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2.
Neurosurgery ; 90(1): 1-6, 2022 01 01.
Article in English | MEDLINE | ID: mdl-33647962

ABSTRACT

The perioperative multidisciplinary team approach has probably been best exemplified by the care of awake craniotomy patients. Advancement in anesthesia and meticulous perioperative care has supported the safety and complexity of the surgical and mapping efforts in glioma resection. The discussions in this review will emphasize on anesthetic and perioperative management strategies to prevent complications and minimize their effects if they occur, including current practice guidelines in anesthesia, updates on the applications of anesthetic medications, and emerging devices. Planning the anesthetic and perioperative management is based on understanding the pharmacology of the medications, the goals of different stages of the surgery and mapping, and anticipating potential problems.


Subject(s)
Anesthesia , Brain Neoplasms , Glioma , Brain Mapping , Brain Neoplasms/surgery , Craniotomy , Glioma/surgery , Humans , Wakefulness
3.
Curr Anesthesiol Rep ; 11(4): 467-476, 2021.
Article in English | MEDLINE | ID: mdl-34720755

ABSTRACT

PURPOSE OF REVIEW: This review illustrates the evolution and progress with standardization of fellowship education in neuroanesthesiology. It provides a structured discussion around the need for curricula and framework which individual training programs in neuroanesthesiology can use to meet defined educational standards thus meeting criteria for accreditation. RECENT FINDINGS: Neuroanesthesiology training has traditionally been heterogenous around the world but international efforts from the community of neuroanesthesiology have culminated in the development of an international council for perioperative training in neuroscience in anesthesiology(ICPNT). This serves not only as an accrediting body but also creates a platform through their neuroanesthesia program relations committee for collaboration and engagement between various training programs internationally, increasing the educational standards of the individual programs and collectively increasing the overall level of standards for neuroanesthesia training. Standardized curriculum and competency-based assessments and milestones would help with narrowing the focus to quality education in neuroanesthesiology. SUMMARY: Structured training around the three pillars of neuroanesthesiology with concomitant accreditation is expected to lead to higher education standards with better patient care. The SNACC created milestones for neuroanesthesiology training during residency and the ICPNT can now use this as a foundation for fellowship training. Having a council to accredit and standardize will likely become indispensable in creating a set path for training in neuroanesthesiology. Additionally, the flexibility built in due to the international nature would allow modified and variable pathways depending upon individual capabilities and interests. The path forward will include widespread adoption of standardization supporting the overarching goal of excellent patient outcomes around the world.

4.
J Neurosurg Anesthesiol ; 33(1): 82-86, 2021 Jan.
Article in English | MEDLINE | ID: mdl-33075035

ABSTRACT

BACKGROUND: The COVID-19 pandemic is an international crisis placing tremendous strain on medical systems around the world. Like other specialties, neuroanesthesiology has been adversely affected and training programs have had to quickly adapt to the constantly changing environment. METHODS: An email-based survey was used to evaluate the effects of the pandemic on clinical workflow, clinical training, education, and trainee well-being. The impact of the International Council on Perioperative Neuroscience Training (ICPNT) accreditation was also assessed. RESULTS: Responses were received from 14 program directors (88% response rate) in 10 countries and from 36 fellows in these programs. Clinical training was adversely affected because of the cancellation of elective neurosurgery and other changes in case workflow, the introduction of modified airway and other protocols, and redeployment of trainees to other sites. To address educational demands, most programs utilized online platforms to organize clinical discussions, journal clubs, and provide safety training modules. Several initiatives were introduced to support trainee well-being during the pandemic. Feelings of isolation and despair among trainees varied from 2 to 8 (on a scale of 1 to 10). Fellows all reported concerns that their clinical training had been adversely affected by the coronavirus disease 2019 (COVID-19) pandemic because of decreased exposure to elective subspecialty cases and limited opportunities to complete workplace-based assessments and training portfolio requirements. Cancellation of examination preparation courses and delayed examinations were cited as common sources of stress. Programs accredited by the ICPNT reported that international networking and collaboration was beneficial to reduce feelings of isolation during the pandemic. CONCLUSION: Neuroanesthesia fellowship training program directors introduced innovative ways to maintain clinical training, educational activity and trainee well-being during the COVID-19 pandemic.


