Efficacy of redox nanoparticles for improving survival of transplanted cells in a mouse model of ischemic stroke.

The success of cell transplantation therapy for ischemic stroke is hindered by the low cell survival rate in poststroke brain, due in part to high free radical production and ensuing oxidative stress. We have developed redox nanoparticles to eliminate reactive oxygen species. In this study, we tested the protective efficacy of these redox nanoparticles in cell culture and a mouse model of ischemic stroke. Induced human dental pulp stem cells were subjected to oxygen-glucose deprivation and reoxygenation to recapitulate ischemia and reperfusion in the penumbra surrounding a cerebral infarct. Cell viability using WST-8 assay, apoptosis using TUNEL, free radicals using MitoSOX, and inflammatory cytokines using ELISA kit were measured in the presence and absence of redox nanoparticles after oxygen-glucose deprivation and reoxygenation. The scavenging activity of redox nanoparticles against reactive oxygen species was detected by electron spin resonance. Moreover, induced cells were transplanted intracerebrally into to the distal middle cerebral artery occlusion model with and without redox nanoparticles, and the survival rate measured. Cell viability was enhanced, while apoptosis, free radical generation, and inflammatory cytokine expression levels were reduced in cultures with redox nanoparticles. Further, reduced redox nanoparticles were detected in the cytoplasm, indicating free radical scavenging. Addition of redox nanoparticles also improved the survival rate of transplanted cells after 6 weeks in vivo. These redox nanoparticles may increase the applicability and success of induced stem cell therapy for ischemic stroke patents by promoting long-term survival.

Vestibular schwannoma extending into the tympanic cavity and jugular fossa by invasion of the petrous bone.

Vestibular schwannomas usually originate in the internal acoustic meatus, and gradually extends into the cerebellopontine cistern. Invasive growth into the petrous bone is extremely rare. We describe a case of a vestibular schwannoma that aggressively extended into the petrous bone and extracranial space. This may have arisen because of an unusually peripheral site of origin on the vestibular nerve.

Simultaneous visualization of multiple radionuclides in vivo.

The insufficient energy and spatial resolutions of radionuclide imaging with conventional scintillation detectors restrict the visualization of multiple radionuclides and of microstructures in tissue. Here we report the development and performance of an imaging system equipped with a cadmium telluride diode detector that achieves an energy resolution of 1.7% at 140 keV and a spatial resolution of 250 µm. The combination of high-resolution spectra fitted to an X-ray analysis model of the emission lines of the radionuclides in a chosen energy band allowed us to accurately determine individual radiation activities from three radionuclides to simultaneously visualize thyroid tissue (via intravenously administered iodine-125), mandibular lymph nodes (via the intramuscular injection of indium-111) and parotid lymph nodes (via a subcutaneous injection of technetium-99m) in mice. Multi-radionuclide imaging may find advantageous applications in biomedical imaging.

Transplanted neural lineage cells derived from dental pulp stem cells promote peripheral nerve regeneration.

Cell therapy for peripheral nerve injury is a promising strategy as regenerative medicine that restores neurological function. However, challenges remain in producing suitable and sufficient amounts of autologous cells for promoting nerve regeneration. This study aimed to identify the characteristics of neural lineage cells (NLCs) differentiated from dental pulp stem cells (DPSCs) and reveal their effect on functional recovery and nerve regeneration after cell transplantation into an immunodeficient rat using a nerve guide conduit. Here we report a protocol of neural induction in monolayer culture and characterize NLCs in vitro. Furthermore, NLCs were transplanted into an immunodeficient rat model with a 10-mm sciatic nerve defect, and cell survival and differentiation were investigated in vivo. Outcomes of nerve regeneration were also assessed using the remyelinated axon numbers, myelin sheath thickness, electrophysiological activities, and gastrocnemius muscle mass. NLCs comprised neuronal, astrocyte, oligodendrocyte, and neural crest lineage cells. NLCs enhanced the activities of endothelial cells, Schwann cells, and neurons in a paracrine-dependent manner in vitro. At 2 weeks post-transplantation, numerous transplanted NLCs differentiated into platelet-derived growth factor receptor alpha (PDGFRα) + oligodendrocyte progenitor cells (OPCs) and a few PDGFRα + /p75 neurotrophin receptor + Schwann cell-like cells derived from OPCs were observed. At 12 weeks post-transplantation, human Schwann cell-like cells survived, and axon growth, remyelination, electrophysiological activities, and muscle atrophy were improved. This study demonstrates the broad application of our protocol of neural induction of DPSCs and portrays the efficacy of transplantation of NLCs derived from human DPSCs as a promising strategy for peripheral nerve regeneration.

