SOCS7-Derived BC-Box Motif Peptide Mediated Cholinergic Differentiation of Human Adipose-Derived Mesenchymal Stem Cells.

Adipose-derived mesenchymal stem cells (ADMSCs) are a type of pluripotent somatic stem cells that differentiate into various cell types such as osteoblast, chondrocyte, and neuronal cells. ADMSCs as donor cells are used to produce regenerative medicines at hospitals and clinics. However, it has not been reported that ADMSCs were differentiated to a specific type of neuron with a peptide. Here, we report that ADMSCs differentiate to the cholinergic phenotype of neurons by the SOCS7-derived BC-box motif peptide. At operations for patients with neurological disorders, a small amount of subcutaneous fat was obtained. Two weeks later, adipose-derived mesenchymal stem cells (ADMSCs) were isolated and cultured for a further 1 to 2 weeks. Flow cytometry analysis for characterization of ADMSCs was performed with CD73, CD90, and CD105 as positive markers, and CD14, CD31, and CD56 as negative markers. The results showed that cultured cells were compatible with ADMSCs. Immunocytochemical studies showed naïve ADMSCs immunopositive for p75NTR, RET, nestin, keratin, neurofilament-M, and smooth muscle actin. ADMSCs were suggested to be pluripotent stem cells. A peptide corresponding to the amino-acid sequence of BC-box motif derived from SOCS7 protein was added to the medium at a concentration of 2 µM. Three days later, immunocytochemistry analysis, Western blot analysis, ubiquitination assay, and electrophysiological analysis with patch cramp were performed. Immunostaining revealed the expression of neurofilament H (NFH), choline acetyltransferase (ChAT), and tyrosine hydroxylase (TH). In addition, Western blot analysis showed an increase in the expression of NFH, ChAT, and TH, and the expression of ChAT was more distinct than TH. Immunoprecipitation with JAK2 showed an increase in the expression of ubiquitin. Electrophysiological analysis showed a large holding potential at the recorded cells through path electrodes. The BC-box motif peptide derived from SOCS7 promoted the cholinergic differentiation of ADMSCs. This novel method will contribute to research as well as regenerative medicine for cholinergic neuron diseases.

Anaplastic myxopapillary ependymoma: A case report and review of literature.

BACKGROUND: Myxopapillary ependymoma (MPE) is a pathological grade I tumor that arises in the filum terminale. MPE with anaplastic features is extremely rare, and only 5 cases have shown malignancy at the time of recurrence. CASE SUMMARY: The patient (a 46-year-old woman) had undergone a MPE operation 30 years ago. After subtotal resection of the tumor located in L4-S1, it had a solid component that extended to the adjacent subcutaneous region. Histologically, the tumor consisted of a typical MPE with anaplastic features. The anaplastic areas of the tumor showed hypercellularity, a rapid mitotic rate, vascular proliferation, and connective tissue proliferation. Pleomorphic cells and atypical mitotic figures were occasionally observed. The MIB-1 index in this area was 12.3%. The immunohistochemical study showed immunoreactivity for vimentin, glial fibrillary acidic protein and S100. The morphological pattern and immunohistochemical profile were consistent with anaplastic MPE. The patient tolerated surgery well without new neurological deficits. She underwent local irradiation for the residual tumor and rehabilitation. CONCLUSION: Although extremely rare, anaplastic MPE occurs in both pediatric and adult patients, similar to other ependymomas. At a minimum, close monitoring is recommended, given concerns about aggressive biological potential. In the future, further study is needed to determine the WHO classification criteria and genetic indicators of tumor progression. The possibility of malignant transformation of MPE should be taken into account, and patients with MPE should be treated with care and follow-up.

Efficacy of Supraclavicular Scalenotomy Followed by External Neurolysis without Rib Resection for Post-traumatic Neurogenic Thoracic Outlet Syndrome.

MINI: Most patients with neurogenic thoracic outlet syndrome (NTOS) have a history of trauma. Scar tissue formation within the scalene muscle and around the nerves after injury cause arm and hand symptoms. We report that supraclavicular scalenotomy followed by external neurolysis without rib resection is very effective as the surgical treatment.

Consecutive case series. Our aim was to evaluate the outcomes of patients who underwent supraclavicular scalenotomy followed by external neurolysis without rib resection for post-traumatic NTOS. Neurogenic thoracic outlet syndrome (NTOS) comprises over 95% of all TOS patients, and most patients with NTOS have a history of trauma before the onset of their symptoms. Patients treated with supraclavicular scalenotomy and neurolysis without rib resection from September 2014 to December 2019 were retrospectively reviewed by using the medical records and operative notes. Patient's characteristics, clinical symptoms before treatment, operative findings, and short- and long-term outcomes were assessed. To assess clinical outcomes at 2 months after surgery (short-term outcomes) and 12 months later (long-term outcomes), we used a 4-grade categorization (Excellent, Good, Fair, and Poor) of patients' subjective evaluations after surgery on the basis of modified Odom's criteria. Excellent and Good were defined as a successful outcome. Ninety-six supraclavicular scalenotomies without rib resection were performed on patients with post-traumatic NTOS. The most common intraoperative observation was the fibrous bands within the anterior scalene muscle in 86 cases (89.6%). The short-term outcome with patients' subjective evaluation in 96 operations at 2 months after surgery showed a 96.9% success rate (Excellent + Good). In 85 cases followed for more than 12 months after surgery, the success rate based on patients' subjective evaluation at the last clinic follow-up appointment as a long-term outcome was 74.1%. In post-traumatic NTOS, it has been reported the arm and hand symptoms are due to pressure on the brachial plexus, which can stem from the swollen muscle following injuries and later from tightness of the scarred muscle. Considering this mechanism and our results, we concluded that supraclavicular scalenotomy and external neurolysis without rib resection made sense, as they were very effective and adequate to improve symptoms of NTOS. Level of Evidence: 5.