Subject(s)
Accreditation/trends , Anesthesiology/education , Anesthesiology/trends , COVID-19 , Fellowships and Scholarships/trends , Neurology/education , Neurology/trends , Pandemics , Clinical Competence , Elective Surgical Procedures , Humans , Neurosurgery/statistics & numerical data , Neurosurgery/trends
5.
Rev. colomb. anestesiol ; 43(2): 151-155, Apr.-June 2015. tab
Article in English | LILACS, COLNAL | ID: lil-749499

ABSTRACT

Interventional Neuroradiology (INR) is firmly established in the management of cerebrovascular diseases. The aim of this manuscript is to present the author's critical review of the literature and interpretation emphasizing perioperative and anesthetic management strategies to prevent complications and minimize their effects if they occur. Planning the anesthetic and perioperative management is predicated on understanding the goals of the therapeutic intervention and anticipating potential problems.


La Neuroradiología Intervencionista (NRI) está firmemente establecida en el manejo de la patología cerebrovascular. El objetivo del presente manuscrito es presentar una revisión crítica de la literatura e interpretación por parte del autor, enfatizando las estrategias perioperatorias y anestésicas para prevenir complicaciones y minimizar sus efectos en caso de que estas se presenten. La planeación de la gestión anestésica y perioperatoria se fundamenta en comprender las metas de la intervención terapéutica y anticiparse a los problemas potenciales.


Subject(s)
Humans
6.
Curr Opin Anaesthesiol ; 27(5): 484-8, 2014 Oct.
Article in English | MEDLINE | ID: mdl-25014255

ABSTRACT

PURPOSE OF REVIEW: The review highlights recent data regarding the safety and efficacy of endovascular treatment of cerebrovascular disease and concerns in anesthesia management. RECENT FINDINGS: Ongoing trials, including the Barrow Ruptured Aneurysm Trial and the International Subarachnoid Aneurysm Trial II, are aimed at improving understanding of the applicability of the International Subarachnoid Aneurysm Trial data and the roles of surgical clipping and endovascular treatment in the broad general patient population of ruptured aneurysms. Two recent studies in unruptured brain arteriovenous malformation management - ARUBA (a multicenter, randomized clinical trial) and the Scottish population-based cohort study - concluded that conservative medical management is superior to interventional therapy (including endovascular embolization) in preventing death or stroke. Three randomized clinical trials failed to prove the superiority of endovascular therapy to standard care for acute ischemic stroke, but pointed out to the need and direction of future trials. Studies of anesthesia for acute ischemic stroke suggested that inadequate brain perfusion may contribute to poorer outcome. SUMMARY: Recent data further support the role of endovascular coiling for ruptured aneurysm in broader patient populations. Further studies are needed to investigate the proper management of unruptured arteriovenous malformations, and the key factors in endovascular therapy and anesthesia management associated with stroke outcome.


Subject(s)
Anesthesia/methods , Embolization, Therapeutic/methods , Intracranial Aneurysm/surgery , Intracranial Arteriovenous Malformations/surgery , Subarachnoid Hemorrhage/surgery , Humans , Neurosurgical Procedures/methods
7.
Anesthesiol Clin ; 30(2): 127-47, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22901603

ABSTRACT

This article outlines the roles of the anesthesiologist in the management of patients undergoing invasive endovascular procedures to treat vascular diseases, primarily of the central nervous system. This practice is usually termed interventional neuroradiology or endovascular neurosurgery. The article emphasizes perioperative and anesthetic management strategies to prevent complications and minimize their effects if they occur. Planning the anesthetic and perioperative management is predicated on understanding the goals of the therapeutic intervention and anticipating potential problems.


Subject(s)
Anesthesia/methods , Endovascular Procedures/methods , Neurosurgical Procedures/methods , Radiography, Interventional/methods , Anticoagulants/therapeutic use , Central Nervous System Vascular Malformations/surgery , Humans , Hypertension/physiopathology , Hypotension, Controlled , Intracranial Arteriosclerosis/surgery , Intraoperative Complications/therapy , Postoperative Care , Stroke/surgery
8.
Stereotact Funct Neurosurg ; 89(2): 76-82, 2011.
Article in English | MEDLINE | ID: mdl-21293166

ABSTRACT

BACKGROUND/AIMS: Venous air embolism (VAE) is a potential complication during neurosurgical procedures, particularly in the sitting position. The diagnosis and management of VAE in patients undergoing awake deep brain stimulation (DBS) lead implantation in the sitting position are underreported. METHODS: We performed a retrospective chart review of 467 consecutive DBS surgeries at the University of California, San Francisco. Data was collected for patient demographics, diagnosis, intraoperative events, and postoperative course. RESULTS: Six cases of clinically diagnosed VAE were found, amounting to a total incidence of 1.3% per procedure. We did not observe a statistical association with patient age, diagnosis, or DBS target. The most common symptoms of intraoperative VAE were coughing, oxygen desaturation, and hypotension. In all cases, VAE was treated by copious irrigation of the surgical field and lowering the patient's head. In 4 cases, DBS implantation was abandoned because of ongoing symptoms of VAE. The respiratory outcome in all patients was good after several days of close observation. CONCLUSION: The incidence of VAE during DBS procedures is small, but prompt recognition and management of VAE are critical to avoid further associated complications.