Induced Neural Cells from Human Dental Pulp Ameliorate Functional Recovery in a Murine Model of Cerebral Infarction.

Human mesenchymal stem cells are a promising cell source for the treatment of stroke. Their primary mechanism of action occurs via neuroprotective effects by trophic factors, anti-inflammatory effects, and immunomodulation. However, the regeneration of damaged neuronal networks by cell transplantation remains challenging. We hypothesized that cells induced to neural lineages would fit the niche, replace the lesion, and be more effective in improving symptoms compared with stem cells themselves. We investigated the characteristics of induced neural cells from human dental pulp tissue and compared the transplantation effects between these induced neural cells and uninduced dental pulp stem cells. Induced neural cells or dental pulp stem cells were intracerebrally transplanted 5 days after cerebral infarction induced by permanent middle cerebral artery occlusion in immunodeficient mice. Effects on functional recovery were also assessed through behavior testing. We used immunohistochemistry and neuron tracing to analyze the differentiation, axonal extension, and connectivity of transplanted cells to the host's neural circuit. Transplantation of induced neural cells from human dental pulp ameliorated functional recovery after cerebral infarction compared with dental pulp stem cells. The induced neural cells comprised both neurons and glia and expressed functional voltage, and they were more related to neurogenesis in terms of transcriptomics. Induced neural cells had a higher viability than did dental pulp stem cells in hypoxic culture. We showed that induced neural cells from dental pulp tissue offer a novel therapeutic approach for recovery after cerebral infarction.

Global Surgery Indicators and Pediatric Hydrocephalus: A Multicenter Cross-Country Comparative Study Building the Case for Health System Strengthening.

Objective: The aim of this study is to compare specific three-institution, cross-country data that are relevant to the Global Surgery indicators and the functioning of health systems. Methods: We retrospectively reviewed the clinical and socioeconomic characteristics of pediatric patients who underwent cerebrospinal fluid (CSF) diversion surgery for hydrocephalus in three different centers: the University of Tsukuba Hospital in Ibaraki, Japan (HIC), the Jose R. Reyes Memorial Medical Center in Manila, Philippines [low-to-middle-income country (LMIC)], and the Federal Neurosurgical Center in Novosibirsk, Russia (UMIC). The outcomes of interest were the timing of CSF diversion surgery and mortality. Statistical tests included descriptive statistics, Cox proportional hazards model, and logistic regression. Nation-level data were also obtained to provide the relevant socioeconomic contexts in discussing the results. Results: In total, 159 children were included, where 13 are from Japan, 99 are from the Philippines, and 47 are from the Russian Federation. The median time to surgery at the specific neurosurgical centers was 6 days in the Philippines and 1 day in both Japan and Russia. For the cohort from the Philippines, non-poor patients were more likely to receive CSF diversion surgery at an earlier time (HR = 4.74, 95% CI 2.34-9.61, p <0.001). In the same center, those with infantile or posthemorrhagic hydrocephalus (HR = 3.72, 95% CI 1.70-8.15, p = 0.001) were more likely to receive CSF diversion earlier compared to those with congenital hydrocephalus, and those with postinfectious (HR = 0.39, 95% CI 0.22-0.70, p = 0.002) or myelomeningocele-associated hydrocephalus (HR = 0.46, 95% CI 0.22-0.95, p = 0.037) were less likely to undergo surgery at an earlier time. For Russia, older patients were more likely to receive or require early CSF diversion (HR = 1.07, 95% CI 1.01-1.14, p = 0.035). External ventricular drain (EVD) insertion was found to be associated with mortality (cOR 14.45, 95% CI 1.28-162.97, p = 0.031). Conclusion: In this study, Filipino children underwent late time-interval of CSF diversion surgery and had mortality differences compared to their Japanese and Russian counterparts. These disparities may reflect on the functioning of the health systems of respective countries.

