RESUMEN
Studying the relationship between cerebral oxygen utilization and cognitive impairment is essential to understanding neuronal functional changes in the disease progression of multiple sclerosis (MS). This study explores the potential of using venous susceptibility in internal cerebral veins (ICVs) as an imaging biomarker for cognitive impairment in relapsing-remitting MS (RRMS) patients. Quantitative susceptibility mapping derived from fully flow-compensated MRI phase data was employed to directly measure venous blood oxygen saturation levels (SvO2) in the ICVs. Results revealed a significant reduction in the susceptibility of ICVs (212.4 ± 30.8 ppb vs 239.4 ± 25.9 ppb) and a significant increase of SvO2 (74.5 ± 1.89% vs 72.4 ± 2.23%) in patients with RRMS compared with age- and sex-matched healthy controls. Both the susceptibility of ICVs (r = 0.508, p = 0.031) and the SvO2 (r = -0.498, p = 0.036) exhibited a moderate correlation with cognitive decline in these patients assessed by the Paced Auditory Serial Addition Test, while no significant correlation was observed with clinical disability measured by the Expanded Disability Status Scale. The findings suggest that venous susceptibility in ICVs has the potential to serve as a specific indicator of oxygen metabolism and cognitive function in RRMS. .
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Venas Cerebrales , Disfunción Cognitiva , Imagen por Resonancia Magnética , Oxígeno , Humanos , Masculino , Femenino , Adulto , Disfunción Cognitiva/etiología , Disfunción Cognitiva/metabolismo , Venas Cerebrales/diagnóstico por imagen , Venas Cerebrales/metabolismo , Oxígeno/metabolismo , Oxígeno/sangre , Imagen por Resonancia Magnética/métodos , Persona de Mediana Edad , Esclerosis Múltiple Recurrente-Remitente/metabolismo , Esclerosis Múltiple Recurrente-Remitente/diagnóstico por imagen , Esclerosis Múltiple Recurrente-Remitente/complicaciones , Esclerosis Múltiple Recurrente-Remitente/psicología , Circulación Cerebrovascular/fisiología , Consumo de Oxígeno , Saturación de OxígenoRESUMEN
Prominence of cerebral veins using susceptibility weighted magnetic resonance imaging (SWI) has been used as a qualitative indicator of cerebral venous oxygenation (CvO2). Quantitative susceptibility mapping (QSM) adds more precision to the assessment of CvO2, but has not been applied to neonatal hypoxic ischemic injury (HII). We proposed to study QSM measures of venous susceptibility and their correlation with direct measures of brain oxygenation and cerebral blood flow (CBF) in the neonatal piglet. The association of QSM intravascular cerebral venous susceptibility, with brain tissue O2 tension, CBF, cortical tissue oxyhemoglobin saturation, and the partial pressure of oxygen in arterial blood measurement during various oxygenation states was determined by linear regression. Compared to normoxia, venous susceptibility in the straight sinus increased 56.8 ± 25.4% during hypoxia, while decreasing during hyperoxia (23.5 ± 32.9%) and hypercapnia (23.3 ± 73.1%), which was highly correlated to all other measures of oxygenation (p < 0.0001) but did not correlate to CBF (p = 0.82). These findings demonstrate a strong relationship between venous susceptibility and brain tissue O2 tension. Our results suggest that QSM-derived venous susceptibility is sensitive to cerebral oxygenation status across various oxygenation states.
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Venas Cerebrales , Animales , Encéfalo/irrigación sanguínea , Mapeo Encefálico/métodos , Venas Cerebrales/metabolismo , Circulación Cerebrovascular/fisiología , Hipoxia/metabolismo , Imagen por Resonancia Magnética/métodos , Oxígeno/metabolismo , PorcinosRESUMEN
Introduction: The World Health Organization declared the coronavirus disease 2019 (COVID-19) pandemic on March 11, 2020. Two vaccine types were developed using two different technologies: viral vectors and mRNA. Thrombosis is one of the most severe and atypical adverse effects of vaccines. This study aimed to analyze published cases of thrombosis after COVID-19 vaccinations to identify patients' features, potential pathophysiological mechanisms, timing of appearance of the adverse events, and other critical issues. Materials and Methods: We performed a systematic electronic search of scientific articles regarding COVID-19 vaccine-related thrombosis and its complications on the PubMed (MEDLINE) database and through manual searches. We selected 10 out of 50 articles from February 1 to May 5, 2021 and performed a descriptive analysis of the adverse events caused by the mRNA-based Pfizer and Moderna vaccines and the adenovirus-based AstraZeneca vaccine. Results: In the articles on the Pfizer and Moderna vaccines, the sample consisted of three male patients with age heterogeneity. The time from vaccination to admission was ≤3 days in all cases; all patients presented signs of petechiae/purpura at admission, with a low platelet count. In the studies on the AstraZeneca vaccine, the sample consisted of 58 individuals with a high age heterogeneity and a high female prevalence. Symptoms appeared around the ninth day, and headache was the most common symptom. The platelet count was below the lower limit of the normal range. All patients except one were positive for PF4 antibodies. The cerebral venous sinus was the most affected site. Death was the most prevalent outcome in all studies, except for one study in which most of the patients remained alive. Discussion: Vaccine-induced thrombotic thrombocytopenia (VITT) is an unknown nosological phenomenon secondary to inoculation with the COVID-19 vaccine. Several hypotheses have been formulated regarding its physiopathological mechanism. Recent studies have assumed a mechanism that is assimilable to heparin-induced thrombocytopenia, with protagonist antibodies against the PF4-polyanion complex. Viral DNA has a negative charge and can bind to PF4, causing VITT. New experimental studies have assumed that thrombosis is related to a soluble adenoviral protein spike variant, originating from splicing events, which cause important endothelial inflammatory events, and binding to endothelial cells expressing ACE2. Conclusion: Further studies are needed to better identify VITT's pathophysiological mechanisms and genetic, demographic, or clinical predisposition of high-risk patients, to investigate the correlation of VITT with the different vaccine types, and to test the significance of the findings.