Subject(s)
Deep Brain Stimulation/adverse effects , Dystonia/therapy , Embolism, Air/epidemiology , Embolism, Air/therapy , Neurosurgical Procedures/adverse effects , Parkinson Disease/therapy , Veins , Adult , Aged , Embolism, Air/etiology , Female , Humans , Incidence , Intraoperative Complications/epidemiology , Intraoperative Complications/etiology , Intraoperative Complications/therapy , Male , Middle Aged , Retrospective Studies , Risk Factors , Supine Position , Therapeutic Irrigation , Treatment Outcome
9.
Anesthesiol Clin ; 28(1): 1-12, 2010 Mar.
Article in English | MEDLINE | ID: mdl-20400036

ABSTRACT

This review outlines the perioperative anesthesia considerations of patients with vascular diseases of the central nervous system, including occlusive cerebrovascular diseases with ischemic risks and various cerebrovascular malformations with hemorrhagic potential. The discussion emphasizes perioperative management strategies to prevent complications and minimize their effects if they occur. Planning the anesthetic and perioperative management is predicated on understanding the goals of the therapeutic intervention and anticipating potential problems.


Subject(s)
Anesthesia , Cerebrovascular Disorders/complications , Anesthetics , Cerebral Hemorrhage/complications , Cerebrovascular Circulation/physiology , Humans , Intracranial Arteriovenous Malformations/complications , Perioperative Care
10.
Stroke ; 40(8): 2879-81, 2009 Aug.
Article in English | MEDLINE | ID: mdl-19498186

ABSTRACT

BACKGROUND AND PURPOSE: Vascular endothelial growth factor (VEGF) can induce matrix metalloproteinase (MMP)-9 activities and focal angiogenesis. We hypothesized that VEGF activation of cerebral MMP-9 would require nitric oxide participation. METHODS: We compared the in vivo effects of: (1) N(G)-monomethyl-l-arginine, a nonspecific nitric oxide synthase inhibitor; (2) L-N(6)-(1-iminoethyl)lysine, an inducible nitric oxide synthase selective inhibitor; and (3) doxycycline, a known nonspecific inhibitor of MMP in the mouse brain, using in situ zymography and endothelial marker CD31. 3-nitrotyrosine was used as a surrogate for nitric oxide activity. Inflammatory cell markers CD68 and MPO were used to confirm leukocyte infiltration. RESULTS: VEGF-stimulated MMP-9 activity expressed primarily around cerebral microvessels. N(G)-monomethyl-l-arginine suppressed cerebral angiogenesis (P<0.05), especially those microvessels associated with MMP-9 activation (P<0.02) induced by VEGF, comparable to the effect of doxycycline. L-N(6)-(1-iminoethyl)lysine showed similar inhibitory effects. 3-nitrotyrosine confirmed nitric oxide levels in the brain. Compared with the lacZ control, VEGF increased inflammatory cell infiltration, especially macrophages, in the induced brain angiogenic focuses. CONCLUSIONS: Inhibition of nitric oxide production decreased MMP-9 activity and focal angiogenesis in the VEGF-stimulated brain. Both specific and nonspecific inhibition of nitric oxide synthase resulted in similar reductions, suggesting that VEGF-stimulated cerebral MMP activity and angiogenesis are predominantly mediated through inducible nitric oxide synthase, a specific nitric oxide synthase isoform mediating inflammatory responses.


