Projection neurons are preferentially affected in West Nile viral encephalitis: Case series and review of mechanisms of neuroinvasion and toxicity in a setting of solid organ transplant.

West Nile virus (WNV) is an emerging human pathogen responsible for a systemic disease with generally indolent clinical course in immunocompetent hosts. Solid organ transplant recipients are vulnerable to WNV-induced encephalitis (WNVE) with no effective treatment and high mortality. We systematically assess various nuclei of the central nervous system in two human autopsy cases of WMVE using in situ hybridization (ISH) in combination with immunohistochemistry (IHC). We identify several types of projection neurons as exclusively affected in WNVE. Cellular and molecular mechanisms of anti-viral innate immunity are reviewed in respect to immunosuppression in solid organ transplant setting.

Intra-arterial spread of Mucormycetes mediates early ischemic necrosis of brain and suggests new venues for prophylactic therapy.

Intracranial invasion by Mucormycosis carries high mortality mostly related to arterial occlusion and ischemic necrosis. We report clinical, imaging and autopsy findings in an adult immunodeficiency syndrome (AIDS) patient with fungal infection extending from a tooth. We report a striking discordance between a restriction of fungal growth to the initial branches of the circle of Willis and extensive ischemic infarcts of deep brain structures. This lends to a suggestion of apparently lost opportunities for brain salvage and prompts a re-assessment of clinical approaches to treat mucormycosis.

V600E BRAF mutation in pilocytic astrocytoma is associated with a more diffuse growth pattern but does not confer a more aggressive clinical behavior.

Activation in mitogen activated protein kinase signaling pathway has recently been described as a predominant event in pilocytic astrocytoma (PA) and is commonly caused by constitutively active mutation in BRAF protein. Whereas PA of posterior fossa in children have a high prevalence of BRAF duplication and fusion, primary molecularm abnormalities in supratentorial tumors of adults are more diverse and also include BRAF V600E point mutation. In our study we evaluated 51 PAs for BRAF duplication and BRAF V600E point mutation. We found a relatively high frequency of V600E mutation in our cohort. Histologically, V600E-carrying PA appeared more infiltrative, yet our limited clinical follow-up failed to detect a deleterious prognostic significance.

Formation of gelsolin amyloid fibrils in the rough endoplasmic reticulum of skeletal muscle in the gelsolin mouse model of inclusion body myositis: comparative analysis to human sporadic inclusion body myositis.

Sporadic inclusion body myositis has a significant impact on the life of the elderly. Despite some similarities to other myopathies with established genetic defects, little is known about mechanisms of its development and no effective treatment is available. Therefore, there is a need for animal models that can faithfully reconstitute important aspects of this human disease. The authors recently expressed a mutant form of human gelsolin in mice under the control of a muscle-specific promoter. This induced myopathic changes reminiscent of human inclusion body myositis. In this study, immunogold labeling is used to further characterize this model. The study demonstrates a presence of gelsolin amyloid deposits within the rough endoplasmic reticulum. It further compares this mouse model to human sporadic inclusion body myositis.

Regulation of Sar1 NH2 terminus by GTP binding and hydrolysis promotes membrane deformation to control COPII vesicle fission.

The mechanisms by which the coat complex II (COPII) coat mediates membrane deformation and vesicle fission are unknown. Sar1 is a structural component of the membrane-binding inner layer of COPII (Bi, X., R.A. Corpina, and J. Goldberg. 2002. Nature. 419:271-277). Using model liposomes we found that Sar1 uses GTP-regulated exposure of its NH2-terminal tail, an amphipathic peptide domain, to bind, deform, constrict, and destabilize membranes. Although Sar1 activation leads to constriction of endoplasmic reticulum (ER) membranes, progression to effective vesicle fission requires a functional Sar1 NH2 terminus and guanosine triphosphate (GTP) hydrolysis. Inhibition of Sar1 GTP hydrolysis, which stabilizes Sar1 membrane binding, resulted in the formation of coated COPII vesicles that fail to detach from the ER. Thus Sar1-mediated GTP binding and hydrolysis regulates the NH2-terminal tail to perturb membrane packing, promote membrane deformation, and control vesicle fission.

