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Squier W.,Neuropathology | Mack J.,Penn State Hershey Medical Center | Green A.,John Radcliffe Hospital | Aziz T.,John Radcliffe Hospital
Child's Nervous System | Year: 2012

This paper reviews the evidence in support of the hypothesis that the trigeminal system mediates brain swelling associated with subdural bleeding. The trigeminovascular system has been extensively studied in migraine; it may play an important but under-recognized role in the response to head trauma. Nerve fibers originating in trigeminal ganglion cells are the primary sensors of head trauma and, through their collateral innervation of the intracranial and dural blood vessels, are capable of inciting a cascade of vascular responses and brain swelling. The extensive trigeminal representation in the brainstem initiates and augments autonomic responses. Blood and tissue injury in the dura incite neurogenic inflammatory responses capable of sensitizing dural nerves and potentiating the response to trauma. Discussion The trigeminal system may provide the anatomophysiological link between small-volume, thin subdural bleeds and swelling of the underlying brain. This physiology may help to explain the poorly understood phenomena of "second-impact syndrome," the infant response to subdural bleeding (the "big black brain"), as well as post-traumatic subdural effusions. Considerable age-specific differences in the density of dural innervation exist; age-specific responses of this innervation may explain differences in the brain's response to trauma in the young. An understanding of this pathophysiology is crucial to the development of intervention and treatment of these conditions. Antagonists to specific neuropeptides of the trigeminal system modify brain swelling after trauma and should be further explored as potential therapy in brain trauma and subdural bleeding. © Springer-Verlag 2012. Source

Viana-Pereira M.,University of Minho | Viana-Pereira M.,Institute of Cancer Research | Lee A.,Institute of Cancer Research | Popov S.,Institute of Cancer Research | And 8 more authors.
PLoS ONE | Year: 2011

High grade gliomas (HGG) are one of the leading causes of cancer-related deaths in children, and there is increasing evidence that pediatric HGG may harbor distinct molecular characteristics compared to adult tumors. We have sought to clarify the role of microsatellite instability (MSI) in pediatric versus adult HGG. MSI status was determined in 144 patients (71 pediatric and 73 adults) using a well established panel of five quasimonomorphic mononucleotide repeat markers. Expression of MLH1, MSH2, MSH6 and PMS2 was determined by immunohistochemistry, MLH1 was assessed for mutations by direct sequencing and promoter methylation using MS-PCR. DNA copy number profiles were derived using array CGH, and mutations in eighteen MSI target genes studied by multiplex PCR and genotyping. MSI was found in 14/71 (19.7%) pediatric cases, significantly more than observed in adults (5/73, 6.8%; p = 0.02, Chi-square test). MLH1 expression was downregulated in 10/13 cases, however no mutations or promoter methylation were found. MSH6 was absent in one pediatric MSI-High tumor, consistent with an inherited mismatch repair deficiency associated with germline MSH6 mutation. MSI was classed as Type A, and associated with a remarkably stable genomic profile. Of the eighteen classic MSI target genes, we identified mutations only in MSH6 and DNAPKcs and described a polymorphism in MRE11 without apparent functional consequences in DNA double strand break detection and repair. This study thus provides evidence for a potential novel molecular pathway in a proportion of gliomas associated with the presence of MSI. © 2011 Viana-Pereira et al. Source

Acerbi F.,Fondazione Istituto Neurologico Carlo Besta | Broggi M.,Fondazione Istituto Neurologico Carlo Besta | Eoli M.,Molecular Neuro Oncology | Anghileri E.,Molecular Neuro Oncology | And 8 more authors.
Acta Neurochirurgica | Year: 2013