The state of neurosurgical training and education in East Asia: analysis and strategy development for this frontier of the world.

OBJECTIVE: The authors, who are from Indonesia, Japan, Malaysia, the Philippines, and Taiwan, sought to illustrate the processes of training neurosurgeons in their respective settings by presenting data and analyses of the current state of neurosurgical education across the East Asian region. METHODS: The authors obtained quantitative data as key indicators of the neurosurgical workforce from each country. Qualitative data analysis was also done to provide a description of the current state of neurosurgical training and education in the region. A strengths, weaknesses, opportunities, and threats (SWOT) analysis was also done to identify strategies for improvement. RESULTS: The number of neurosurgeons in each country is as follows: 370 in Indonesia, 10,014 in Japan, 152 in Malaysia, 134 in the Philippines, and 639 in Taiwan. With a large neurosurgical workforce, the high-income countries Japan and Taiwan have relatively high neurosurgeon to population ratios of 1 per 13,000 and 1 per 37,000, respectively. In contrast, the low- to middle-income countries Indonesia, Malaysia, and the Philippines have low neurosurgeon to population ratios of 1 per 731,000, 1 per 210,000, and 1 per 807,000, respectively. In terms of the number of training centers, Japan has 857, Taiwan 30, Indonesia 7, Malaysia 5, and the Philippines 10. In terms of the number of neurosurgical residents, Japan has 1000, Taiwan 170, Indonesia 199, Malaysia 53, and the Philippines 51. The average number of yearly additions to the neurosurgical workforce is as follows: Japan 180, Taiwan 27, Indonesia 10, Malaysia 4, and the Philippines 3. The different countries included in this report have many similarities and differences in their models and systems of neurosurgical education. Certain important strategies have been formulated in order for the system to be responsive to the needs of the catchment population: 1) establishment of a robust network of international collaboration for reciprocal certification, skills sharing, and subspecialty training; 2) incorporation of in-service residency and fellowship training within the framework of improving access to neurosurgical care; and 3) strengthening health systems, increasing funding, and developing related policies for infrastructure development. CONCLUSIONS: The varied situations of neurosurgical education in the East Asian region require strategies that take into account the different contexts in which programs are structured. Improving the education of current and future neurosurgeons becomes an important consideration in addressing the health inequalities in terms of access and quality of care afflicting the growing population in this region of the world.

Prediction of the Cerebral Hyperperfusion Phenomenon after Carotid Endarterectomy Using a Transit Time Flowmeter.

The purpose of this study was to investigate the relationship between the cerebral hyperperfusion phenomenon (CHP) and carotid artery flow volume as measured by a transit time flowmeter during carotid endarterectomy (CEA). We retrospectively investigated 74 patients who underwent both transit time flowmetry and single photon emission computed tomography (SPECT). The flow volumes of the internal carotid artery (ICA) before and after the endarterectomy were recorded during surgery as the pre- and the post-ICA (mL/min), respectively. We defined the difference between the pre- and the post-ICA as the ΔIC (mL/min). Two independent board-certified neurosurgeons analyzed the asymmetry index (affected side/contralateral side) of regional qualitative cerebral blood flow before and after the CEA respectively. We defined the CHP as an excessive increase in this asymmetry index between preoperative and postoperative SPECT. The CHP was observed in five of the 74 patients (6.8%). The pre-ICA of the CHP cases was significantly lower than that of the non-CHP cases (in mL/min, median 29 vs. 97; P = 0.01). The ΔIC of the CHP cases was significantly higher than that of the non-CHP cases (in mL/min, median 154 vs. 50; P = 0.002). The cut-off value of the ΔIC was 81 mL/min (sensitivity 100%, specificity 78.3%, area under the curve 0.912). The findings of this study suggest that the ΔIC is associated with the CHP. The transit time flowmeter is useful to predict the CHP during surgery.

Random Skin Biopsies Before Brain Biopsy for Intravascular Large B-Cell Lymphoma.

