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ABSTRACT: These findings emphasize that the mTOR pathway may contribute to maintenance of quiescence of CSCs, and provide a basis for manipulating CSCs in the treatment of GBM. Future research should focus on further defining the PI3K/Akt/mTOR molecular network in the regulation of stem cell quiescence and provide rationale for targeting the cancer-initiating cells of GBM.
Advances in enzyme regulation 10/2010; 51(1):164-70.
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ABSTRACT: Germinal matrix (GM) vasculature is selectively vulnerable to hemorrhage in premature infants during the first 48 hr of life. This is attributed to rapid angiogenesis of this brain region, resulting in formation of nascent vessels that show a paucity of pericytes and immaturity of extracellular matrix. Integrins are key regulators of angiogenesis and contribute to stabilization of cerebral vasculature by providing endothelial- and astrocyte-matrix adhesion. Therefore, we asked whether GM exhibited a distinct regional pattern of integrin expression that was dissimilar from that of the cerebral cortex and white matter in human fetuses and premature infants. To this end, we measured protein and gene expression of integrins in the GM, cortex, and white matter of human fetuses (15-22 weeks), premature infants (23-35 weeks), and mature infants (36-40 weeks). We found that protein levels of alpha5beta1 integrin were greater in the GM than in the cortex or white matter by 1.6-fold for both fetuses and premature infants. alpha5beta1 integrin mRNA expression was higher in the GM than in the cortex or white matter by 2-fold for fetuses but not for premature infants. alphaVbeta3, alphaVbeta5, alphaVbeta8, and alpha4beta1 integrin expression were comparable among GM, cortex, and white matter in fetuses and premature infants. Because alpha5beta1 integrin is a central regulator of angiogenesis, its elevation in the GM of fetuses and premature infants indicates that this might be a key activator of endothelial proliferation in this brain region. We speculate that selective alpha5beta1 integrin inhibition might suppress angiogenesis in the GM and thus prevent brain hemorrhage in premature infants.
Journal of Neuroscience Research 12/2009; 88(6):1193-204. · 2.74 Impact Factor
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ABSTRACT: Intraventricular hemorrhage (IVH) is a common complication of prematurity that results in neurological sequelae, including cerebral palsy, posthemorrhagic hydrocephalus, and cognitive deficits. Despite this, there is no standardized animal model exhibiting neurological consequences of IVH in prematurely delivered animals. We asked whether induction of moderate-to-severe IVH in premature rabbit pups would produce long-term sequelae of cerebral palsy, posthemorrhagic hydrocephalus, reduced myelination, and gliosis.
The premature rabbit pups, delivered by cesarean section, were treated with intraperitoneal glycerol at 2 hours postnatal age to induce IVH. The development of IVH was diagnosed by head ultrasound at 24 hours of age. Neurobehavioral, histological, and ultrastructural evaluation and diffusion tensor imaging studies were performed at 2 weeks of age.
Although 25% of pups with IVH (IVH pups) developed motor impairment with hypertonia and 42% developed posthemorrhagic ventriculomegaly, pups without IVH (non-IVH) were unremarkable. Immunolabeling revealed reduced myelination in the white matter of IVH pups compared with saline- and glycerol-treated non-IVH controls. Reduced myelination was confirmed by Western blot analysis. There was evidence of gliosis in IVH pups. Ultrastructural studies in IVH pups showed that myelinated and unmyelinated fibers were relatively preserved except for focal axonal injury. Diffusion tensor imaging showed reduction in fractional anisotropy and white matter volume confirming white matter injury in IVH pups.
The rabbit pups with IVH displayed posthemorrhagic ventriculomegaly, gliosis, reduced myelination, and motor deficits, like humans. The study highlights an instructive animal model of the neurological consequences of IVH, which can be used to evaluate strategies in the prevention and treatment of posthemorrhagic complications.
Stroke 09/2009; 40(10):3369-77. · 5.73 Impact Factor
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ABSTRACT: Myocardial bridging of a coronary artery is an anatomic anomaly in which a major epicardial coronary artery extends intramurally into the myocardium for a part of the vessel's course. The left anterior descending coronary artery (LAD) is most frequently involved. Myocardial bridging is often asymptomatic, although myocardial pathology, arrhythmias and sudden cardiac death have been reported. In this study we quantitated the degree of myocardial intersitial fibrosis in histological sections of the anterior wall of the left ventricle obtained from the hearts of 6 individuals with myocardial bridging of the LAD and compared it to age-, weight-, and sex-matched controls without bridging. We found that patients with the bridging of the LAD had 33% increased myocardial interstitial fibrosis as compared to the control group (P=0.0006). Our data suggest that myocardial bridging may be an independent risk factor for development of myocardial ischemia and interstitial fibrosis.
