Takahiro Nakura

Activation of Ras/MEK/ERK signaling in chronic subdural hematoma outer membranes.

Chronic subdural hematoma (CSDH) is considered to be an angiogenic disease. Vascular endothelial growth factor (VEGF), one of the important growth factors regulating angiogenesis, is expressed in the neomembranes and also in hematoma fluid, and the Ras/MEK/ERK signaling pathway has been implicated in angiogenesis by VEGF. In the present study, the status of this signaling pathway in CSDH outer membranes was examined using outer membranes obtained during trepanation surgery. The expression levels of Ras, Ras-GAP, c-Raf, MEK, ERK, phosphorylated (p)-ERK, endothelial nitric oxide synthase (eNOS) and actin were examined by western blot analysis; the expression of p-ERK was also examined by immunohistochemistry. Ras, Ras-GAP, c-Raf, MEK, ERK and eNOS were detected in all cases. In addition, the expression of p-ERK was confirmed in all cases, and p-ERK was localized to the endothelial cells of the vessels in CSDH outer membranes. These findings indicated that Ras/MEK/ERK signaling is activated in the CSDH outer membranes and suggested the possibility that the Ras/MEK/ERK pathway might be activated by VEGF and play a critical role in the angiogenesis of CSDHs.

Soluble gp130 regulatess interleukin-6 in cerebrospinal fluid after subarachnoid haemorrhage

Background Interleukin-6 (IL-6) is a proinflammatory cytokine reported to play an important role in induction of cerebral vasospasm after subarachnoid haemorrhage (SAH). Soluble gp130 (sgp130) and soluble IL-6 receptor (sIL-6R) are known to act as signal transducing receptors of IL-6, the former as an antagonist and the latter as an agonist. However, there have been no reports concerning regulation of the IL-6 signalling pathway in cerebrospinal fluid (CSF) after SAH. Mehods Concentrations of IL-6, sgp130 and sIL-6R were measured serially until day 14 in CSF from nine patients with SAH. CSF samples obtained from patients suffering from unruptured aneurysm were used as controls. Colocalisation of IL-6 and sgp130 in CSF on day 1 was further examined by immunoprecipitaiton. Results Concentrations of IL-6 in CSF increased immediately after the onset of SAH and remained chronically elevated over control values. Both sgp130 and sIL-6R also exhibited increased on day 1, followed by a decrease limited to the gp130 case after day 5. Sgp130 coimmunoprecipitated with IL-6 in CSF on day 1 after SAH. Conclusions Our findings suggest that sgp130 regulates IL-6 signalling as an antagonist in CSF immediately after SAH. As the concentration of sgp130 decreases after day 5, IL-6 signals might then be more easily transmitted, presumably resulting in cerebral vasospasm.

Expression of Mitogen-Activated Protein Kinases in Chronic Subdural Hematoma Outer Membranes

Growth factors and inflammatory cytokines activate the mitogen-activated protein kinase (MAPK) cascade. Previous studies have shown that chronic subdural hematoma (CSDH) fluid contains these factors and cytokines. In this study, expression of three major MAPK cascade transmitters in the outer membrane of CSDH was assessed. Eleven patients whose outer membrane and CSDH fluid were successfully obtained during trepanation surgery were included in this study. Expression of extracellular signal-regulated kinase (ERK), phosphorylated (p)-ERK, p38, p-p38, c-Jun N-terminal kinase (JNK), p-JNK, and actin was examined by Western blot and immunostaining. We examined whether CSDH fluid could activate MAPKs in cultured endothelial cells (ECs) or fibroblasts in vitro. Western blot analysis showed that p-ERK was present in all samples, whereas p-p38 and p-JNK were detected, but not in all cases. Immunostaining showed that all three p-MAPKs were expressed in vascular endothelium. However, only p-ERK was expressed in fibroblasts. Expression of p-extracellular signal-regulated kinase kinase (MEK) and p-ERK in ECs and fibroblasts was significantly induced immediately after treatment with CSDH fluid, whereas p-p38 and p-JNK expression was significantly induced in ECs 60 min after treatment, but not in fibroblasts. Activation of MEK was significantly inhibited by treatment with antibodies directed against interleukin-6 and vascular endothelial growth factor in ECs, but not in fibroblasts. Inflammatory cytokines and growth factors in CSDH fluids might activate major MAPKs in ECs, which might be associated with neovascularization in the outer membrane of CSDH. These MAPK pathways could become novel targets for treatment of CSDHs.

