Targeting Neurogenesis in Seeking Novel Treatments for Ischemic Stroke.

The interruption of cerebral blood flow leads to ischemic cell death and results in ischemic stroke. Although ischemic stroke is one of the most important causes of long-term disability and mortality, limited treatments are available for functional recovery. Therefore, extensive research has been conducted to identify novel treatments. Neurogenesis is regarded as a fundamental mechanism of neural plasticity. Therefore, therapeutic strategies targeting neurogenesis are thought to be promising. Basic research has found that therapeutic intervention including cell therapy, rehabilitation, and pharmacotherapy increased neurogenesis and was accompanied by functional recovery after ischemic stroke. In this review, we consolidated the current knowledge of the relationship between neurogenesis and treatment for ischemic stroke. It revealed that many treatments for ischemic stroke, including clinical and preclinical ones, have enhanced brain repair and functional recovery post-stroke along with neurogenesis. However, the intricate mechanisms of neurogenesis and its impact on stroke recovery remain areas of extensive research, with numerous factors and pathways involved. Understanding neurogenesis will lead to more effective stroke treatments, benefiting not only stroke patients but also those with other neurological disorders. Further research is essential to bridge the gap between preclinical discoveries and clinical implementation.

IDH-mutant Astrocytoma Arising in the Brainstem with Symptom Improvement by Foramen Magnum Decompression: A Case Report.

Diffusely infiltrative midline gliomas are known to have a poor prognosis. The standard treatment for typical diffuse midline glioma in the pons is local radiotherapy as surgical resection is inappropriate. This case reports a brainstem glioma in which stereotactic biopsy and foramen magnum decompression were concomitantly performed to confirm the diagnosis and improve symptoms. A 23-year-old woman was referred to our department with a chief complaint of headache for six months. Magnetic resonance imaging (MRI) showed diffuse T2 hyperintense swelling of the brainstem with the pons as the main locus. Enlargement of the lateral ventricles was observed because of cerebrospinal fluid obstruction out of the posterior fossa. This was atypical for a diffuse midline glioma in terms of the longstanding slow progression of symptoms and patient age. Stereotactic biopsy was performed for diagnosis, and foramen magnum decompression (FMD) was concomitantly performed to treat the obstructive hydrocephalus. The histological diagnosis was astrocytoma, IDH-mutant. Post-surgery, the patient's symptoms were relieved, and she was discharged on the fifth day after surgery. The hydrocephalus was resolved, and the patient returned to normal life without any symptoms. The tumor size follow-up with MRI demonstrated no marked change for 12 months. Even though diffuse midline glioma is considered to have a poor prognosis, clinicians should contemplate if it is atypical. In atypical cases like the one described herein, surgical treatment may contribute to pathological diagnosis and symptom improvement.

Continuous vagus nerve stimulation exerts beneficial effects on rats with experimentally induced Parkinson's disease: Evidence suggesting involvement of a vagal afferent pathway.

BACKGROUND: Vagus nerve stimulation (VNS) exerts neuroprotective and anti-inflammatory effects in preclinical models of central nervous system disorders, including Parkinson's disease (PD). VNS setting applied for experimental models is limited into single-time or intermittent short-duration stimulation. We developed a VNS device which could deliver continuous stimulation for rats. To date, the effects of vagal afferent- or efferent-selective stimulation on PD using continuous electrical stimulation remains to be determined. OBJECTIVE: To investigate the effects of continuous and selective stimulation of vagal afferent or efferent fiber on Parkinsonian rats. METHODS: Rats were divided into 5 group: intact VNS, afferent VNS (left VNS in the presence of left caudal vagotomy), efferent VNS (left VNS in the presence of left rostral vagotomy), sham, vagotomy. Rats underwent the implantation of cuff-electrode on left vagus nerve and 6-hydroxydopamine administration into the left striatum simultaneously. Electrical stimulation was delivered just after 6-OHDA administration and continued for 14 days. In afferent VNS and efferent VNS group, the vagus nerve was dissected at distal or proximal portion of cuff-electrode to imitate the selective stimulation of afferent or efferent vagal fiber respectively. RESULTS: Intact VNS and afferent VNS reduced the behavioral impairments in cylinder test and methamphetamine-induced rotation test, which were accompanied by reduced inflammatory glial cells in substantia nigra with the increased density of the rate limiting enzyme in locus coeruleus. In contrast, efferent VNS did not exert any therapeutic effects. CONCLUSION: Continuous VNS promoted neuroprotective and anti-inflammatory effect in experimental PD, highlighting the crucial role of the afferent vagal pathway in mediating these therapeutic outcomes.

Synergistic therapeutic effects of intracerebral transplantation of human modified bone marrow-derived stromal cells (SB623) and voluntary exercise with running wheel in a rat model of ischemic stroke.