International journal of cardiology 03/2008; 124(3):391-2. · 7.08 Impact Factor
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ABSTRACT: Germinal matrix (GM) is a richly vascularized collection of neuronal-glial precursor cells in the developing brain, which is selectively vulnerable to hemorrhage in premature infants. It has rapid angiogenesis associated with high levels of vascular endothelial growth factor (VEGF). Because pericytes provide structural stability to blood vessels, we asked whether pericytes were fewer in the GM than in the subjacent white matter and neocortex and, if so, whether angiogenic inhibition could increase the pericyte density in the GM. We found pericyte coverage and density less in the GM vasculature than in the cortex or white matter in human fetuses, premature infants, and premature rabbit pups. Notably, although VEGF suppression significantly enhanced pericyte coverage in the GM, it remained less than in other brain regions. Therefore, to further elucidate the basis of fewer pericytes in the GM vasculature, we examined expression of ligand-receptor systems responsible for pericyte recruitment. Transforming growth factor-beta1 (TGF-beta1) protein expression was lower, whereas sphingosine-1-phosphate1 (S1P1) and N-cadherin levels were higher in the GM than in the cortex or white matter. Low TGF-beta1 may be involved in promoting endothelial proliferation, whereas elevated S1P1 with N-cadherin may assist vascular maturation. Hence, a paucity of pericytes in the GM vasculature may contribute to its propensity to hemorrhage, and a lower expression of TGF-beta1 could be a basis of reduced pericyte density in its vasculature.
Journal of Neuroscience 11/2007; 27(44):12012-24. · 7.11 Impact Factor
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Vahe Michael Zohrabian,
Hari Nandu,
Nicholas Gulati,
Greg Khitrov,
Connie Zhao,
Avinash Mohan,
Joseph Demattia, Alex Braun,
Kaushik Das,
Raj Murali,
Meena Jhanwar-Uniyal
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ABSTRACT: Gene expression profiling of metastatic brain tumors from primary lung adenocarcinoma, using a 17k-expression array, revealed that 1561 genes were consistently altered. Further functional classification placed the genes into seven categories: cell cycle and DNA damage repair, apoptosis, signal transduction molecules, transcription factors, invasion and metastasis, adhesion, and angiogenesis. Genes involved in apoptosis, such as caspase 2 (CASP2), transforming growth factor-beta inducible early gene (TIEG), and neuroprotective heat shock protein 70 (Hsp70) were underexpressed in metastatic brain tumors. Alterations in Rho GTPases (ARHGAP26, ARHGAP1), as well as down-regulation of the metastasis suppressor gene KiSS-1 were noted, which may contribute to tumor aggression. Overexpression of the invasion-related gene neurofibromatosis 1 (NF1), and angiogenesis-related genes vascular endothelial growth factor-B (VEGF-B) and placental growth factor (PGF) was also evidenced. Brain-specific angiogenesis inhibitors 1 and 3 (BAI1 and BAI3) were underexpressed as well. Examination of cell-adhesion and migration-related genes revealed an increased expression of integrins and extracellular matrices collagen and laminin. The study also showed alterations in p53 protein-associated genes, among these increased gene expression of p53, up-regulation of Reprimo or candidate mediator of the p53-dependent G2-arrest, down-regulation of p53-regulated apoptosis-inducing protein 1 (p53AIP1), decreased expression of tumor protein inducible nuclear protein 1 (p53DINP1), and down-regulation of Mdm4 (MDMX). The results demonstrated that genes involved in adhesion, motility, and angiogenesis were consistently up-regulated in metastatic brain tumors, while genes involved in apoptosis, neuroprotection, and suppression of angiogenesis were markedly down-regulated, collectively making these cancer cells prone to metastasis.