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Vacuna nCoV-2019 mRNA-1273/inmunología , Vacuna BNT162/inmunología , COVID-19/inmunología , ChAdOx1 nCoV-19/inmunología , SARS-CoV-2/fisiología , Trombosis/epidemiología , Vacuna nCoV-2019 mRNA-1273/efectos adversos , Complejo Antígeno-Anticuerpo/metabolismo , Vacuna BNT162/efectos adversos , COVID-19/complicaciones , COVID-19/epidemiología , Venas Cerebrales/metabolismo , Venas Cerebrales/patología , ChAdOx1 nCoV-19/efectos adversos , Femenino , Cefalea , Humanos , Vacunación Masiva , Factor Plaquetario 4/inmunología , Factores Sexuales , Análisis de Supervivencia , Trombosis/etiología , Trombosis/mortalidadRESUMEN
Distinguishing brain venules from arterioles with arteriolosclerosis is less reliable using traditional staining methods. We aimed to immunohistochemically assess the monocarboxylate transporter 1 (MCT1), a specific marker of venous endothelium found in rodent studies, in different caliber vessels in human brains. Both largeand small-caliber cerebral vessels were dissected from four autopsy donors. Immunoreactivity for MCT1 was examined in all autopsied human brain tissues, and then each vessel was identified by neuropathologists using hematoxylin and eosin stain, the Verhoeff's Van Gieson stain, immunohistochemical stain with antibodies for α-smooth muscle actin and MCT1 in sequence. A total of 61 cerebral vessels, including 29 arteries and 32 veins were assessed. Immunoreactivity for MCT1 was observed in the endothelial cells of various caliber veins as well as the capillaries, whereas that was immunenegative in the endothelium of arteries. The different labeling patterns for MCT1 could aid in distinguishing various caliber veins from arteries, whereas assessment using the vessel shape, the internal elastic lamina, and the pattern of smooth muscle fibers failed to make the distinction between small-caliber veins and sclerotic arterioles. In conclusion, MCT1 immunohistochemical staining is a sensitive and reliable method to distinguish cerebral veins from arteries.
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Arteriolas/citología , Encéfalo/citología , Arterias Cerebrales/citología , Venas Cerebrales/citología , Células Endoteliales/metabolismo , Transportadores de Ácidos Monocarboxílicos/metabolismo , Simportadores/metabolismo , Vénulas/citología , Arteriolas/metabolismo , Encéfalo/metabolismo , Arterias Cerebrales/metabolismo , Venas Cerebrales/metabolismo , Diagnóstico Diferencial , Humanos , Vénulas/metabolismoRESUMEN
Bedside detection and early treatment of lasting cerebral ischemia may improve outcome after out-of-hospital cardiac arrest (OHCA). This feasibility study explores the possibilities to use microdialysis (MD) for continuous monitoring of cerebral energy metabolism by analyzing the draining cerebral venous blood. Eighteen comatose patients were continuously monitored with jugular bulb and radial artery (reference) MD following resuscitation. Median time from cardiac arrest to MD was 300 min (IQR 230-390) with median monitoring time 60 h (IQR 40-81). The lactate/pyruvate ratio in cerebral venous blood was increased during the first 20 h after OHCA, and significant differences in time-averaged mean MD metabolites between jugular venous and artery measurements, were documented (p < 0.02). In patients with unfavorable outcome (72%), cerebral venous lactate and pyruvate levels remained elevated during the study period. In conclusion, the study indicates that jugular bulb microdialysis (JBM) is feasible and safe. Biochemical signs of lasting ischemia and mitochondrial dysfunction are frequent and associated with unfavorable outcome. The technique may be used in comatose OHCA patients to monitor biochemical variables reflecting ongoing brain damage and support individualized treatment early after resuscitation.
