil ischemic brains. PMID:17080546

Chung, Shu-Ying; Cheng, Fu-Chou; Lee, Ming-Shih; Lin, Jing-Ying; Lin, Ming-Cheng; Wang, Ming-Fu



The effect of fenfluramine dosage regimen and reduced food intake on levels of 5HT in rat brain  

Microsoft Academic Search

Summary Male Wistar rats received fenfluramine in subacute (5mg\\/kg b.i.d. i.p. for 4 days) or escalating (0.5,1,1.5,2, 3,4 and 5mg\\/kg b.i.d. i.p., each dose given for 4 days) doses. Saline-treated controls received foodad libitum, or were pair-fed with the fenfluramine-treated animals. Rats were killed 1, 15 and 30 days after drug withdrawal. On day 1, plasma and brain fenfluramine levels

S. Rose; J. G. Hindmarsh; P. Collins; P. Jenner




Microsoft Academic Search

Conventional imaging techniques, such as computed tomography (CT) and magnetic resonance imaging (MR), are of immeasurable assistance in the diagnosis and characterization of primary intracranial tumors. Factors which can be accurately deduced via these techniques includes the location, size, mass effect and edema associated with brain tumors; usually a differential diagnosis of tumor type can be generated based on characteristics

Ferenc A. Jolesz


Glucocorticoid treatment of brain tumor patients: changes of apparent diffusion coefficient values measured by MR diffusion imaging  

Microsoft Academic Search

Glucocorticoids (GCC) generally are administered to patients with brain tumors to relieve neurological symptoms by decreasing the water content in a peritumoral zone of edema. We hypothesized that diffusion imaging and apparent diffusion coefficient (ADC) values could detect subtle changes of water content in brain tumors and in peritumoral edema after GCC therapy. The study consisted of 13 patients with

Sosuke Minamikawa; Kinuko Kono; Keiko Nakayama; Hiroyuki Yokote; Takahiko Tashiro; Akimasa Nishio; Mitsuhiro Hara; Yuichi Inoue



The episodic engram transformed: Time reduces retrieval-related brain activity but correlates it with memory accuracy.  


We took snapshots of human brain activity with fMRI during retrieval of realistic episodic memory over several months. Three groups of participants were scanned during a memory test either hours, weeks, or months after viewing a documentary movie. High recognition accuracy after hours decreased after weeks and remained at similar levels after months. In contrast, BOLD activity in a retrieval-related set of brain areas during correctly remembered events was similar after hours and weeks but significantly declined after months. Despite this reduction, BOLD activity in retrieval-related regions was positively correlated with recognition accuracy only after months. Hippocampal engagement during retrieval remained similar over time during recall but decreased in recognition. Our results are in line with the hypothesis that hippocampus subserves retrieval of real-life episodic memory long after encoding, its engagement being dependent on retrieval demands. Furthermore, our findings suggest that over time episodic engrams are transformed into a parsimonious form capable of supporting accurate retrieval of the crux of events, arguably a critical goal of memory, with only minimal network activation. PMID:23154929

Furman, Orit; Mendelsohn, Avi; Dudai, Yadin