Critical role of TNF-alpha-TNFR1 signaling in intracranial aneurysm formation

BACKGROUND: Intracranial aneurysm (IA) is a socially important disease due to its high incidence in the general public and the severity of resultant subarachnoid hemorrhage that follows rupture. Despite the social importance of IA as a cause of subarachnoid hemorrhage, there is no medical treatment to prevent rupture, except for surgical procedures, because the mechanisms regulating IA formation are poorly understood. Therefore, these mechanisms should be elucidated to identify a therapeutic target for IA treatment. In human IAs, the presence of inflammatory responses, such as an increase of tumor necrosis factor (TNF)-alpha, have been observed, suggesting a role for inflammation in IA formation. Recent investigations using rodent models of IAs have revealed the crucial role of inflammatory responses in IA formation, supporting the results of human studies. Thus, we identified nuclear factor (NF)-kappaB as a critical mediator of inflammation regulating IA formation, by inducing downstream pro-inflammatory genes such as MCP-1, a chemoattractant for macrophages, and COX-2. In this study, we focused on TNF-alpha signaling as a potential cascade that regulates NF-kappaB-mediated IA formation. RESULTS: We first confirmed an increase in TNF-alpha content in IA walls during IA formation, as expected based on human studies. Consistently, the activity of TNF-alpha converting enzyme (TACE), an enzyme responsible for TNF-alpha release, was induced in the arterial walls after aneurysm induction in a rat model. Next, we subjected tumor necrosis factor receptor superfamily member 1a (TNFR1)-deficient mice to the IA model to clarify the contribution of TNF-alpha-TNFR1 signaling to pathogenesis, and confirmed significant suppression of IA formation in TNFR1-deficient mice. Furthermore, in the IA walls of TNFR1-deficient mice, inflammatory responses, including NF-kappaB activation, subsequent expression of MCP-1 and COX-2, and infiltration of macrophages into the IA lesion, were greatly suppressed compared with those in wild-type mice. CONCLUSIONS: In this study, using rodent models of IAs, we clarified the crucial role of TNF-alpha-TNFR1 signaling in the pathogenesis of IAs by inducing inflammatory responses, and propose this signaling as a potential therapeutic target for IA treatment

Straight sinus thrombosis during neurosurgical operation.

BACKGROUND:Perioperative straight sinus thrombosis is extremely rare.CASE DESCRIPTION:A 59-year-old female was admitted to our department because of incidentally found small anterior cerebral artery (A1) aneurysm with microbleeding. After clipping the cerebral aneurysm, she had delayed emergence from anesthesia, total aphasia, and right hemiparesis. Fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) of the head showed hyperintensity in the bilateral caudate nuclei, putamina, and thalami, and computed tomography of the head showed a hyperdense straight sinus, suggesting straight sinus thrombosis. Her neurologic symptoms improved gradually, and she achieved a full clinical recovery, with radiological evidence of recanalization of the straight sinus at follow-up.CONCLUSION:The possibility of straight sinus thrombosis should be considered in postoperative patients with unexplained postoperative deficits when MRI demonstrates hyperintensity in the bilateral basal ganglia and thalami on FLAIR signal images

Recurrent subdural hematoma secondary to headbanging: A case report.

BACKGROUND:"Headbanging" is the slang term used to denote violent shaking of one\u27s head in time with the music. This abrupt flexion-extension movement of the head to rock music extremely rarely causes a subdural hematoma.CASE DESCRIPTION:A 24-year-old female was admitted to our department because of right sided partial seizure and acute or subacute subdural hematoma over the left cerebral convexity. She had no history of recent head trauma but performed headbanging at a punk rock concert at 3 days before admission. Since, she had a previous acute subdural hematoma on the same side after an accidental fall from a baby buggy when she was 11 months old, the present was recurrent subdural hematoma probably due to headbanging.CONCLUSIONS:Headbanging has the hazardous potential to cause a subdural hematoma

mTORC1 signaling in primary central nervous system lymphoma.