Subject(s)
Brain/metabolism , Matrix Metalloproteinase 9/metabolism , Neovascularization, Pathologic/chemically induced , Neovascularization, Pathologic/metabolism , Nitric Oxide/biosynthesis , Vascular Endothelial Growth Factor A/toxicity , Animals , Brain/drug effects , Enzyme Activation/drug effects , Enzyme Activation/physiology , Male , Mice , Nitric Oxide/antagonists & inhibitors
11.
Arterioscler Thromb Vasc Biol ; 28(12): 2151-7, 2008 Dec.
Article in English | MEDLINE | ID: mdl-18802012

ABSTRACT

OBJECTIVE: We investigated the role of bone marrow-derived cells (BMDCs) in an angiogenic focus, induced by VEGF stimulation. METHODS AND RESULTS: BM from GFP donor mice was isolated and transplanted into lethally irradiated recipients. Four weeks after transplantation, groups of mice received adeno-associated viral vector (AAV)-VEGF or AAV-lacZ gene (control) injection and were euthanized at 1 to 24 weeks. BMDCs were characterized by double-labeled immunostaining. The function of BMDCs was further examined through matrix metalloproteinase (MMP)-2 and -9 activity. We found that capillary density increased after 2 weeks, peaked at 4 weeks (P<0.01), and sustained up to 24 weeks after gene transfer. GFP-positive BMDCs infiltration in the angiogenic focus began at 1 week, peaked at 2 weeks, and decreased thereafter. The GFP-positive BMDCs were colocalized with CD45 (94%), CD68 (71%), 5% Vimentin (5%), CD31/von Willebrand factor (vWF) (1%), and alpha-smooth muscle actin (alpha -SMA, 0.5%). Infiltrated BMDCs expressed MMP-9. MMP-9 KO mice confirmed the dependence of the angiogenic response on MMP-9 availability. CONCLUSIONS: Nearly all BMDCs in the angiogenic focus showed expression for leukocytes/macrophages, indicating that BMDCs minimally incorporated into the neovasculature. Colocalization of MMPs with GFP suggests that BMDCs play a critical role in VEGF-induced angiogenic response through up-regulation of MMPs.


Subject(s)
Bone Marrow Cells/cytology , Brain/blood supply , Brain/cytology , Neovascularization, Physiologic , Animals , Blood-Brain Barrier/physiology , Bone Marrow Cells/metabolism , Bone Marrow Transplantation , Dependovirus/genetics , Green Fluorescent Proteins/genetics , Humans , Intercellular Adhesion Molecule-1/metabolism , Leukocytes/cytology , Leukocytes/metabolism , Macrophages/cytology , Macrophages/metabolism , Male , Matrix Metalloproteinase 9/deficiency , Matrix Metalloproteinase 9/genetics , Matrix Metalloproteinase 9/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Recombinant Proteins/genetics , Transduction, Genetic , Vascular Endothelial Growth Factor A/genetics
12.
Cerebrovasc Dis ; 25(1-2): 157-63, 2008.
Article in English | MEDLINE | ID: mdl-18212521

ABSTRACT

BACKGROUND: Tetracyclines may be useful in preventing pathological vascular remodeling, thus decreasing the risk of spontaneous hemorrhage from brain vascular malformations. METHODS: Arteriovenous malformation (AVM) and intracranial aneurysm patients undergoing noninvasive management were treated with minocycline or doxycycline (200 mg/day) up to 2 years in a prospective open-label safety pilot trial. The primary outcome was to compare dose-limiting intolerance, defined as treatment-related dose reduction or withdrawal between the agents. RESULTS: Twenty-six patients with AVMs (n = 12) or aneurysms (n = 14) were recruited. Adverse event rates were similar to other reported trials of these agents; 4 of 13 (31%) minocycline and 3 of 13 (23%) doxycycline patients had dose-limiting intolerance (hazard ratio = 3.1, 95% CI = 0.52-18.11, log rank p = 0.70). CONCLUSIONS: It is feasible to propose a long-term trial to assess the potential benefit of tetracycline therapy to decrease hemorrhagic risk in brain vascular malformations.


Subject(s)
Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/adverse effects , Doxycycline/administration & dosage , Doxycycline/adverse effects , Minocycline/administration & dosage , Minocycline/adverse effects , Adolescent , Adult , Aged , Dose-Response Relationship, Drug , Feasibility Studies , Follow-Up Studies , Humans , Intracranial Aneurysm/drug therapy , Intracranial Arteriovenous Malformations/drug therapy , Middle Aged , Pilot Projects , Prospective Studies , Treatment Outcome
13.
Stroke ; 38(9): 2563-8, 2007 Sep.
Article in English | MEDLINE | ID: mdl-17673717