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Lesiones Encefálicas/diagnóstico , Isquemia Encefálica/diagnóstico , Paro Cardíaco Extrahospitalario/complicaciones , Adulto , Anciano , Biomarcadores/sangre , Encéfalo/metabolismo , Lesiones Encefálicas/sangre , Isquemia Encefálica/sangre , Venas Cerebrales/metabolismo , Metabolismo Energético , Estudios de Factibilidad , Femenino , Humanos , Ácido Láctico/análisis , Ácido Láctico/sangre , Masculino , Microdiálisis/métodos , Persona de Mediana Edad , Paro Cardíaco Extrahospitalario/sangre , Oxígeno/metabolismo , Estudios Prospectivos , Ácido Pirúvico/análisis , Ácido Pirúvico/sangreRESUMEN
Cerebral cavernous malformations are acquired vascular anomalies that constitute a common cause of central nervous system hemorrhage and stroke. The past 2 decades have seen a remarkable increase in our understanding of the pathogenesis of this vascular disease. This new knowledge spans genetic causes of sporadic and familial forms of the disease, molecular signaling changes in vascular endothelial cells that underlie the disease, unexpectedly strong environmental effects on disease pathogenesis, and drivers of disease end points such as hemorrhage. These novel insights are the integrated product of human clinical studies, human genetic studies, studies in mouse and zebrafish genetic models, and basic molecular and cellular studies. This review addresses the genetic and molecular underpinnings of cerebral cavernous malformation disease, the mechanisms that lead to lesion hemorrhage, and emerging biomarkers and therapies for clinical treatment of cerebral cavernous malformation disease. It may also serve as an example for how focused basic and clinical investigation and emerging technologies can rapidly unravel a complex disease mechanism.
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Venas Cerebrales/anomalías , Hemangioma Cavernoso del Sistema Nervioso Central/genética , Hemangioma Cavernoso del Sistema Nervioso Central/terapia , Mutación , Animales , Venas Cerebrales/metabolismo , Predisposición Genética a la Enfermedad , Hemangioma Cavernoso del Sistema Nervioso Central/metabolismo , Hemangioma Cavernoso del Sistema Nervioso Central/patología , Humanos , Fenotipo , Transducción de SeñalRESUMEN
Appropriate vascular function is essential for the maintenance of central nervous system homeostasis and is achieved through virtue of the blood-brain barrier; a specialized structure consisting of endothelial, mural, and astrocytic interactions. While appropriate blood-brain barrier function is typically achieved, the central nervous system vasculature is not infallible and cerebrovascular anomalies, a collective terminology for diverse vascular lesions, are present in meningeal and cerebral vasculature supplying and draining the brain. These conditions, including aneurysmal formation and rupture, arteriovenous malformations, dural arteriovenous fistulas, and cerebral cavernous malformations, and their associated neurological sequelae, are typically managed with neurosurgical or pharmacological approaches. However, increasing evidence implicates interacting roles for inflammatory responses and disrupted central nervous system fluid flow with respect to vascular perturbations. Here, we discuss cerebrovascular anomalies from an immunologic angle and fluid flow perspective. We describe immune contributions, both common and distinct, to the formation and progression of diverse cerebrovascular anomalies. Next, we summarize how cerebrovascular anomalies precipitate diverse neurological sequelae, including seizures, hydrocephalus, and cognitive effects and possible contributions through the recently identified lymphatic and glymphatic systems. Finally, we speculate on and provide testable hypotheses for novel nonsurgical therapeutic approaches for alleviating neurological impairments arising from cerebrovascular anomalies, with a particular emphasis on the normalization of fluid flow and alleviation of inflammation through manipulations of the lymphatic and glymphatic central nervous system clearance pathways.