Oncology Reports 09/2007; 18(2):321-8. · 1.84 Impact Factor
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Praveen Ballabh,
Hongmin Xu,
Furong Hu, Alex Braun,
Kira Smith,
Aracelie Rivera,
Nanhong Lou,
Zoltan Ungvari,
Steven A Goldman,
Anna Csiszar,
Maiken Nedergaard
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ABSTRACT: The germinal matrix of premature infants is selectively vulnerable to hemorrhage within the first 48 h of life. To assess the role of vascular immaturity in germinal matrix hemorrhage (GMH), we evaluated germinal matrix angiogenesis in human fetuses and premature infants, as well as in premature rabbit pups, and noted active vessel remodeling in all three. Vascular endothelial growth factor (VEGF), angiopoietin-2 and endothelial cell proliferation were present at consistently higher levels in the germinal matrix relative to the white matter anlagen and cortical mantle. On that basis, we asked whether prenatal treatment with either of two angiogenic inhibitors, the COX-2 inhibitor celecoxib, or the VEGFR2 inhibitor ZD6474, could suppress the incidence of GMH in premature rabbit pups. Celecoxib treatment decreased angiopoietin-2 and VEGF levels as well as germinal matrix endothelial proliferation. Furthermore, treatment with celecoxib or ZD6474 substantially decreased the incidence of GMH. Thus, by suppressing germinal matrix angiogenesis, prenatal celecoxib or ZD6474 treatment may be able to reduce both the incidence and severity of GMH in susceptible premature infants.
Nature Medicine 04/2007; 13(4):477-85. · 22.46 Impact Factor
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ABSTRACT: Meningioangiomatosis (MA) is a rare benign disorder. It may occur sporadically or in association with neurofibromatosis (NF). The sporadic type typically presents with seizures, whereas that associated with NF is often asymptomatic. Of the 100 cases reported, only 14 are associated with NF. We now report 2 additional cases of MA associated with neurofibromatosis 2 (NF2) in a single family, with one occurring in the cerebellum. The etiology, pathology, and imaging features of MA are presented.
A 38-year-old woman (patient 1) presented with a 4-month history of ataxia. She had been diagnosed previously with NF2. Magnetic resonance imaging (MRI) scans of the brain revealed bilateral acoustic neuromas and multiple calcified intracranial lesions. Her 13-year-old daughter (patient 2) presented with complex partial seizures. MRI scans of the brain revealed bilateral acoustic neuromas and a right parietal mass. Patient 1 underwent a suboccipital craniotomy to resect the right-sided acoustic neuroma. A small portion of normal-appearing cerebellar cortex was resected to avoid undue retraction. Histopathologic examination showed the presence of a lesion consistent with MA. Patient 2 underwent a right temporal-parietal craniotomy to remove the enhancing epileptogenic right posterior temporoparietal lesion. Histopathologic analysis showed a lesion consistent with meningioma and MA.
MA has been reported infrequently in association with NF2. We now report 2 cases of MA associated with NF2 in one family, and we add the cerebellum to possible locations of occurrence. MA should be considered in the differential diagnosis of cortical lesions, particularly in patients with NF2.
Surgical Neurology 07/2006; 65(6):595-603. · 1.67 Impact Factor
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ABSTRACT: Astrocyte end-feet ensheathe blood vessels in the brain and are believed to provide structural integrity to the cerebral vasculature. We sought to determine in developing infants whether the coverage of blood vessels by astrocyte end-feet is decreased in germinal matrix (GM) compared with cerebral cortex and white matter (WM), which may cause fragility of the GM vasculature. Therefore, we evaluated the perivascular coverage by astrocyte end-feet in these areas. We double-labeled the brain sections with astroglial markers [glial fibrillary acidic protein (GFAP), aquaporin-4 (AQP4), and S-100beta] and a vascular marker, laminin. Perivascular coverage by GFAP+ astrocyte end-feet increased consistently as a function of gestational age (GA) in cortex and WM from 19 to 40 wk. Compared with GFAP, AQP4+ astrocyte end-feet developed at an earlier GA, ensheathing about 63% of blood vessels for 23-40 wk in cortex, WM, and GM. Coverage by GFAP+ perivascular end-feet was decreased in GM compared with cortex and WM from 23 to 34 wk. There was no difference in the coverage by AQP4+ end-feet among the three areas in these infants. The expression of AQP4, a water channel molecule, in the astrocyte end-feet was not significantly different between premature and mature infants, suggesting similar risk of brain edema in preterm and term infants in pathologic conditions. More importantly, the lesser degree of GFAP expression in astrocyte end-feet of GM compared with cortex and WM may reflect a cytoskeletal structural difference that contributes to the fragility of GM vasculature and propensity to hemorrhage.