BACKGROUND: Mesenchymal stromal cell (MSC) transplantation therapy is a promising therapy for stroke patients. In parallel, rehabilitation with physical exercise could ameliorate stroke-induced neurological impairment. In this study, we aimed to clarify whether combination therapy of intracerebral transplantation of human modified bone marrow-derived MSCs, SB623 cells, and voluntary exercise with running wheel (RW) could exert synergistic therapeutic effects on a rat model of ischemic stroke. METHODS: Wistar rats received right transient middle cerebral artery occlusion (MCAO). Voluntary exercise (Ex) groups were trained in a cage with RW from day 7 before MCAO. SB623 cells (4.0 × 105 cells/5 µl) were stereotactically injected into the right striatum at day 1 after MCAO. Behavioral tests were performed at day 1, 7, and 14 after MCAO using the modified Neurological Severity Score (mNSS) and cylinder test. Rats were euthanized at day 15 after MCAO for mRNA level evaluation of ischemic infarct area, endogenous neurogenesis, angiogenesis, and expression of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF). The rats were randomly assigned to one of the four groups: vehicle, Ex, SB623, and SB623 + Ex groups. RESULTS: SB623 + Ex group achieved significant neurological recovery in mNSS compared to the vehicle group (p < 0.05). The cerebral infarct area of SB623 + Ex group was significantly decreased compared to those in all other groups (p < 0.05). The number of BrdU/Doublecortin (Dcx) double-positive cells in the subventricular zone (SVZ) and the dentate gyrus (DG), the laminin-positive area in the ischemic boundary zone (IBZ), and the mRNA level of BDNF and VEGF in SB623 + Ex group were significantly increased compared to those in all other groups (p < 0.05). CONCLUSIONS: This study suggests that combination therapy of intracerebral transplantation SB623 cells and voluntary exercise with RW achieves robust neurological recovery and synergistically promotes endogenous neurogenesis and angiogenesis after cerebral ischemia, possibly through a mechanism involving the up-regulation of BDNF and VEGF.

Anomalous Strain Recovery after Stress Removal of Graded Rubber.

Mechanical responses after the uniaxial deformation of graded styrene-butadiene rubber (SBR) with a gradient in the crosslink points in the thickness direction were investigated as compared with those of homogenously vulcanized SBR samples. The elongational residual strain of a graded sample was found to depend on the part with a high crosslink density. Therefore, it showed good rubber elasticity. After stress removal, moreover, the graded sample showed a marked warpage. This suggested that shrinking stress acted on the surface with a high crosslink density, which would avoid a crack growth on the surface. The sample shape was then recovered to be flat very slowly, indicating that the shrinking stress worked for a long time. This unique rubber elasticity, i.e., slow strain recovery with an excellent strain recovery, makes graded rubber highly significant.

Transplantation of modified human bone marrow-derived stromal cells affords therapeutic effects on cerebral ischemia in rats.

AIMS: SB623 cells are human bone marrow stromal cells transfected with Notch1 intracellular domain. In this study, we examined potential regenerative mechanisms underlying stereotaxic transplantation of SB623 cells in rats with experimental acute ischemic stroke. METHODS: We prepared control group, empty capsule (EC) group, SB623 cell group (SB623), and encapsulated SB623 cell (eSB623) group. Transient middle cerebral artery occlusion (MCAO) was performed on day 0, and 24 h after MCAO, stroke rats received transplantation into the envisioned ischemic penumbra. Modified neurological severity score (mNSS) was evaluated, and histological evaluations were performed. RESULTS: In the mNSS, SB623 and eSB623 groups showed significant improvement compared to the other groups. Histological analysis revealed that the infarction area in SB623 and eSB623 groups was reduced. In the eSB623 group, robust cell viability and neurogenesis were detected in the subventricular zone that increased significantly compared to all other groups. CONCLUSION: SB623 cells with or without encapsulation showed therapeutic effects on ischemic stroke. Encapsulated SB623 cells showed enhanced neurogenesis and increased viability inside the capsules. This study reveals the mechanism of secretory function of transplanted SB623 cells, but not cell-cell interaction as primarily mediating the cells' functional benefits in ischemic stroke.

A Pediatric Case of Cauda Equina Dermoid Cyst Resected by Minimally Invasive Unilateral Hemilaminectomy.

A 3-year-old boy had difficulty sitting up and walking for several months. Magnetic resonance imaging (MRI) revealed an intradural tumor at the L3-4 level. The tumor was successfully resected by unilateral hemilaminectomy and diagnosed as dermoid cyst. The patient had an uneventful postoperative course without pain, and MRI found no recurrence after surgery. A small bone defect remained that might be favorably reconstructed with autologous and artificial bone. Hemilaminectomy allowed us to resect the cauda equina dermoid cyst with minimal invasiveness. Pediatric patients require follow-up as they are more likely to experience spinal deformity or instability after surgery.

4-Hydroxyl-2-Nonenal Localized Expression Pattern in Retrieved Clots is Associated with Large Artery Atherosclerosis in Stroke Patients.