ABSTRACT

BACKGROUND AND PURPOSE: Human brain arteriovenous malformation tissue displays increased levels of vascular endothelial growth factor (VEGF) as well as matrix metalloproteinase (MMP)-9, a tissue protease associated with various intracerebral hemorrhage (ICH). We hypothesized that increased MMP-9 was associated with ICH induced by vascular endothelial growth factor hyperstimulation and that this effect could be attenuated by nonspecific MMP inhibition. METHODS: We used a mouse model with adenoviral vector-mediated vascular endothelial growth factor transduction in the brain. The association of MMP-9 expression and the brain tissue hemoglobin levels, an index of ICH, after stereotactic injection of adenoviral vector-mediated vascular endothelial growth factor into caudate putamen was assessed. A dose-response study with adenoviral vector-mediated vascular endothelial growth factor and a time course study at both 24 and 48 hours postinjection were performed. Effects of minocycline, a nonspecific MMP inhibitor, and pyrrolidine dithiocarbamate, an upstream regulator of MMPs, on MMP-9 activity and thereby the degree of ICH were also tested. RESULTS: Adenoviral vector-mediated vascular endothelial growth factor at the higher dose and at 48 hours induced MMP-9 levels 6-fold (n=6, P=0.02) and increased brain tissue hemoglobin (43.4+/-11.5 versus 30.3+/-4.1 mug/mg, n=6, P=0.003) compared with the adenoviral vector control. Immnunostaining was positive for MMP-9 around the cerebral vessels and the hemorrhagic areas. Minocycline and pyrrolidine dithiocarbamate administration suppressed vascular endothelial growth factor-induced MMP-9 activity (n=6, P=0.003 and P=0.01, respectively) and the associated increases in hemoglobin levels (n=5-6, P=0.001 and P=0.02, respectively). CONCLUSIONS: Vascular endothelial growth factor-induced ICH is associated with increased MMP-9 expression. Suppression of MMP-9 by minocycline or pyrrolidine dithiocarbamate attenuated ICH, suggesting the therapeutic potential of MMP inhibitors in cerebral vascular rupture.


Subject(s)
Cerebral Hemorrhage/chemically induced , Matrix Metalloproteinase 9/metabolism , Vascular Endothelial Growth Factor A/pharmacology , Adenoviridae/genetics , Adenoviridae/metabolism , Animals , Anti-Bacterial Agents/metabolism , Antioxidants/metabolism , Brain/anatomy & histology , Brain/pathology , Brain/physiology , Disease Models, Animal , Humans , Intracranial Arteriovenous Malformations/metabolism , Male , Matrix Metalloproteinase Inhibitors , Mice , Minocycline/metabolism , Pyrrolidines/metabolism , Thiocarbamates/metabolism , Vascular Endothelial Growth Factor A/genetics , Vascular Endothelial Growth Factor A/metabolism
14.
Front Biosci ; 11: 3121-8, 2006 Sep 01.
Article in English | MEDLINE | ID: mdl-16720380

ABSTRACT

Brain arteriovenous malformations (BAVM) have high matrix metalloproteinase-9 (MMP-9) expression, the source of which is unclear. We hypothesized MMP-9 production might be due to inflammation in BAVM. Compared to control brain tissues (n = 5), BAVM tissue (n = 139) had a higher expression (by ELISA) of myeloperoxidase (MPO) (193 +/- 189 vs. 6 +/- 3, ng/mg, P < .001), MMP-9 (28 +/- 32 vs. 0.7 +/- 0.6, ng/mg, P < .001), and IL-6 (102 +/- 218 vs. 0.1 +/- 0.1, pg/mg, P < .001), but not eNOS (114 +/- 87 vs. 65 +/- 9, pg/mg, P = .09). MMP-9 expression in BAVM highly correlated with myeloperoxidase (R2 = .76, P < .001), as well as with IL-6 (R2 = .32, P < .001). In contrast, MMP-9 in BAVM poorly correlated with the endothelial marker, eNOS (R2 = .03, P = .05), and CD31 (R2 = .004, P = .57). Compared to non-embolized patients (n = 46), patients with pre-operative embolization (n = 93) had higher levels of myeloperoxidase (236 +/- 205 vs. 106 +/- 108, ng/mg, P < .001) and MMP-9 (33 +/- 35 vs. 16 +/- 20, ng/mg, P < .001), however the correlation between MMP-9 and myeloperoxidase was equally strong for both groups (R2 = .69, n = 93, P < .001, for both). MMP-9 expression correlated with the lipocalin-MMP-9 complex, suggesting neutrophils as the MMP-9 source. MPO co-localized with majority of MMP-9 signal by immunohistochemistry. Our data suggest that inflammation is a prominent feature of BAVM lesional phenotype, and neutrophils appear to be a major source of MMP-9 in these lesions.