Pediatric Research 06/2006; 59(5):673-9. · 2.70 Impact Factor
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ABSTRACT: Tumors located in the region of the foramen of Monro often present with signs and symptoms of obstructive hydrocephalus. Various types of lesions occur in this location. We describe a case of a dysembryoplastic neuroepithelial tumor of the septum pellucidum presenting with obstructive hydrocephalus and its successful endoscopic excision. The surgical considerations and pathologic findings are discussed.
Pediatric Neurosurgery 02/2006; 42(2):105-7. · 0.70 Impact Factor
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ABSTRACT: Tight junction (TJ) molecules confer cell-to-cell adhesion to endothelial cells and, thus, provide structural integrity to blood vessels. Therefore, decreased expression of these molecules may be a cause of germinal matrix (GM) fragility and their propensity to hemorrhage in premature infants. The objective of this study was to compare the expression of endothelial TJ molecules, including claudin-5, occludin, and junction adhesion molecules (JAM), among blood vessels of GM, cortex, and white matter for fetuses and premature infants of gestational age 16-40 wk, and to examine their maturational changes with advancing gestational age. We measured the expression of claudin-1, claudin-5, occludin, and JAM in GM, cortex, and white matter in postmortem brain samples. We performed immunohistochemical staining on brain sections and Western blot to quantify these molecules. We found that claudin-5, occludin, and JAM-1 were expressed as early as 16 wk in GM, cortex, and white matter. Claudin-1, JAM-2, and JAM-3 were not detected in the GM, cortex, and white matter. Claudin-5, occludin, and JAM-1 did not change significantly as a function of gestational age. There was no significant difference in the expression of these molecules in the vasculature of GM compared with cortex and white matter. Because the primary endothelial TJ molecules, including claudin-5, occludin, and JAM-1, are expressed as early as 16 wk in the blood brain barrier and since as they are not decreased in GM vasculature compared with cortex and white matter, they are unlikely to be responsible for GM fragility and vulnerability to hemorrhage in premature infants.
Pediatric Research 11/2005; 58(4):791-8. · 2.70 Impact Factor
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ABSTRACT: The germinal matrix (GM) located in the thick subependymal cell layer of the thalamostriate groove is a major site of cerebral hemorrhage in premature infants. Comparing the morphology of vasculature among GM, gray and white matter of the brain may help in understanding the pathogenesis of GM hemorrhage and also of periventricular leukomalacia. The objective of the present study was to determine the morphology of blood vessels in the GM, gray matter, and white matter and to examine maturational changes in the morphology of these vessels as a function of gestational age. We measured vessel density, percentage of blood vessel area, mean surface area, length, breadth, perimeter, radius, and shape of blood vessels in coronal sections of the GM, gray matter, and white matter in postmortem human brain samples for 17 fetuses and premature infants of gestational age 16-40 wk and 2 adults. We performed immunohistochemical staining using anti-laminin primary antibody, confocal microscopy to acquire images, and analysis using Metamorph version 6.1. Vessel density and the percentage of blood vessel area increased as a function of gestational age in the GM, gray matter, and white matter (p < 0.001 each). The blood vessel density and the percentage of blood vessel area were largest in the GM followed by gray matter and then white matter in all of the gestational age categories (p < 0.001 for all comparisons). Increased vascularity of the GM compared with gray and white matter may play a role in GM hemorrhage, whereas a relatively low vascularity of white matter may increase the propensity for the occurrence of periventricular leukomalacia in premature infants
Pediatric Research 08/2004; 56(1):117-24. · 2.70 Impact Factor
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ABSTRACT: The blood-brain barrier (BBB) is a diffusion barrier, which impedes influx of most compounds from blood to brain. Three cellular elements of the brain microvasculature compose the BBB-endothelial cells, astrocyte end-feet, and pericytes (PCs). Tight junctions (TJs), present between the cerebral endothelial cells, form a diffusion barrier, which selectively excludes most blood-borne substances from entering the brain. Astrocytic end-feet tightly ensheath the vessel wall and appear to be critical for the induction and maintenance of the TJ barrier, but astrocytes are not believed to have a barrier function in the mammalian brain. Dysfunction of the BBB, for example, impairment of the TJ seal, complicates a number of neurologic diseases including stroke and neuroinflammatory disorders. We review here the recent developments in our understanding of the BBB and the role of the BBB dysfunction in CNS disease. We have focused on intraventricular hemorrhage (IVH) in premature infants, which may involve dysfunction of the TJ seal as well as immaturity of the BBB in the germinal matrix (GM). A paucity of TJs or PCs, coupled with incomplete coverage of blood vessels by astrocyte end-feet, may account for the fragility of blood vessels in the GM of premature infants. Finally, this review describes the pathogenesis of increased BBB permeability in hypoxia-ischemia and inflammatory mechanisms involving the BBB in septic encephalopathy, HIV-induced dementia, multiple sclerosis, and Alzheimer disease.