OBJECTIVE: To evaluate effectiveness of random skin biopsies for intravascular large B-cell lymphoma (IVLBCL) with or without central nervous system (CNS) involvement. METHODS: Data from 21 patients with suspected IVLBCL (7 with CNS involvement and 14 without CNS involvement) who underwent single (4 patients), double (1 patient), and random (16 patients) skin biopsies were retrospectively analyzed. RESULTS: IVLBCL was diagnosed in 16 patients (including 6 with CNS involvement). Sensitivity, specificity, and positive predictive value of random skin biopsies were 75%, 100%, and 100%. Ratio of tumor-positive biopsy samples to plasma soluble interleukin-2 receptor (sIL-2R) values was significantly correlated in cases with data on both variables. sIL-2R values in the 6 tumor-negative skin samples (median, 1415 U/mL; range, 487-3200 U/mL) were significantly lower than in tumor-positive skin samples (median, 3550 U/mL; range, 595-8700 U/mL) with at least 1 skin specimen obtained. Mean ratio of tumor-positive biopsy samples in IVLBCL cases with low sIL-2R (<3000 U/mL) was only 45%, indicating a requirement for 3-site multiple sampling. No differences in median sIL-2 values between cases of IVLBCL with and without CNS involvement were found (2795 U/mL vs. 3550 U/mL). Steroids administered before diagnosis yielded false-negative results in 3 of 5 IVLBCL cases (all false-negative cases were IVLBCL with CNS involvement), whereas none of 11 IVLBCL cases without steroid administration yielded false-negative results. CONCLUSIONS: Random skin biopsies before brain biopsy are recommended in patients with suspected IVLBCL regardless of CNS involvement, but low sIL-2R values and steroids may yield false-negative results.

Symptomatic Remote Cyst after BCNU Wafer Implantation for Malignant Glioma.

A 43-year-old man was operated on for right frontal oligoastrocytoma. 14 years after the surgery, magnetic resonance imaging and positron emission tomography revealed a new lesion near the surgical cavity. He underwent gross total resection of the lesion and implantation of bis-chloroethylnitrosourea (BCNU) wafers after intraoperative pathological diagnosis of recurrent high-grade glioma. A few days after the operation, the level of consciousness gradually worsened and left hemiparesis developed. A computed tomography scan revealed a cyst remote to the surgical cavity which did not exist 3 days prior. We performed anterior cyst wall fenestration and removed all wafers. The characteristic pathological finding at the wafer implantation site was severe inflammation within and around small vessels. This inflammatory reaction was not seen on the surface of the brain parenchyma. After surgery and rehabilitation, the patient's Karnofsky Performance Status stabilized to a pre-incident score of 90 and he returned to work. The exact pathophysiological mechanism of the cyst was not clear, but check-valve and/or osmotic gradient mechanisms related to BCNU wafer implantation could have contributed to this phenomenon. As remote cyst development happened a week after surgery, surgeons should be aware of such a rare condition when implanting wafers as consciousness impairment and hemiparesis may occur. Close radiological follow-up is therefore necessary.

Delayed Brain Edema and Swelling following Craniectomy for Evacuation of an Epidural Abscess that Improved by Cranioplasty: Case Report.

We report a unique case of delayed brain swelling following craniectomy that improved rapidly after cranioplasty, and discuss the potential mechanism underlying this delayed and reversible brain swelling. A 22-year-old woman developed surgical site infection after removal of a convexity meningioma. Magnetic resonance imaging revealed an epidural abscess around the surgical site. Subsequently, the abscess was evacuated, and the bone flap was removed. Later, brain edema around the skull defect emerged and progressed gradually, despite resolution of the infection. The edematous brain developed focal swelling outward through the bone defect without ventricle dilatation. Because we suspected that the edema and swelling were caused by the state of the bone defect, we performed a cranioplasty 10 weeks after the bone flap removal, and brain edema improved rapidly. We hypothesized that the brain edema was initially caused by surgical stress and inflammation, followed by compression of cortical veins between the dural edge and brain tissue, leading to disruption of venous return and exacerbation of brain edema. When delayed focal brain edema and external swelling progress gradually after bone flap removal, after excluding other pathological conditions, cranioplasty should be considered to improve cortical venous congestion caused by postsurgical adhesion.