Subject(s)
Biomarkers/analysis , Inflammation , Intracranial Arteriovenous Malformations/enzymology , Leukocytes/enzymology , Matrix Metalloproteinase 9/biosynthesis , Adult , Case-Control Studies , Embolization, Therapeutic , Endothelial Cells/enzymology , Female , Humans , Interleukin-6/analysis , Interleukin-6/biosynthesis , Intracranial Arteriovenous Malformations/immunology , Intracranial Arteriovenous Malformations/therapy , Male , Neutrophils/enzymology , Nitric Oxide Synthase Type III/analysis , Nitric Oxide Synthase Type III/biosynthesis , Peroxidase/analysis , Platelet Endothelial Cell Adhesion Molecule-1/analysis , Platelet Endothelial Cell Adhesion Molecule-1/biosynthesis , Prospective Studies
15.
J Cereb Blood Flow Metab ; 26(9): 1157-64, 2006 Sep.
Article in English | MEDLINE | ID: mdl-16395286

ABSTRACT

Brain arteriovenous malformations (BAVMs) are a potentially life-threatening disorder. Matrix metalloproteinase (MMP)-9 activity was greatly increased in BAVM tissue specimens. Doxycycline was shown to decrease cerebral MMP-9 activities and angiogenesis induced by vascular endothelial growth factor (VEGF). In the present study, we determined the dose-response effects of doxycycline and minocycline on cerebral MMP-9 using our mouse model with VEGF focal hyperstimulation delivered with adenoviral vector (AdVEGF) in the brain. Mice were treated with doxycycline or minocycline, respectively, at 1, 5, 10, 30, 50, or 100 mg/kg/day through drinking water for 1 week. Our results have shown that MMP-9 messenger ribonucleic acid (mRNA) expression was inhibited by doxycycline starting at 10 mg/kg/day (P<0.02). Minocycline showed more potent inhibition on MMP-9 mRNA expression, starting at 1 (P<0.005) and further at more than 30 (P<0.001) mg/kg/day. At the enzymatic activity level, doxycycline started to suppress MMP-9 activity at 5 mg/kg/day (P<0.001), while minocycline had an effect at a lower dose, 1 mg/kg/day (P<0.02). The inhibition of cerebral MMP-9 mRNA and activity were highly correlated with drug levels in the brain tissue. We also assessed the potential relevant signaling pathway in vitro to elucidate the mechanisms underlying the MMP-9 inhibition by tetracyclines. In vitro, minocycline, but not doxycycline, inhibits MMP-9, at least in part, via the extracellular signaling-related kinase 1/2 (ERK1/2)-mediated pathway. This study provided the evidence that the tetracyclines inhibit stimulated cerebral MMP-9 at multiple levels and are effective at very low doses, offering great potential for therapeutic use.


Subject(s)
Anti-Bacterial Agents/pharmacology , Matrix Metalloproteinase 9/metabolism , Tetracyclines/pharmacology , Vascular Endothelial Growth Factor A/pharmacology , Animals , Anti-Bacterial Agents/metabolism , Blotting, Western , Brain/metabolism , Brain Chemistry/drug effects , Cell Movement/drug effects , Cells, Cultured , Dose-Response Relationship, Drug , Doxycycline/metabolism , Doxycycline/pharmacology , Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors , Gelatin/metabolism , Intracranial Arteriovenous Malformations/enzymology , Male , Mice , Minocycline/metabolism , Minocycline/pharmacology , Muscle, Smooth, Vascular/cytology , Muscle, Smooth, Vascular/drug effects , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Reverse Transcriptase Polymerase Chain Reaction , Stimulation, Chemical , Tetracyclines/metabolism
16.
Stroke ; 37(1): 231-4, 2006 Jan.
Article in English | MEDLINE | ID: mdl-16322490

ABSTRACT

BACKGROUND AND PURPOSE: Identification of single-nucleotide polymorphisms (SNPs) associated with increased risk of new intracranial hemorrhage (ICH) after brain arteriovenous malformation (BAVM) diagnosis would facilitate risk stratification and identify potential targets for therapeutic intervention. METHODS: Patients with BAVM were longitudinally followed. Primary outcome was new ICH after diagnosis; censoring events were last follow-up or any BAVM treatment. We genotyped 4 promoter SNPs in 2 inflammatory cytokine genes: interleukin-6 (IL-6-174G>C; IL-6-572G>C) and tumor necrosis factor-alpha (TNF-alpha-238G>A; TNF-alpha-308G>A). Association of genotype with risk of new ICH was screened using chi2; SNPs associated with new ICH were further characterized using Cox proportional hazards. RESULTS: We genotyped 280 patients (50% female; 59% white, mean+/-SD age at diagnosis 37+/-17 years; 40% presenting with ICH). TNF-alpha-238G>A was associated with increased risk of new ICH after diagnosis (chi2; P=0.003). After adjusting for age, race/ethnicity, and clinical presentation, the risk of new ICH was increased for patients with TNF-alpha-238 AG genotype (hazard ratio, 4.01; P=0.015). No other SNP was found to be associated with new ICH. CONCLUSIONS: A TNF-alpha SNP was associated with increased risk of new ICH in the natural course of BAVMs. The role of inflammatory cytokines in the pathogenesis of BAVM hemorrhage merits further study.