Pathomorphological description of the shunted portion of a filum terminale arteriovenous fistula

BACKGROUND CONTEXT The clinical morphology of a filum terminale arteriovenous fistula (f-AVF) is well known; however, pathological details of the fistulized portion are unknown. Herein, we report the pathological findings of the f-AVF. STUDY DESIGN Case report and literature review. PURPOSE To present a detailed pathological examination of the fistulized portion of the f-AVF. METHODS A 71-year-old man presented with gradually worsening bilateral foot paresthesias and anal dysesthesia. T2-weighted magnetic resonance imaging showed flow voids surrounding an edematous conus medullaris and cauda equina with spinal stenosis at L3-L4 and L4-L5. Spinal digital subtraction angiography demonstrated an f-AVF fed by the left T9 intercostal artery. RESULTS We performed laminotomies of L3 and L4 to open the dura mater and found a hypertrophic filum terminale. It was resected, leaving a length of 2 cm between the abnormal proximal end and normal distal end. The f-AVF completely disappeared after the surgery. On pathological examination, the filum terminale included two vessels at the proximal end and one at the distal end. At the proximal end, immunostaining showed one vessel that was definitively an artery with both an internal elastic membrane (IEM) and smooth muscle. The other was a vein and lacked an IEM. On the distal side, the collagen fibers gradually increased, the IEM partially disappeared from the arterial wall, and the vein became arterialized with a thin IEM. At the distal end the two vessels joined. Therefore, we speculated that the fistulized portion of the f-AVF was not a fistula point but had some lengths where the artery had characteristics of a vein and there was venous arterialization. CONCLUSIONS The filum arteriovenous shunting occurred at the portion where there was venous arterialization and the artery had the characteristics of a vein. Therefore, resecting the filum terminale requires more proximal from the normal distal end.

Installation of a Neuromate Robot for Stereotactic Surgery: Efforts to Conform to Japanese Specifications and an Approach for Clinical Use—Technical Notes

The neuromate is a commercially available, image-guided robotic system for use in stereotactic surgery and is employed in Europe and North America. In June 2015, this device was approved in accordance with the Pharmaceutical Affairs Law in Japan. The neuromate can be specified to a wide range of stereotactic procedures in Japan. The stereotactic X-ray system, developed by a Japanese manufacturer, is normally attached to the operating table that provides lateral and anteroposterior images to verify the positions of the recording electrodes. The neuromate is designed to be used with the patient in the supine position on a flat operating table. In Japan, deep brain stimulation surgery is widely performed with the patients head positioned upward so as to minimize cerebrospinal fluid leakage. The robot base where the patients head is fixed has an adaptation for a tilted head position (by 25 degrees) to accommodate the operating table at proper angle to hold the patients upper body. After these modifications, the accuracy of neuromate localization was examined on a computed tomography phantom preparation, showing that the root mean square error was 0.12 ± 0.10 mm. In our hospital, robotic surgeries, such as those using the Da Vinci system or neuromate, require operative guidelines directed by the Medical Risk Management Office and Biomedical Research and Innovation Office. These guidelines include directions for use, procedural manuals, and training courses.

Plasmapore-Coated Titanium Cervical Cages Induce More Rapid and Complete Bone Fusion After Anterior Cervical Discectomy and Fusion as Compared to Noncoated Titanium Cages