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Inmunidad Adaptativa , Encéfalo/irrigación sanguínea , Malformaciones Vasculares del Sistema Nervioso Central , Arterias Cerebrales/anomalías , Venas Cerebrales/anomalías , Inmunidad Innata , Animales , Malformaciones Vasculares del Sistema Nervioso Central/líquido cefalorraquídeo , Malformaciones Vasculares del Sistema Nervioso Central/genética , Malformaciones Vasculares del Sistema Nervioso Central/inmunología , Malformaciones Vasculares del Sistema Nervioso Central/terapia , Arterias Cerebrales/inmunología , Arterias Cerebrales/metabolismo , Venas Cerebrales/inmunología , Venas Cerebrales/metabolismo , Predisposición Genética a la Enfermedad , Herencia , Humanos , Fenotipo , Factores de RiesgoRESUMEN
The cranial window (CW) technique provides a simple and low-cost method to assess tumor angiogenesis in the brain. The CW combined with histology using selective markers for tumor and endothelial cells can allow a sensitive monitoring of novel antiangiogenesis therapies in preclinical models. The CW was established in cyclosporine immunosuppressed rats that were stereotactically grafted with fluorescent U87MG glioblastoma cells. One to 3 weeks after grafting, brain vasculature was visualized in vivo and assessed by immunofluorescence microscopy using antibodies against endothelial and smooth-muscle cells and blood brain barrier. At 1-2 weeks after grafting, the CW reliably detected the hypertrophy of venous-venous anastomoses and cortical veins. These structures increased highly significantly their pregrafting diameter. Arterialized veins and hemorrhages were seen by three weeks after grafting. Immunofluorescence microscopy showed significant branching and dilation of microvessels, particularly those surrounded by tumor cells. Mechanistically, these changes lead to loss of vascular resistance, increased venous outflow, and opening of venous-venous anastomoses on the cortical surface. Data from the present study, namely, the hypertrophy of cortical venous-venous anastomoses, microvessel branching, and dilation of the microvessels surrounded by tumor cells, indicate the power of this in vivo model for the sensitive monitoring of early tumor angiogenesis.
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Bioensayo , Neoplasias Encefálicas , Encéfalo , Venas Cerebrales , Glioblastoma , Neoplasias Experimentales , Neovascularización Patológica , Animales , Encéfalo/irrigación sanguínea , Encéfalo/metabolismo , Encéfalo/patología , Neoplasias Encefálicas/irrigación sanguínea , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Venas Cerebrales/metabolismo , Venas Cerebrales/patología , Glioblastoma/irrigación sanguínea , Glioblastoma/metabolismo , Glioblastoma/patología , Humanos , Masculino , Neoplasias Experimentales/irrigación sanguínea , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Ratas , Ratas WistarRESUMEN
We studied the effect of increased systemic levels of the proinflammatory cytokine IL-1ß on the vasomotor reactions of pial microvessels in anesthetized rats under conditions of experimentally simulated progressively increasing acute normobaric hypoxia. Vital microscopy showed that more pronounced dilatation of pial vessels in response to IL-1ß under hypoxic conditions was almost completely prevented by pretreatment with non-specific NO synthase blocker L-NAME. These findings indicate the involvement of NO-dependent mechanisms in the vasodilator effect of proinflammatory cytokines under conditions of acute hypoxic exposure.
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Arteriolas/efectos de los fármacos , Venas Cerebrales/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Hipoxia/tratamiento farmacológico , Interleucina-1beta/farmacología , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico Sintasa de Tipo III/metabolismo , Enfermedad Aguda , Animales , Arteriolas/metabolismo , Arteriolas/fisiopatología , Venas Cerebrales/diagnóstico por imagen , Venas Cerebrales/metabolismo , Venas Cerebrales/fisiopatología , Hipoxia/diagnóstico por imagen , Hipoxia/metabolismo , Hipoxia/fisiopatología , Inyecciones Intravenosas , Interleucina-1beta/antagonistas & inhibidores , Microscopía Intravital , Masculino , Óxido Nítrico Sintasa de Tipo III/antagonistas & inhibidores , Ratas , Ratas Wistar , Vasodilatación/efectos de los fármacosRESUMEN
Cerebral edema after brain surgery remains a life-threatening complication in the clinic. For a better operating field view, superior petrosal vein (SPV) can be easily damaged during neurosurgery. SPV sacrifice may sometimes be inevitable in clinic. However, the safety of SPV sacrifice is still a controversial question. Whether petrosal vein injury has an effect on cerebral edema after brain surgery is still unknown. In this study, rabbits were divided into two groups. The rabbits in the surgery group underwent petrosal vein sacrifice. The control group was subjected to sham surgery. Cerebellum and brain stem tissues were collected at 4 h, 8 h, 12 h, 24 h, 48 h and 72 h post-surgery. The superoxidase dismutase (SOD) activity and expression of malondialdehyde (MDA) were tested in the collected samples. Quantitiative real time polymerase chain reaction and immunohistochemistry were used to detect the mRNA and protein levels, respectively, of aquaporin 4 (AQP4) in the tissue samples. Compared to the control sham group, the activity of SOD and MDA expression in cerebellum was decreased and increased, respectively, at 4 h, 8 h, 12 h and 24 h post-, surgery The SOD activity and expression of MDA in brain stem was decreased and increased, respectively, only in 4 h after surgery, compared with control group. The mRNA and protein levels of AQP4 were increased in cerebellum at 4 h, 8 h, 12 h and 24 h after surgery, but in the brain stem, the levels were increased only at 4 h after surgery compared with sham group. Our results thus show that SPV sacrifice influences oxidative stress and the expression of AQP4 in cerebellum and brain stem of rabbits; highlighting the importance of protecting the petrosal vein during neurosurgery.