Subject(s)
Arteriovenous Malformations/genetics , Arteriovenous Malformations/pathology , Brain/pathology , Hemorrhage/genetics , Promoter Regions, Genetic , Tumor Necrosis Factor-alpha/genetics , Adult , Female , Genotype , Haplotypes , Humans , Interleukin-6/genetics , Male , Middle Aged , Models, Statistical , Polymorphism, Single Nucleotide , Proportional Hazards Models , Risk , Time Factors
17.
Stroke ; 36(7): 1533-7, 2005 Jul.
Article in English | MEDLINE | ID: mdl-15947259

ABSTRACT

BACKGROUND AND PURPOSE: A better understanding of angiogenic factors and their effects on cerebral angiogenesis is necessary for the development of effective therapeutic strategies for ischemic brain injury. Vascular endothelial growth factor (VEGF) has been shown to induce angiogenesis in the adult mouse brain. However, the function of angiopoietin-2 (Ang-2) in cerebral angiogenesis has not been clarified. The goal of this study was to identify the combined effects of VEGF and Ang-2 on cerebral angiogenesis and the blood-brain barrier (BBB). METHODS: Six groups of 6 adult male CD-1 mice underwent AdlacZ (viral vector control), AdVEGF, AdAng2, VEGF protein, VEGF protein plus AdAng2, or saline (negative control) injection. Microvessels were counted using lectin staining on tissue sections after 2 weeks of treatment. Matrix metalloproteinase-9 (MMP-9) activity was determined by zymography. The presence of zonula occludens-1 (ZO-1) protein was determined by Western blot and immunohistochemistry. RESULTS: Mice treated with VEGF protein infusion plus AdAng-2 significantly increased microvessel counts relative to all other groups (P<0.05). The changes in MMP-9 activity paralleled the reduced ZO-1 expression in the VEGF plus Ang-2-treated group compared with the other 5 groups (P<0.05). Double-labeled immunostaining demonstrated that ZO-1-positive staining was significantly decreased on the microvessel wall in the VEGF plus Ang-2-treated group. CONCLUSIONS: Our study demonstrates that the combination of VEGF and Ang-2 promotes more angiogenesis compared with VEGF alone. Furthermore, the combination of VEGF and Ang-2 may lead to BBB disruption because it increases MMP-9 activity and inhibits ZO-1 expression.


Subject(s)
Angiopoietin-2/physiology , Brain/blood supply , Brain/metabolism , Neovascularization, Pathologic , Vascular Endothelial Growth Factor A/metabolism , Adenoviridae/genetics , Angiopoietin-2/metabolism , Animals , Blood-Brain Barrier , Blotting, Western , Brain/pathology , Brain Ischemia/pathology , Extracellular Matrix/metabolism , Immunohistochemistry , Lac Operon , Male , Matrix Metalloproteinase 9/metabolism , Membrane Proteins/metabolism , Mice , Microcirculation , Microscopy, Fluorescence , Phosphoproteins/metabolism , Zonula Occludens-1 Protein
18.
Curr Opin Anaesthesiol ; 18(5): 484-9, 2005 Oct.
Article in English | MEDLINE | ID: mdl-16534280