BACKGROUND:Mammalian target of rapamycin (mTOR) complex 1 (mTORC1) acts as a downstream effector of phosphatidyl-inositol-3 kinase, which is frequently hyperactivated in glioblastoma multiforme and links to cell signaling in cellular proliferation, differentiation, metabolism, and survival. Although many studies have suggested the importance of mTORC1 in tumorigenesis, its role remains unclear in brain tumors other than glioblastoma.METHODS:In the present study, we evaluated the activation of mTORC1 in 24 cases of primary central nervous system lymphoma (PCNSL).RESULTS:Immunohistochemical analysis showed overexpression of Rheb, which is immediately upstream of mTORC1, in 20 cases of PCNSL. Immunohistochemical analysis also showed overexpression of phospho-4E-BP1 (Thr37/46) and phospho-S6 (Ser235/236), which are increased after mTORC1 activation as mTORC1 downstream effectors in 17 and 21 cases, respectively.CONCLUSION:Our data suggest that abnormal activation of the mTORC1 signaling pathway may cause tumor growth in patients with PCNSL

Prostaglandin E-2-EP2-NF-kappa B signaling in macrophages as a potential therapeutic target for intracranial aneurysms

Intracranial aneurysms are common but are generally untreated, and their rupture can lead to subarachnoid hemorrhage. Because of the poor prognosis associated with subarachnoid hemorrhage, preventing the progression of intracranial aneurysms is critically important. Intracranial aneurysms are caused by chronic inflammation of the arterial wall due to macrophage infiltration triggered by monocyte chemoattractant protein-1 (MCP-1), macrophage activation mediated by the transcription factor nuclear factor kappa B (NF-kappa B), and inflammatory signaling involving prostaglandin E-2 (PGE(2)) and prostaglandin E receptor subtype 2 (EP2). We correlated EP2 and cyclooxygenase-2 (COX-2) with macrophage infiltration in human intracranial aneurysm lesions. Monitoring the spatiotemporal pattern of NF-kappa B activation during intracranial aneurysm development in mice showed that NF-kappa B was first activated in macrophages in the adventitia and in endothelial cells and, subsequently, in the entire arterial wall. Mice with a macrophage-specific deletion of Ptger2 (which encodes EP2) or macrophage-specific expression of an I kappa B alpha mutant that restricts NF-kappa B activation had fewer intracranial aneurysms with reduced macrophage infiltration and NF-kappa B activation. In cultured cells, EP2 signaling cooperated with tumor necrosis factor-alpha (TNF-alpha) to activate NF-kappa B and synergistically induce the expression of proinflammatory genes, including Ptgs2 (encoding COX-2). EP2 signaling also stabilized Ccl2 (encoding MCP-1) by activating the RNA-stabilizing protein HuR. Rats administered an EP2 antagonist had reduced macrophage infiltration and intracranial aneurysm formation and progression. This signaling pathway in macrophages thus facilitates intracranial aneurysm development by amplifying inflammation in intracranial arteries. These results indicate that EP2 antagonists may therefore be a therapeutic alternative to surgery.Peer reviewe

Li diffusion in Lix_xCoO2_2 probed by muon-spin spectroscopy

The diffusion coefficient of Li$^+$ ions ($D_{\rm Li}$) in the battery material Li$_x$CoO$_2$ has been investigated by muon-spin relaxation ($\mu^+$SR). Based on the experiments in zero-field and weak longitudinal-fields at temperatures up to 400 K, we determined the fluctuation rate ($\nu$) of the fields on the muons due to their interaction with the nuclear moments. Combined with susceptibility data and electrostatic potential calculations, clear Li$^+$ ion diffusion was detected above $\sim150$K. The $D_{\rm Li}$ estimated from $\nu$ was in very good agreement with predictions from first-principles calculations, and we present the $\mu^+$SR technique as an % novel and optimal probe to detect $D_{\rm Li}$ for materials containing magnetic ions.Comment: 4 pages, 4 figures. accepted for publication in PR

Primary diffuse large B-cell lymphoma of the choroid plexus: A case report and review of the literature.