Paraplegia caused by cerebral contusions in the bilateral precentral gyri.

BACKGROUND: Paraplegia is mainly caused by spinal cord disease and rarely occurs due to head trauma. In this report, we describe a case of paraplegia caused by cerebral contusions in the bilateral precentral gyri. CASE DESCRIPTION: A 72-year-old man was admitted to our hospital with mildly impaired consciousness and severe pure motor paralysis in both legs. He was healthy until the morning of the day, but his wife found him injured in front of his house upon returning home. He had a subcutaneous hematoma in his occipital region, and seemed to have slipped by accident. Computed tomography of the brain and magnetic resonance imaging (MRI) of his spinal cord revealed no apparent cause of the paraplegia, although an MRI of his brain clearly revealed cerebral contusions in the bilateral precentral gyri. The cerebral contusion was diagnosed as the cause of pure motor paralysis of lower extremities. He received rehabilitation, and manual muscle testing of his legs revealed improvements. In the subacute phase, the precentral gyrus lesion disappeared on MRI. CONCLUSION: We must emphasize that cerebral contusion can be a differential diagnosis for paraplegia. In the acute phase, fluid-attenuated inversion recovery (FLAIR) MRI coronal and sagittal images are useful for identifying precentral gyri contusions. Paraplegia caused by a cerebral contusion may be misdiagnosed as a spinal concussion due to the disappearance of the precentral gyrus lesion on FLAIR MRI in the subacute phase.

Endovascular treatments for posterior cerebral artery aneurysms and vascular insufficiency of fetal-type circulation after parent artery occlusion.

We present a retrospective analysis of endovascular treatments for posterior cerebral artery (PCA) aneurysms and discuss the susceptibility of a fetal-type PCA to vascular insufficiency after parent artery occlusion. Among 1207 aneurysms treated with endovascular therapy between March 1997 and March 2013 in our institution, 10 patients (0.8%) presented PCA aneurysms. The principal strategy was to employ selective coil embolization for the aneurysm. However, in certain cases of fusiform or dissecting aneurysms, we performed parent artery occlusion with coils. Clinical and radiological data were collected from hospital charts and evaluated retrospectively. The mean age was 52.7±15.6years (range, 12-65years). Five patients (50%) were admitted with a subarachnoid hemorrhage, and one patient presented with slowly developing paralysis. The remaining four patients were diagnosed incidentally. Five patients underwent selective coil embolization, and five patients underwent parent artery occlusion. All endovascular therapies were successfully performed. However, two patients in the parent artery occlusion group suffered cerebral infarction, and both patients exhibited a fetal-type PCA. The remaining three patients in the parent artery occlusion group exhibited an adult-type PCA and did not suffer a cerebral infarction. Endovascular treatment with either selective coil embolization or parent artery occlusion is safe and effective as the long as the anatomical type of the PCA is considered. Patients with a fetal-type PCA may develop vascular insufficiency upon parent artery occlusion. Neurosurgeons should attempt to preserve the parent artery using a flow-diverting stent or stent-assisted technique for a fetal-type PCA aneurysm.

[A Case of Traumatic Carotid Cavernous Fistula Treated with a Single Procedure Selective Transarterial Embolization Using Hydrogel Coils].

A 30-year-old man was admitted to our hospital after a bicycle accident. Proptosis, conjunctival congestion, and orbital vascular bruit appeared one month after the accident. Neuroradiological findings showed a traumatic carotid cavernous fistula(CCF). CCF is a pathologic arteriovenous shunt between the carotid artery and cavernous sinus. A detachable balloon was the standard device used for treatment of high flow direct CCF, although it is currently unavailable in Japan. Therefore, many other constructive strategies are being developed. We successfully treated this patient with single transarterial embolization using hydrogel coils. Hydrogel coils are platinum coils coated with polymeric water gels, and can be used at a prospect of delayed volume expansion. In our case, the patency of the internal carotid artery was maintained using the coils, and the symptoms improved shortly after the procedure. The use of hydrogel coils for the treatment of CCF appears to be safe and effective.