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Acuaporina 4/metabolismo , Tronco Encefálico/metabolismo , Cerebelo/metabolismo , Venas Cerebrales/metabolismo , Malondialdehído/metabolismo , Superóxido Dismutasa/metabolismo , Animales , Venas Cerebrales/lesiones , ConejosRESUMEN
Accumulating evidence corroborates the role of the "central vein sign" in the radiological diagnosis of multiple sclerosis (MS). Here, we report human magnetic resonance imaging (MRI) and corresponding pathological data that inflammation-dependent intracerebral remodeling of the vessel wall is directly associated with the prominence of intralesional veins on susceptibility-based MRI. In adult marmosets with experimental autoimmune encephalomyelitis, vessel-wall fibrosis was detected early in the demyelinating process, even in lesions <2 weeks old, though fibrosis was more evident after 6 weeks. Vascular remodeling consisted of both luminal enlargement and eccentric thickening of the perivascular space (fibrillar collagen type I deposition) and affected almost exclusively white matter, but not subpial cortical, lesions. The long-term effect of vessel remodeling in MS lesions is currently unknown, but it might potentially affect tissue repair. ANN NEUROL 2019;85:934-942.
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Venas Cerebrales/química , Venas Cerebrales/diagnóstico por imagen , Enfermedades Desmielinizantes/diagnóstico por imagen , Colágenos Fibrilares/análisis , Colágenos Fibrilares/fisiología , Adulto , Anciano , Anciano de 80 o más Años , Animales , Callithrix , Venas Cerebrales/metabolismo , Enfermedades Desmielinizantes/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Objective- Endothelial cells (ECs) sense and respond to flow-induced mechanical stress, in part, via microtubule-based projections called primary cilia. However, many critical steps during vascular morphogenesis occur independent of flow. The involvement of cilia in regulating these stages of cranial vascular morphogenesis is poorly understood because cilia have not been visualized in primary head vessels. The objective of this study was to investigate involvement of cilia in regulating the early stages of cranial vascular morphogenesis. Approach and Results- Using high-resolution imaging of the Tg(kdrl:mCherry-CAAX) y171 ;(bactin::Arl13b:GFP) zebrafish line, we showed that cilia are enriched in the earliest formed cranial vessels that assemble via vasculogenesis and in angiogenic hindbrain capillaries. Cilia were more prevalent around the boundaries of putative intravascular spaces in primary and angiogenic vessels. Loss of cardiac contractility and blood flow, because of knockdown of cardiac troponin T type 2a ( tnnt2a) expression, did not affect the distribution of cilia in primary head vasculature. In later stages of development, cilia were detected in retinal vasculature, areas of high curvature, vessel bifurcation points, and during vessel anastomosis. Loss of genes crucial for cilia biogenesis ( ift172 and ift81) induced intracerebral hemorrhages in an EC-autonomous manner. Exposure to high shear stress induced premature cilia disassembly in brain ECs and was associated with intracerebral hemorrhages. Conclusions- Our study suggests a functional role for cilia in brain ECs, which is associated with the emergence and remodeling of the primary cranial vasculature. This cilia function is flow-independent, and cilia in ECs are required for cerebral-vascular stability.
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Arterias Cerebrales/embriología , Venas Cerebrales/embriología , Cilios , Células Endoteliales , Endotelio Vascular/embriología , Neovascularización Fisiológica , Pez Cebra/embriología , Animales , Animales Modificados Genéticamente , Arterias Cerebrales/metabolismo , Venas Cerebrales/metabolismo , Cilios/metabolismo , Células Endoteliales/metabolismo , Endotelio Vascular/metabolismo , Regulación del Desarrollo de la Expresión Génica , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Malformaciones Arteriovenosas Intracraneales/embriología , Malformaciones Arteriovenosas Intracraneales/genética , Malformaciones Arteriovenosas Intracraneales/metabolismo , Proteínas Luminiscentes/genética , Proteínas Luminiscentes/metabolismo , Mecanotransducción Celular , Morfogénesis , Troponina T/genética , Troponina T/metabolismo , Pez Cebra/genética , Pez Cebra/metabolismo , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismo , Proteína Fluorescente RojaRESUMEN
BACKGROUND: Cerebral vein thrombosis (CVT) is a rare, life-threatening disease affecting one adult per 100,000 per year. Genetic risk factors are deficiencies of the natural anticoagulant proteins antithrombin, protein C, protein S or single nucleotide polymorphisms such as factor V Leiden and prothrombin 20210A. In 20% of patients, the cause of CVT remains unknown. AIM: To identify novel genetic risk factors for CVT using targeted next-generation DNA sequencing (NGS). METHODS: We investigated 171 CVT patients and 298 healthy controls. Patients were selected using the following criteria: objective diagnosis of CVT, no active cancer. We performed targeted NGS analysis of the protein-coding regions of 734 candidate genes related to hemostasis and inflammation, 150 ancestry informative markers and 28 thrombosis-associated variants. RESULTS: We identified 3723 common and low frequency variants with minor allele frequency (MAF) >1% in 590 genes. Single variant association testing using logistic regression analysis identified rs8176719 insertion/deletion (indel) variant in the ABO gene associated with CVT (age and sex adjusted OR 2.03; 95% CI 1.52-2.73; Pâ¯=â¯2.07â¯×â¯10-6; Bonferroni Pâ¯=â¯0.008). In addition, we identified 8839 rare variants (MAFâ¯≤â¯1%) in 723 genes. Gene-based association analysis of these rare variants using a burden test revealed only a tentative association of non-coding variants located in the F8 locus with CVT. CONCLUSION: Targeted NGS identified a common indel variant rs8176719 in the ABO gene. Gene-based tests of association failed to reveal genomic loci with a cumulative burden of rare variants associated with CVT.