ABSTRACT

PURPOSE OF REVIEW: This review highlights recent data regarding factors associated with brain arteriovenous malformation hemorrhage and different treatment options. RECENT FINDINGS: More risk factors were identified in association with intracranial hemorrhage, including age at initial diagnosis of arteriovenous malformation, co-existing extranidal aneurysms and genetic factors. Patients with unruptured arteriovenous malformations were found to be more susceptible to worsening in neurological function after microsurgery compared with those presenting with hemorrhagic arteriovenous malformation. Radiosurgery has achieved satisfactory obliteration of deep arteriovenous malformations, but with increased actuarial hemorrhage rates from the first to the fifth year. Although the Intraoperative Hypothermia for Aneurysm Surgery Trial failed to show a significant neurological improvement, the superior efficiency of endovascular cooling has offered optimism in cerebral protection during neurovascular surgeries by shortening the time to achieve hypothermia and rewarming. A multi-center trial (ARUBA) has been proposed to test the hypothesis that, for unruptured brain arteriovenous malformations, there is no difference between interventional and conservative management. Recent studies have also shown the promise of using tetracyclines to decrease the rate of spontaneous arteriovenous malformation rupture. SUMMARY: The recent identification of clinical and genetic factors associated with brain arteriovenous malformation hemorrhage, as well as studies on treatment outcomes, will help risk stratification in management choices. Future studies are needed to identify arteriovenous malformation patients at the greatest risk of spontaneous hemorrhage and to develop specific medical therapies.

19.
Stroke ; 35(7): 1715-9, 2004 Jul.
Article in English | MEDLINE | ID: mdl-15166398

ABSTRACT

BACKGROUND AND PURPOSE: A number of central nervous system (CNS) disorders are associated with abnormalities in or activation of angiogenesis, including vascular malformations. To test the hypothesis that the nonspecific matrix metalloproteinase (MMP) inhibitor, doxycycline, suppresses vascular endothelial growth factor (VEGF)-induced cerebral angiogenesis through inhibition of MMPs, we used a mouse model with enhanced cerebral angiogenesis induced by focal hyperstimulation of VEGF from adenovirus DNA (AdVEGF) transduction. METHODS: The time course study of MMP activity was performed at 7 and 14 days after AdVEGF transduction. MMP activity and expression were examined by zymography and immunohistochemistry, respectively. As an index of cerebral angiogenesis, microvessel counting was performed in the brains of 3 groups of mice (n=6): (1) control; (2) AdVEGF only; and (3) AdVEGF plus doxycycline (30 mg/kg per day). RESULTS: Brain MMP-9 activities increased 4-fold (883+/-137 versus 179+/-179; 1-sided P<0.001) at 7 days after AdVEGF transduction. VEGF transduction increased vessel counts by 19% (255+/-27 versus 215+/-15, 1-sided P<0.01). Doxycycline treatment decreased MMP-9 activity (89+/-72 versus 883+/-137; 1-sided P<0.001) and cerebral microvessel number (231+/-17 versus 255+/-27; 1-sided P<0.05). CONCLUSIONS: Doxycycline is effective in decreasing stimulated cerebral MMP-9 activity and parenchymal angiogenesis. The decrease in MMP-9 activity is associated with decreased microvessel counts. Brain pathophysiological processes that involve abnormally enhanced angiogenesis may be amenable to manipulation by MMP inhibitors, including tetracycline derivatives.


Subject(s)
Angiogenesis Inhibitors/pharmacology , Brain/blood supply , Doxycycline/pharmacology , Matrix Metalloproteinase Inhibitors , Neovascularization, Physiologic/drug effects , Adenoviridae , Animals , Brain/enzymology , Enzyme Inhibitors/pharmacology , Male , Matrix Metalloproteinase 9/metabolism , Mice , Models, Animal , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/enzymology , Transduction, Genetic , Vascular Endothelial Growth Factor A/genetics
20.
J Vasc Interv Radiol ; 15(1 Pt 2): S13-9, 2004 Jan.
Article in English | MEDLINE | ID: mdl-15101512

ABSTRACT

Acute ischemic stroke is considered a neurologic emergency. The perioperative anesthesia management of acute ischemic stroke is challenging owing to the dynamic pathophysiology of the disease itself and the patients' comorbid factors and conditions. Herein, the authors review preoperative assessment, intraoperative and postoperative physiologic monitoring, and anesthesia management, with a focus on the control of the cerebrovascular and cardiovascular circulations. Issues specific to anesthesia monitoring and management in the radiology suite are emphasized.


Subject(s)
Anesthesia , Brain Ischemia/physiopathology , Brain Ischemia/therapy , Monitoring, Physiologic , Stroke/physiopathology , Stroke/therapy , Acute Disease , Brain Ischemia/diagnosis , Gastric Emptying/physiology , Heart Rate/physiology , Humans , Intracranial Embolism/diagnosis , Intracranial Embolism/physiopathology , Intracranial Embolism/therapy , Myocardial Ischemia/diagnosis , Myocardial Ischemia/physiopathology , Myocardial Ischemia/therapy , Stroke/diagnosis
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