Neurobiology of Disease 07/2004; 16(1):1-13. · 5.40 Impact Factor
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Leonardo Salviati,
Sabrina Sacconi,
Minerva M Rasalan,
David F Kronn, Alex Braun,
Peter Canoll,
Mercy Davidson,
Sara Shanske,
Eduardo Bonilla,
Arthur P Hays,
Eric A Schon,
Salvatore DiMauro
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ABSTRACT: Mutations in the SCO2 gene have been associated with fatal cardioencephalomyopathy.
To report a novel SCO2 mutation with prominent spinal cord involvement mimicking spinal muscular atrophy (Werdnig-Hoffmann disease).
An infant girl presented at birth with generalized weakness, hypotonia, and lactic acidosis. At 1 month of age she developed hypertrophic cardiomyopathy and died of heart failure 1 month later. Neuroradiological studies were unremarkable. Muscle biopsy specimens showed groups of atrophic and hypertrophic fibers, but mutation screening of the SMN gene was negative. Histochemical and biochemical studies of respiratory chain complexes were performed, and the whole coding region of the SCO2 gene was sequenced.
Findings from muscle histochemistry studies showed virtually undetectable cytochrome c oxidase activity, but normal succinate dehydrogenase reaction. Biochemical analysis in muscle confirmed a severe isolated cytochrome c oxidase deficiency. Pathologic findings of the brain were unremarkable, but the ventral horns of the spinal cord showed moderate-to-severe loss of motor neurons and astrocytosis. Sequencing of the SCO2 gene showed the common E140K mutation, and a novel 10 base-pair duplication of nucleotides 1302 to 1311, which disrupts the reading frame of the messenger RNA and gives rise to a truncated protein.
The SCO2 mutations should be considered in the differential diagnosis of children with spinal muscular atrophy without mutations in the SMN gene.
Archives of Neurology 06/2002; 59(5):862-5. · 7.58 Impact Factor
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ABSTRACT: Glioblastoma multiforme (GBM) develops from astrocytes and is the most aggressive primary cancer in humans. Invading cells grow rapidly and form their own blood vessels making them difficult to surgically remove or treat. GBM may develop de novo (primary) or through progression from a low-grade or anaplastic astrocytoma (secondary). Mutational inactivation of the p53 gene and presence of aberrant p53 expression are reported in GBM, suggesting that p53 has a role in tumor progression. This study of seven de novo GBM and four secondary GBM patients, indicated that nine out of eleven (82%) had overexpression of p53. Our histopathological analysis showed that the expression of p53 in three out of four (75%) secondary GBM was confined to the nucleus and the p53 positive cells were randomly distributed throughout the tumor. The expression of p53 in four out of seven (57%) de novo GBM was cytoplasmic, diffusive, and confined to the perivascular region of the tumor. In two (29%) de novo samples both nuclear as well as cytoplasmic staining that was not confined to the perivascular area was observed. The results suggest that cytoplasmic p53 may contribute to the formation and maintenance of de novo GBM by virtue of its control of the vasculature of tumors. Furthermore, cytoplasmic p53 may reflect an association of p53 with Cullin 7, PARC, or with the sequestering partner of p53, mortalin. These results underscore the significance of p53 in the tumorigenesis of de novo GBM.
Anticancer research 26(6C):4633-9. · 1.73 Impact Factor
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ABSTRACT: Fibromuscular dysplasia (FMD) is a segmental noninflammatory nonatherosclerotic vascular disease that has been described in almost every arterial bed, including the cerebral and coronary arteries. FMD of cerebral vessels has been associated with development of saccular aneurysms in the involved vessels. Acute dissection of coronary arteries is also a rare complication of FMD. Herein, we report the first case of both complications of FMD occurring in a single patient-a ruptured anterior communicating artery aneurysm and a right coronary artery dissection occurring in a 38-year-old woman. At autopsy, FMD was found in multiple vascular beds. Our findings reveal the potential for involvement of several vascular beds in patients with FMD, resulting in multiple vascular complications.
Angiology 58(6):764-7. · 1.51 Impact Factor