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Venas Cerebrales/patología , Trombosis Intracraneal/genética , Sistema del Grupo Sanguíneo ABO/genética , Adulto , Estudios de Casos y Controles , Venas Cerebrales/metabolismo , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Mutación INDEL , Trombosis Intracraneal/patología , Desequilibrio de Ligamiento , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Análisis de Secuencia de ADN/métodosRESUMEN
OBJECTIVE: Arteriovenous malformations (AVMs) are characterised by tangles of dysplastic blood vessels which shunt blood from arteries to veins with no intervening capillary bed. It is not known at what stage of development and differentiation, AVM vessels became aberrant. To address this, we have analysed the expression of vascular differentiation, vascular maturation and brain capillary specific genes in AVM nidus. METHODOLOGY: We performed immunohistochemistry and western blot analysis of vascular differentiation (HEY2, DLL4, EFNB2, and COUP-TFII), vascular maturation (ENG and KLF2) and brain capillary specific genes (GGTP and GLUT1) on ten surgically excised human brain AVMs and ten normal human brain tissues. RESULTS: Immunohistochemical analysis revealed that AVM vessels co-express both artery and vein differentiation genes. H-score analysis revealed that there is statistically significant (P < 0.0001) increase in expression of these proteins in AVM vessels compared to control vessels. These findings were further confirmed by western blot analysis and found to be statistically significant (P < 0.0001 and P < 0.001) for all proteins except Hey2. Both immunostaining and western blot analysis revealed that AVM vessels express GGTP and GLUT1, markers specific to brain capillaries. Immunofluorescent staining demonstrated that expression of KLF2, a vascular maturation marker is significantly (P <0.001) decreased in AVM vessels and was further confirmed by western blot analysis (P < 0.001). Immunohistochemical and western blot analysis demonstrated that another vascular maturation protein Endoglin had high expression in AVM vessels compared to control vessels. The results were found to be statistically significant (P < 0.0001). SUMMARY: Our findings suggest that vascular structures of AVMs co-express markers specific for arteries, veins and capillaries. We conclude that AVM nidus constitutes of aberrant vessels which are not terminally differentiated and inadequately matured.
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Arterias Cerebrales/metabolismo , Venas Cerebrales/metabolismo , Malformaciones Arteriovenosas Intracraneales/patología , Adulto , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Encéfalo/metabolismo , Encéfalo/patología , Factor de Transcripción COUP II/metabolismo , Diferenciación Celular , Arterias Cerebrales/patología , Venas Cerebrales/patología , Endoglina/metabolismo , Femenino , Expresión Génica , Transportador de Glucosa de Tipo 1/metabolismo , Humanos , Malformaciones Arteriovenosas Intracraneales/metabolismo , Masculino , Proteínas Represoras/metabolismo , Adulto JovenRESUMEN
OBJECTIVE: MRI and CT scans are usually normal in mild traumatic brain injury (mTBI) although 15-20% of such patients suffer for months from fatigue, headache, anxiety, sleep and other disorders. mTBI is suspected to be a cerebrovascular injury, similar to moderate and severe TBI. Brain SPECT is more sensitive and shows perfusion abnormalities immediately after mTBI. This work explores the perfusion abnormalities for young patients suffering from fatigue several months after mTBI. PATIENTS AND METHODS: Twelve mTBI patients (age:8-36 yr, 4 male) with no history of fatigue prior to trauma were prospectively studied following onset of fatigue 6-12 months after mTBI utilizing 99â¯m-Tc ECD brain SPECT with early and delayed radiotracer imaging. RESULTS: The perfusion pattern in the mTBIâ¯+â¯fatigue group included left hemispheric deficits in frontal lobes (early phase: 15.2⯱â¯4.2%, delayed phase: 9.9⯱â¯2.2%) and medial temporal lobes (early phase 11.2⯱â¯3.7%, delayed phase: 9.0⯱â¯2.3%). Seven patients additionally showed excess tracer accumulation in the parenchyma surrounding internal jugular bulb inferior to temporal lobe. This was modeled as due to increased cellular permeability from TBI induced oxidative stress affecting endothelial tight junctions and consequent tracer leakage across jugular bulbs. Prolonged posture changes from erect to supine position during imaging increase jugular cross-sectional area and venous wall pressure as has been observed in other disease processes and seem to be responsible for tracer leakage from jugular bulbs in our study. CONCLUSION: This work supports an oxidative stress and BBB disruption model for mTBI. The frontal and temporal lobe perfusion deficits are attributed to anatomical vulnerabilities of these lobes. During a mild TBI both of these lobes are susceptible to grazing impacts with underlying bony ridges. We propose a relation between mTBI and fatigue arising from oxidative stress in mTBI affecting ATP generation and altering endothelial homeostasis for both micro-and-large vasculatures. The tracer leakage observed around jugular veins is due to posture induced changes in venous cross-sections and wall pressure as well as from compromised endothelium post TBI induced oxidative stress.