OBJECTIVE The aim of this study was to examine the solid bone fusion rates between Plasmapore-coated titanium cages (PPC group) and non-Plasmapore-coated titanium cages (N-PPC group) in patients who received anterior cervical decompression and fusion (ACDF). METHODS Of 78 patients who received ACDF at the hospital, a follow-up period greater than 2 years was possible for 61 patients, including 30 in the PPC group and 42 in the N-PPC group. Evaluations were performed at 3, 6, 12, and 24 months after surgery. Radiological stabilization (RS) was defined as the restriction of spinous process movement to <3 mm and the absence of a halo around the cages on flexion-extension radiographs. Solid bone fusion (SBF) was defined as the formation of bony bridges between the fixed vertebral bodies in sagittal computed tomography sections. The rates of RS and SBF were compared between both groups. RESULTS The differences in RS were not significant between the 2 groups during the follow-up period. However, the SBF rates at 6 and 12 months were significantly higher in the PPC group (26.7% and 56.7%) than in the N-PPC group (5% and 21.4%). Moreover, 63.3% (19 of 30) of patients in the PPC group demonstrated RS at 3 months, and of these patients, SBF was observed in 100% (19 patients) after 24 months, respectively. In comparison, the SBF rates in the N-PPC group were 86%. CONCLUSIONS Plasmapore-coated titanium cages enabled more rapid solid bone fusion. We suggest that these types of cages might help to reduce postoperative radiograms.

Expression of suppressor of cytokine signaling 3 in cerebrospinal fluid after subarachnoid hemorrhage

BackgroundIL-6 is a proinflammatory cytokine reported to play an important role in the induction of cerebral vasospasm after subarachnoid hemorrhage (SAH). Suppressor of cytokine signaling 3 (SOCS3) is known to act as an inhibitor of signal transduction of IL-6. However, there have been no reports on the expression of SOCS3 in cerebrospinal fluid (CSF) after SAH.FindingsThe concentration of IL-6 was measured serially up until day 10, in CSF of eight patients with SAH. CSF samples obtained from patients suffering from an unruptured aneurysm were used as controls. The expression of SOCS3 in CSF was further examined by immunoprecipitation methods. Concentrations of IL-6 in CSF increased immediately after the onset of SAH and remained chronically elevated over control values. SOCS3 was significantly expressed in CSF on days 1 to 3 after SAH.ConclusionsOur findings suggest that SOCS3 regulates IL-6 signaling as an antagonist in CSF, immediately following SAH. As the expression of SOCS3 decreases after day 5, IL-6 signals might then be more easily transmitted, presumably resulting in cerebral vasospasm.

Posterior inferior cerebellar artery with an extradural origin from the V3 segment: higher incidence on the nondominant vertebral artery

OBJECTIVE The posterior inferior cerebellar artery (PICA) and the vertebral artery (VA) often exhibit anatomical variations at the craniovertebral junction (CVJ). An example of this is the PICA originating extradurally from the V3 segment of the VA. To date, some cadaveric investigations have been reported, but the incidence and relationship of this variation to the VA and the atlas as observed on clinical imaging have not been discussed. This study evaluated the prevalence of PICAs originating from the V3 on CT scanning. Other variations of the atlas and VA were also analyzed. METHODS CT images from a series of 153 patients who underwent 3D CT angiography (CTA) were analyzed, and variations of the PICA, VA, and atlas were investigated. RESULTS A total of 142 patients (284 sides) were analyzed; 11 patients (7.2%) were excluded due to poor image quality. The most common VA variation was the PICA originating from V3 (9.5% of 284 sides), which was more frequently observed on the nondominant VA than the dominant VA (22.5% vs 6.25%, p = 0.0005). A VA with a PICA end was identified in 4 sides (1.4%), which is the same incidence as observed in the persistent first intersegmental VA (1.4%). VA fenestration was only found in 1 side (0.35%). Regarding the atlas, ponticulus posticus was observed in 24 sides (8.5%). There was no relationship between the incidence of ponticulus posticus and the variations of the VA. CONCLUSIONS A PICA originating from V3 was the most common VA variation at the CVJ and was more common on the nondominant VA. Three-dimensional CTA is useful for the evaluation of this variance. Surgeons should be mindful of this variation during operations.

Medulloblastoma with epithelioid features in the cerebellar vermis.

A 6‐year‐old girl was admitted with a mass lesion in the cerebellar vermis. She underwent subtotal tumor resection, and on immunohistopathology the tumor consisted of two different parts: typical medulloblastoma (MB) characteristics and atypical teratoid/rhabdoid tumor (AT/RT) features, despite positive integrase interactor 1 expression. The patient was diagnosed with MB with epithelioid features. Chemoradiation therapy was started because of tumor recurrence at the primary site and dissemination to the spinal cord, as determined on magnetic resonance imaging 2 weeks after surgery. The patient died due to tumor progression 13 months after initial diagnosis, although transient partial remission was achieved.