Malignant rhabdoid meningioma arising in the setting of preexisting ganglioglioma: a diagnosis supported by fluorescence in situ hybridization. Case report.

A highly malignant brain neoplasm with rhabdoid morphological features emerged in the bed of a subtotally resected ganglioglioma in a 54-year-old retired nuclear submarine officer. A combined application of neuroimaging, immunohistochemical studies, electron microscopy, and fluorescence in situ hybridization (FISH) was used to establish the morphological identity of the tumor. The rhabdoid appearance of the tumor cells indicated either an especially malignant variant of rhabdoid meningioma or an atypical teratoid/rhabdoid tumor with an unusually late onset. Whereas immunohistochemical studies and electron microscopy could only be used to narrow down the differential diagnosis, FISH revealed loss of one copy of NF2 with preservation of the INI1 region on 22q, thus establishing the identity of the tumor.

Malignant intracerebral nerve sheath tumors: a case report with review of the literature.

The occurrence of benign nerve sheath tumors within the neuroaxis is uncommon. Even rarer is the finding within brain parenchyma, termed malignant intracerebral nerve sheath tumors (MINST). We present a case of MINST which occurred in the frontal lobe of an 18-year-old male that recurred almost 4 years later. Imaging demonstrated a 4.0 cm lesion with an associated mass effect. He underwent a right fronto-parietal craniotomy for gross total resection. Pathology was inconclusive with a Glioblastoma Multiforme (GBM) as the most likely diagnosis, though gliosarcoma and MINST were also highly considered. Postoperatively, he was treated with chemotherapy and radiation and followed for almost 4 years, when an MRI indicated a recurrence. Resection of the recurrence was highly suggestive of MINST. Surgery was followed by radiation and chemotherapy, but, less than 7 months later, he was readmitted for a surgical-site infection, and, after multiple surgeries, and his family terminated care. Recognizing this unusual tumor in the differential diagnosis of a heterogeneously enhancing intracerebral mass can help surgeons diagnose and treat it. This report also exhaustively reviews the literature and presents diagnostic and treatment strategies.

Oligodendroglial-specific transcriptional factor SOX10 is ubiquitously expressed in human gliomas.

The two most common types of gliomas: astrocytoma and oligodendroglioma are distinguished based on their morphologic similarities to mature astrocytes and oligodendroglia. Whereas prototypical examples of the tumors have distinct pathogenetic and prognostic differences, the majority of the gliomas falls in the intermediate category and their distinction is problematic. The transcriptional factor SOX10 is one of the key determinants of oligodendroglial differentiation. We applied immunohistochemistry to analyze whether the expression of SOX10 can differentiate astrocytoma and oligodendroglioma. The majority of oligodendrogliomas, but also a large fraction of astrocytomas, including the least differentiated glioblastomas, expressed SOX10, albeit at lower levels. Comparison with 1p and 19q deletion status by FISH analysis also revealed no obvious associations. High levels of expression were also found in pilocytic astrocytoma, consistent with recent studies suggesting that pilocytic astrocytomas have greater overlap with oligodendroglial than astrocytic tumors. Our data raise a possibility that histogenesis of gliomas have more common features than previously anticipated.

Epithelioid hemangioendothelioma of the suprasellar area: a case report and review of the literature.

Intra-axial involvement of the brain by an epithelioid hemangioendothelioma is rare, and biological properties of the tumor are uncertain. Most of the primary brain manifestations are confined to the cerebral hemispheres. We report magnetic resonance imaging and microscopic findings of a case of suprasellar involvement by an epithelioid hemangioendothelioma. The tumor was treated with a subtotal resection only, and no progression of the disease was noted during a 6-month follow-up. Review of the literature suggested that most epithelioid hemangioendotheliomas in the brain are unifocal tumors with a rather favorable clinical outcome.

Mechanical aortic injury in apoE-deficient mice as a model for development of atherosclerosis: demonstration of leukocyte rolling early after injury.