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Conmoción Encefálica/diagnóstico por imagen , Venas Cerebrales/diagnóstico por imagen , Traumatismos Craneocerebrales/diagnóstico por imagen , Fatiga/diagnóstico por imagen , Microvasos/diagnóstico por imagen , Tomografía Computarizada de Emisión de Fotón Único/métodos , Adolescente , Adulto , Encéfalo/irrigación sanguínea , Encéfalo/diagnóstico por imagen , Conmoción Encefálica/complicaciones , Conmoción Encefálica/metabolismo , Venas Cerebrales/metabolismo , Niño , Traumatismos Craneocerebrales/complicaciones , Traumatismos Craneocerebrales/metabolismo , Fatiga/etiología , Fatiga/metabolismo , Femenino , Humanos , Masculino , Microvasos/metabolismo , Postura/fisiología , Adulto JovenRESUMEN
BACKGROUND: The CO2 reactivity is often used to assess vascular function, but it is still unclear whether this reactivity is affected by aging. OBJECTIVE: To investigate the effects of aging on the CO2 reactivity in ocular and cerebral vessels, both of which are highly sensitive to hypercapnia, we compared the CO2 reactivity in the retinal artery (RA), retinal and choroidal vessels (RCV), optic nerve head (ONH), and middle cerebral artery (MCA) between young and middle-aged subjects. METHODS: We measured the CO2 reactivity in 14 young and 11 middle-aged males using laser-speckle flowgraphy during a 3-min inhalation of CO2-rich air. RESULTS: The CO2 reactivity in the RA and ONH were lower in the middle-aged group than in the young group, but no significant effect of age was observed in the RCV or MCA. The CO2 reactivity in the RA and ONH were correlated significantly with age, whereas those in the RCV or MCA were not. CONCLUSIONS: These findings suggest that there are regional differences in the effect of age on the CO2 reactivity among not only ocular and cerebral vessels, but also the retinal and choroidal vessels, even though these vessels are in neighboring areas.
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Dióxido de Carbono/metabolismo , Venas Cerebrales/metabolismo , Flujometría por Láser-Doppler/métodos , Arteria Retiniana/metabolismo , Vasos Retinianos/metabolismo , Adulto , Anciano , Envejecimiento , Venas Cerebrales/citología , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Arteria Retiniana/citología , Vasos Retinianos/citología , Adulto JovenRESUMEN
Reorganization of the neurovascular unit has been suggested in the epileptic brain, although the dynamics and functional significance remain unclear. Here, we tracked the in vivo dynamics of perivascular mural cells as a function of electroencephalogram (EEG) activity following status epilepticus. We segmented the cortical vascular bed to provide a size- and type-specific analysis of mural cell plasticity topologically. We find that mural cells are added and removed from veins, arterioles, and capillaries after seizure induction. Loss of mural cells is proportional to seizure severity and vascular pathology (e.g., rigidity, perfusion, and permeability). Treatment with platelet-derived growth factor subunits BB (PDGF-BB) reduced mural cell loss, vascular pathology, and epileptiform EEG activity. We propose that perivascular mural cells play a pivotal role in seizures and are potential targets for reducing pathophysiology.