Background: Fluorescein is widely used as a fluorescent tracer for many applications. Its capability to accumulate in cerebral areas with blood-brain barrier damage makes it an ideal dye for intraoperative visualization of malignant gliomas (MG). We report our preliminary experience in fluorescein-guided removal of grade IV gliomas using a dedicated filter on the surgical microscope. Methods: In September 2011 we started a prospective phase II trial (FLUOGLIO) to evaluate the safety and obtain initial indications about the efficacy of fluorescein-guided surgery for MG. Patients with suspected MG amenable to complete resection of contrast-enhancing areas were eligible to participate in this study. This report is based on a preliminary analysis of the results of 12 patients with grade IV gliomas out of 15 consecutive cases (age range 48-72 years) enrolled since September 2011. Fluorescein was injected intravenously (i.v.) after intubation (5-10 mg/kg). The tumor was removed using a microsurgical technique and fluorescence visualization by BLU 400 or YELLOW 560 filters on a Pentero microscope (Carl Zeiss, Germany). The study was approved by our ethics committee and registered on the European Regulatory Authorities website (EudraCT no. 2011-002527-18). Results: Histological analysis confirmed grade IV gliomas in 12/15 cases. Median preoperative tumor volume was 33.15 cm3 (9.6-87.8 cm3). No adverse reaction related to the administration of fluorescein was registered. Contrast-enhanced tumor was completely removed in 75 % of the patients. Conclusion: This preliminary analysis suggested that the use of intravenous fluorescein during surgery on grade IV gliomas is safe and allows a high rate of complete resection of contrast-enhanced tumor at the early postoperative MRI. © 2013 Springer-Verlag Wien. Source

Sav A.,Acibadem Medical Center | Scheithauer B.W.,Mayo Medical School | Taylor W.A.S.,Neurosurgery | Miller G.,Mayo Medical School | Stewart W.,Neuropathology
Clinical Neuropathology | Year: 2010

Objective: To describe a unique intraosseous perineurioma affecting the L2 vertebral body and pedicle of a 28-year-old female. Material: A lytic, expansive lesion virtually limited to bone was gross totally excised; only minimal epidural extension was noted. Methods: Histologic, immunohistochemical and ultrastructural studies were performed. Results: The tumor was partially encapsulated, moderately cellular, and showed classic features of benign soft tissue perineurioma, being composed of interlacing fascicles of spindle cells with undulating nuclei and long, very narrow, cytoplasmic processes. Immunohistochemistry showed reactivity for EMA, Glut-1, claudin, collagen-4 and CD34; no S-100 or neurofilament protein staining was seen to suggest an origin in nerve. Conclusion: Perineurioma, a tumor affecting soft tissue, and presumably nerve-unassociated, may affect bone. No prior entirely osseous examples have been reported. This tumor expands the differential diagnosis of spindle cell tumors of bone. ©2010 Dustri-Verlag Dr. K. Feistle. Source

Ravenscroft G.,University of Western Australia | Jackaman C.,University of Western Australia | Sewry C.A.,Wolfson Center for Inherited Neuromuscular Diseases | McNamara E.,University of Western Australia | And 8 more authors.
PLoS ONE | Year: 2011

Mutations in the skeletal muscle α-actin gene (ACTA1) cause congenital myopathies including nemaline myopathy, actin aggregate myopathy and rod-core disease. The majority of patients with ACTA1 mutations have severe hypotonia and do not survive beyond the age of one. A transgenic mouse model was generated expressing an autosomal dominant mutant (D286G) of ACTA1 (identified in a severe nemaline myopathy patient) fused with EGFP. Nemaline bodies were observed in multiple skeletal muscles, with serial sections showing these correlated to aggregates of the mutant skeletal muscle α-actin-EGFP. Isolated extensor digitorum longus and soleus muscles were significantly weaker than wild-type (WT) muscle at 4 weeks of age, coinciding with the peak in structural lesions. These 4 week-old mice were ~30% less active on voluntary running wheels than WT mice. The α-actin-EGFP protein clearly demonstrated that the transgene was expressed equally in all myosin heavy chain (MHC) fibre types during the early postnatal period, but subsequently became largely confined to MHCIIB fibres. Ringbinden fibres, internal nuclei and myofibrillar myopathy pathologies, not typical features in nemaline myopathy or patients with ACTA1 mutations, were frequently observed. Ringbinden were found in fast fibre predominant muscles of adult mice and were exclusively MHCIIB-positive fibres. Thus, this mouse model presents a reliable model for the investigation of the pathobiology of nemaline body formation and muscle weakness and for evaluation of potential therapeutic interventions. The occurrence of core-like regions, internal nuclei and ringbinden will allow analysis of the mechanisms underlying these lesions. The occurrence of ringbinden and features of myofibrillar myopathy in this mouse model of ACTA1 disease suggests that patients with these pathologies and no genetic explanation should be screened for ACTA1 mutations. © 2011 Ravenscroft et al. Source

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