A mouse model of aortic endothelium regeneration following mechanical injury was studied in wild-type and apoE-deficient (apoE0) animals. The injury induced a topologically nonuniform and complex reparative response. Compared to wild-type animals, apoE0 mice had unaltered ability to regenerate endothelium. Despite the pro-coagulative state of the apoE0 mice, no arterial thromboses were detected. Only deeper arterial injury with damage to the internal elastic membrane was associated with the development of atherosclerotic lesions in apoE0 mice. During the limited observation period of 7 days, superficial arterial injury in apoE0 mice was inconsequential. In addition, for the first time in vivo, rolling of polymorphonuclear leukocytes over the damaged endothelium was documented.

Failure of prosencephalic unfolding and neuronal migration in acardia.

Acardia is a fatal complication of twin pregnancy. It is caused by a retrograde flow of arterial blood from a "pump" into an acardiac twin through placental arterial and venous connections. The heart function of the recipient twin is either blocked or insufficient to support perfusion of the upper body. Severe developmental anomalies ensue. While most acardiacs are anencepahalic, a few twins with a rudimental heart ("hemicardiac") are able to support a variably complex brain. Here we report three cases of hemicardiac twinning with neuronal migrational defects. The most severe abnormalities affected the supratentorial compartment. They can be conceptually divided in two groups. The first, which we tentatively linked to agenesis of the choroid plexus, can be described as a failure of prosencephalic unfolding. The resulting defects included collapsed neocortex, agenesis of the hippocampi and scrambled basal ganglia and diencephalon. The second group of lesions can be theoretically deduced to a result of disruption of the glia-pial boundary with subsequent formation of leptomeningeal heterotopia and zona cerebrovasculosa. Our observations highlight that even in the milieu of a normal genetic background, severe restriction of brain perfusion could lead to neuronal migration defects. Our data also show that adequate unraveling of the brain architecture is crucially dependent on both the parenchymal vascularization and production of the cerebrospinal fluid by the choroid plexus.

Non-enhancing de novo glioblastoma: report of two cases.

Malignant gliomas arise from two distinct pathways, as de novo lesions or from secondary transformation from low-grade lesions. Herein, we describe the cases of two patients to illustrate the proposition that de novo malignant gliomas can originate as non-enhancing tumors and rapidly progress to a pattern of ring enhancement characteristic of a glioblastoma. Both patients presented with new-onset seizures (simple partial and generalized). Their neurological examinations were unremarkable. Initial MRI evaluations revealed a right precentral gyrus and right medial temporal lobe lesions in each case, respectively. These lesions demonstrated increased T2 signal changes without contrast enhancement. The biopsy of the right frontal lesion in the first patient was consistent with an anaplastic astrocytoma; the second patient was followed expectantly. Repeat MRI for both patients within 17 weeks disclosed ring-enhancing lesions, consistent with an unusually rapid evolution to glioblastoma multiforme (GBM). Subsequent resection of the right medial temporal lesion in the second patient revealed a GBM. Neither tumor displayed abnormal overexpression of P53 by immunohistochemistry. Early MRI of de novo glioblastomas may demonstrate a non-enhancing tumor suggestive of a low-grade lesion. These tumors can rapidly evolve into ring-enhancing lesions more consistent with the traditional imaging findings.

Aberrant Pax1 and Pax9 expression in Jarcho-Levin syndrome: report of two Caucasian siblings and literature review.

We report two consecutive Caucasian male siblings of nonconsanguineous parents autopsied at 22 and 13 weeks gestational age both with prenatal diagnosis of Jarcho-Levin syndrome (JLS). Segmentation anomalies of the vertebrae and ribs encompass a spectrum of syndromes with or without associated anomalies of other developmental fields, and include spondylothoracic dysostosis (STD), JLS, Casamassima-Morton-Nance (CMN) syndrome, and spondylocostal dysostosis (SCD), among others. In both these new JLS cases the autopsies confirmed that there were severe developmental alterations in the thoracic and vertebral skeleton (including "crab-like" thorax), accompanied in the older fetus by renal defects. Because vertebral development is controlled by a limited number of master genes including Pax1 and Pax9, we analyzed protein expression from these genes in these two cases compared to age-matched controls. Immunochemical analysis showed a significant reduction in levels of Pax1 and Pax9 protein expression in chondrocytes of the vertebral column. Implications for the etiology and pathogenesis of JLS and related disorders are discussed.