OBJECTIVES: The relationship between stroke etiology and clot pathology remains controversial. MATERIALS AND METHODS: We performed histological analysis of clots retrieved from 52 acute ischemic stroke patients using hematoxylin and eosin staining and immunohistochemistry (CD42b and oxidative/hypoxic stress markers). The correlations between clot composition and the stroke etiological group (i.e., cardioembolic, cryptogenic, or large artery atherosclerosis) were assessed. RESULTS: Of the 52 clots analyzed, there were no significant differences in histopathologic composition (e.g., white blood cells, red blood cells, fibrin, and platelets) between the 3 etiological groups (P = .92). By contrast, all large artery atherosclerosis clots showed a localized pattern with the oxidative stress marker 4-hydroxyl-2-nonenal (P < .01). From all 52 clots, 4-hydroxyl-2-nonenal expression patterns were localized in 28.8% of clots, diffuse in 57.7% of clots, and no signal in 13.5% of clots. CONCLUSIONS: A localized pattern of 4-hydroxyl-2-nonenal staining may be a novel and effective marker for large artery atherosclerosis (sensitivity 100%, specificity 82%).

A Patient with a Cavernous Sinus Dural Arteriovenous Fistula in Whom an Approach through the Jugular Venous Arch Involving Facial Vein Return Was Adopted.

Objective: We report the case of a cavernous sinus dural arteriovenous fistula (CSdAVF) treated by transvenous embolization (TVE) via the jugular venous arch (JVA) connecting bilateral superficial cervical veins. Case Presentation: A male patient in his 50s presenting with diplopia and headache was diagnosed with a CSdAVF. The first session of TVE resulted in incomplete obliteration of the fistula due to poor accessibility through the inferior petrosal sinus (IPS), and postoperative computed tomography angiography (CTA) disclosed a newly developed drainage route into the facial vein (FV) connecting to the anterior jugular vein (AJV) and the JVA. The patient underwent the second session of TVE through the JVA, FV, and the superior ophthalmic vein (SOV), and obliteration was achieved. Conclusion: There is a considerable variation in the anatomy of facio-cervical veins in patients with CSdAVF. Meticulous preoperative evaluation of the venous drainage route using modern diagnostic tools is indispensable to achieve successful results in patients with CSdAVF.

Practical Use of a Communication Application on Mobile Devices by Our Stroke Team.

Objective: To describe our 1-year experience of the practical use of a mobile communication application by our stroke team. Methods: The mobile Join application (Allm Inc., Tokyo, Japan) was introduced into our stroke team for the purpose of immediate sharing of the patient information. We analyzed the usage situation for 1 year after the introduction of Join, particularly its efficacy in improving the door-to-puncture time (D2P) for thrombectomy cases, and reported our inter-hospital collaboration with the use of Join. Results: The total number of events notified by Join was 337, and they included acute stroke potentially leading to reperfusion therapy in 23% (76 events), head trauma in 14%, brain hemorrhage in 12%, other infarction in 10%, subarachnoid hemorrhage in 8%, and the others in 34%. The information of the patients was shared among the team members before arrival to our hospital in 42% of acute stroke cases. Of 31 patients undergoing mechanical thrombectomy, the median interval between arrival and groin puncture for the directly transported patients with/without pre-hospital information was 77.5 min/87 min, respectively, whereas that of the patients transferred from primary hospitals with/without pre-hospital information was 19 min/71 min (p <0.0001), respectively, demonstrating the efficacy of information sharing in advance through Join in improving the timing of endovascular therapy. For inter-hospital collaboration using the telestroke system, we concluded the partnership agreement with three local primary hospitals by communication via Join at a reasonable cost. Conclusion: Active and effective utilization of the mobile Join application for communication by our stroke team was demonstrated, and it is expected to promote inter-hospital collaboration in stroke treatment.

The mll6786 gene encodes a repressor protein controlling the degradation pathway for vitamin B6 in Mesorhizobium loti.

Pyridoxine is converted to succinic semialdehyde, acetate, ammonia and CO(2) through the actions of eight enzymes. The genes encoding the enzymes occur as a cluster on the chromosomal DNA of Mesorhizobium loti, a symbiotic nitrogen-fixing bacterium. Here, it was found that disruption of the mll6786 gene, which is located between the genes encoding the first and eighth enzymes of the pathway, caused constitutive expression of the eight enzymes. The protein encoded by the mll6786 gene is a member of the GntR family and is designated as PyrR. PyrR comprises 223 amino acid residues and is a dimeric protein with a subunit molecular mass of 25 kDa. The purified PyrR with a C-terminal His(6) -tag could bind to an intergenic 67-bp DNA region, which contains a palindrome sequence and a deduced promoter sequence, between the mll6786 and mlr6787 genes, encoding PyrR and AAMS amidohydrolase, respectively.