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Becaplermina/metabolismo , Permeabilidad Capilar , Arterias Cerebrales , Venas Cerebrales , Estado Epiléptico , Animales , Becaplermina/genética , Arterias Cerebrales/metabolismo , Arterias Cerebrales/patología , Arterias Cerebrales/fisiopatología , Venas Cerebrales/metabolismo , Venas Cerebrales/patología , Venas Cerebrales/fisiopatología , Electroencefalografía , Ratones , Ratones Transgénicos , Estado Epiléptico/genética , Estado Epiléptico/metabolismo , Estado Epiléptico/patología , Estado Epiléptico/fisiopatologíaRESUMEN
A surgeon's understanding of the surgical anatomy can be greatly enhanced by the dissection of preserved cadaveric specimens. A reliable and inexpensive biological model for testing and standardization of dye injection concentrations is proposed utilizing the goat's head as a biological model. The first phase was concerned with standardization of the dye by titrating its concentration and injecting various amounts into cerebral vessels of a goat's head until an optimal concentration had been ascertained. In the second phase, this optimum concentration of the dye was injected into four human cadaveric heads following the same technique standardized using the goat's head. Upon dissecting the four cadaveric human heads which were injected with silicon dyes and preserved in 10% formalin, the vessels were all well-opacified and the brain was of near normal consistency and good for dissection, without showing any features of putrefaction. The goat model, having similar color, texture, and the handling as the cadaveric head, offers an opportunity to test indigenously manufactured polymerizing dyes in the future. This biological model, therefore, has the potential to considerably reduce the cost of cadaver preparation.
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Arterias Cerebrales/anatomía & histología , Arterias Cerebrales/metabolismo , Venas Cerebrales/anatomía & histología , Venas Cerebrales/metabolismo , Silicio/metabolismo , Oligoelementos/metabolismo , Cadáver , Cabeza , Humanos , Inyecciones/métodos , Inyecciones/normas , Procedimientos Neuroquirúrgicos/métodos , Procedimientos Quirúrgicos Vasculares/métodosRESUMEN
Cerebrovascular diseases that cause ischaemic or haemorrhagic stroke with subsequent loss of life or functional capacity due to damage of the brain tissue are among the leading causes of human suffering and economic burden inflicted by diseases in the developed world. Diseases affecting intracranial vessels are significant contributors to ischaemic and haemorrhagic strokes. Brain arteriovenous malformations, which are a collection of abnormal blood vessels connecting arteries to veins, are the most common cause of intracranial haemorrhage in children and young adults. Saccular intracranial aneurysms, which are pathological saccular dilations mainly occurring at bifurcations of the large intracranial arteries near the circle of Willis, are highly prevalent in the middle-aged population, causing significant anxiety and concern; their rupture, although rare, is a significant cause of intracranial haemorrhage in those past middle age that is associated with a very sinister prognosis. Cerebral small-vessel disease, which comprise all pathological processes affecting vessels <500 microns in diameter, account for the majority of intracerebral haemorrhages and â¼25% of ischaemic strokes and 45% of dementias in the elderly. In this review, we summarize the developmental, structural, and functional features of intracranial vessels. We then describe the role of smooth muscle cells in brain arteriovenous malformations, intracranial aneurysms, and small-vessel diseases, and discuss how the peculiar ontogeny, structure, and function of intracranial vessels are related to the development of these diseases.
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Trastornos Cerebrovasculares/patología , Músculo Liso Vascular/patología , Miocitos del Músculo Liso/patología , Animales , Arterias Cerebrales/metabolismo , Arterias Cerebrales/patología , Arterias Cerebrales/fisiopatología , Venas Cerebrales/metabolismo , Venas Cerebrales/patología , Venas Cerebrales/fisiopatología , Circulación Cerebrovascular , Trastornos Cerebrovasculares/metabolismo , Trastornos Cerebrovasculares/fisiopatología , Hemodinámica , Humanos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/fisiopatología , Miocitos del Músculo Liso/metabolismo , Fenotipo , Transducción de SeñalRESUMEN
In certain surgical procedures, sacrificing the superior petrosal vein (SPV) is required. Previous studies have reported transient cerebellar edema, venous infarction, or hemorrhage that might occur after sectioning of the SPV. The present study investigated the pathophysiological changes in cerebellum and brain stem after SPV sacrifice. Rabbits were divided into the operation group where the SPV was sacrificed and the control group where the SPV remained intact. Each group was further subdivided into 4, 8, 12, 24, 48, and 72 h groups which represented the time period from sacrificing of the SPV to killing of the rabbits. The water content (WC), Na+ content, K+ content, and pathophysiological changes in cerebellum and brain stem tissue were measured. In comparison with the control, the WC and Na+ content of cerebellar tissue were increased in the 4, 8, 12, and 24 h operation subgroups (P<0.05), but only increased in the 4-h subgroup of the brain stem tissue (P<0.05). The K+ content of the cerebellar tissue decreased in the 4, 8, 12, and 24 h operation subgroups (P<0.05) but only decreased in the 4-h subgroup of brain stem tissue (P<0.05). Nissl staining and TEM demonstrated that cerebellar edema occurred in the 4, 8, 12, and 24 h operation subgroups but not in the 48- and 72-h subgroups. Brain stem edema occurred in the 4-h operation subgroup. In summary, cerebellum and brain stem edema can be observed at different time points after sacrificing of the SPV in the rabbit model.