Background:Primary lymphomas in the choroid plexus are much less frequent than primary lymphomas in the brain parenchyma.Case Description:A 66-year-old male patient was referred to our department with a right intraventricular mass that had been diagnosed by biopsy at another hospital as anaplastic ependymoma. The patient underwent subtotal removal of the tumor via a transcortical inferior temporal gyrus approach. The mass was attached to the choroid plexus in the right atrium. Histopathological examination showed diffuse large B-cell lymphoma. Ophthalmological examination, blood tests, computed tomography of the whole body, and bone marrow biopsy did not show any other lesion, leading to the diagnosis of primary choroid plexus lymphoma. The patient underwent chemotherapy with three courses of high-dose methotrexate and one course of carboplatin and etoposide followed by whole-brain irradiation (1.8 Gy × 22).Conclusion:We present a rare case of primary choroid plexus lymphoma, which should be considered in the differential diagnosis of choroid plexus tumors

Exploring mechanisms of ventricular enlargement in idiopathic normal pressure hydrocephalus: a role of cerebrospinal fluid dynamics and motile cilia.

Idiopathic normal pressure hydrocephalus (iNPH) is considered an age-dependent chronic communicating hydrocephalus associated with cerebrospinal fluid (CSF) malabsorption; however, the aetiology of ventricular enlargement in iNPH has not yet been elucidated. There is accumulating evidence that support the hypothesis that various alterations in CSF dynamics contribute to ventricle dilatation in iNPH. This review focuses on CSF dynamics associated with ventriculomegaly and summarises the current literature based on three potential aetiology factors: genetic, environmental and hydrodynamic. The majority of gene mutations that cause communicating hydrocephalus were associated with an abnormal structure or dysfunction of motile cilia on the ventricular ependymal cells. Aging, alcohol consumption, sleep apnoea, diabetes and hypertension are candidates for the risk of developing iNPH, although there is no prospective cohort study to investigate the risk factors for iNPH. Alcohol intake may be associated with the dysfunction of ependymal cilia and sustained high CSF sugar concentration due to uncontrolled diabetes increases the fluid viscosity which in turn increases the shear stress on the ventricular wall surface. Sleep apnoea, diabetes and hypertension are known to be associated with the impairment of CSF and interstitial fluid exchange. Oscillatory shear stress to the ventricle wall surfaces is considerably increased by reciprocating bidirectional CSF movements in iNPH. Increased oscillatory shear stress impedes normal cilia beating, leading to motile cilia shedding from the ependymal cells. At the lack of ciliary protection, the ventricular wall is directly exposed to increased oscillatory shear stress. Additionally, increased oscillatory shear stress may be involved in activating the flow-mediated dilation signalling of the ventricular wall. In conclusion, as the CSF stroke volume at the cerebral aqueduct increases, the oscillatory shear stress increases, promoting motor cilia shedding and loss of ependymal cell coverage. These are considered to be the leading causes of ventricular enlargement in iNPH

Primary pericranial Ewing\u27s sarcoma on the temporal bone: A case report.

BACKGROUND:Primary Ewing\u27s sarcoma originating in the pericranium is an extremely rare disease entity.CASE DESCRIPTION:A 9-year-old female patient was admitted to our department due to a left temporal subcutaneous mass. The mass was localized under the left temporal muscle and attached to the surface of the temporal bone. Head computed tomography revealed a mass with bony spicule formation on the temporal bone, however, it did not show bone destruction or intracranial invasion. F-18 fluorodeoxyglucose positron emission tomography showed no lesions other than the mass on the temporal bone. Magnetic resonance imaging showed that the mass was located between the temporal bone and the pericranium. The mass was completely resected with the underlying temporal bone and the overlying deep layer of temporal muscle, and was diagnosed as primary Ewing\u27s sarcoma. Because the tumor was located in the subpericranium, we created a new classification, "pericranial Ewing\u27s sarcoma," and diagnosed the present tumor as pericranial Ewing\u27s sarcoma.CONCLUSION:We herein present an extremely rare case of primary pericranial Ewing\u27s sarcoma that developed on the temporal bone