BC-Box Motif in SOCS6 Induces Differentiation of Epidermal Stem Cells into GABAnergic Neurons.

The BC-box motif in suppressor of cytokine signaling 6 (SOCS6) promotes the neuronal differentiation of somatic stem cells, including epidermal stem cells. SOCS6 protein belongs to the group of SOCS proteins and inhibits cytokine signaling. Here we showed that epidermal stem cells were induced to differentiate into GABAnergic neurons by the intracellular delivery of a peptide composed of the amino-acid sequences encoded by the BC-box motif in SOCS6 protein. The BC-box motif (SLQYLCRFVI) in SOCS6 corresponded to the binding site of elongin BC. GABAnergic differentiation mediated by the BC-box motif in SOCS6 protein was caused by ubiquitination of JAK2 and inhibition of the JAK2-STAT3 pathway. Furthermore, GABAnergic neuron-like cells generated from epidermal stem cells were transplanted into the brain of a rodent ischemic model. Then, we demonstrated that these transplanted cells were GAD positive and that the cognitive function of the ischemic model rodents with the transplanted cells was improved. This study could contribute to not only elucidating the mechanism of GABAnergic neuronal differentiation but also to neuronal regenerative medicine utilizing GABAnergic neurons.

Role of VHL-JAK-STAT signaling pathway in central nervous system hemangioblastoma associated with von Hippel-Lindau disease.

INTRODUCTION: Central nervous system hemangioblastoma is a benign tumor associated with or without von Hippel-Lindau (VHL) disease which is an autosomal dominant hereditary disease that results from a germline mutation in the VHL gene. A main axis of signaling pathways in central nervous system hemangioblastoma is VHL-HIF signaling pathway. Here, we propose an alternative VHL-JAK-STAT signaling pathway in hemangioblastoma and discuss the role. METHODS: Using MACS method, Scl+ hemangioblast-like cells were isolated from multipotent nestin-expressing stem cells. Then, ubiquitination of JAK2 in those cells and immunoprecipitation between JAK2 and VHL were examined. Then, expressions of JAK2 and STAT3 in those cells and expressions of VHL-associated hemangioblastoma tissues were examined. In addition, the VHL genes of patients bearing hemangioblastoma were analyzed. RESULTS: JAK2 and STAT3 in Scl+ hemangioblast-like cells were ubiquitinated after VHL- expression vector was transferred to those cells. Expressions of JAK2 and STAT3 in those cells were well recognized before the transfer, but those disappeared after the transfer. Expressions of both JAK2 and STAT3 in hemangioblastoma tissues were well shown. The VHL gene analysis revealed that patients bearing hemangioblastoma carried missense mutations in 5, small deletions in 2, large deletions in 4, and nonsense mutation in 1 CONCLUSIONS: VHL-JAK-STAT signaling pathway might play an important role in proliferation, angiogenesis, and maintenance of stem-cell-nature in hemangioblastoma as an alternative signaling pathway to supplement VHL-HIF signaling pathway.

Predictors of the Response to an Epidural Blood Patch in Patients with Spinal Leakage of Cerebrospinal Fluid.

BACKGROUND AND PURPOSE: An epidural blood patch (EBP) is a highly effective therapy for spinal cerebrospinal fluid (CSF) leakage. However, the factors predicting the response to an EBP have not been fully elucidated. The aim of this study was to elucidate factors predicting the response to an EBP. METHODS: We retrospectively examined the relationship between the response to an EBP and clinical variables of 118 patients with spinal CSF leakage, such as patient age, sex, etiology, interval from the onset to EBP application, CSF opening pressure (OP), radioisotope (RI) cisternography findings, rate of RI remaining in the CSF space, computed tomography (CT) myelography findings, magnetic resonance imaging (MRI) findings, and subjective symptoms (headache, vertigo/dizziness, visual disturbance, nausea, numbness, nuchal pain, back pain/lumbago, fatigability, photophobia, and memory disturbance). The correlations between these variables and the responses to EBPs were analyzed statistically. RESULTS: A positive response to an EBP was significantly (p<0.05) correlated with the following variables: <1.5 years from the onset to EBP application, age <40 years, CSF OP <7 cm H2O, epidural CSF leakage in RI cisternography, epidural CSF collection in MRI, <20% RI remaining after 24 hours, orthostatic headache, nausea, nuchal pain, and photophobia. The other variables did not show significant correlations with the responses to EBPs. CONCLUSIONS: It might be prudent to take the following variables into account when applying an EBP to treat spinal CSF leakage: the interval from the onset to EBP application, age, CSF OP, epidural CSF leakage in RI, epidural CSF collection in MRI, rate of remaining RI, orthostatic headache, nuchal pain, photophobia, and nausea.

VHL-Associated Optic Nerve Hemangioblastoma Treated with Stereotactic Radiosurgery.

Central nervous system hemangioblastomas are generally restricted to the cerebellum, spinal cord, and brainstem. Supratentorial hemangioblastomas are uncommon, and optic nerve hemangioblastomas are extremely rare, with fewer than 25 reports including this case. In this report, we present the case of a 36-year-old woman with von Hippel-Lindau (VHL) disease who presented with progressive diminution of vision in the left eye due to a retrobulbar optic nerve hemangioblastoma. The patient had a history of cerebellar/spinal hemangioblastomas and pancreatic cysts, and her father and brother were patients with VHL disease. Gadolinium-enhanced magnetic resonance imaging showed intraorbital retrobulbar-enhanced mass on the left optic nerve. The optic nerve hemangioblastoma was treated with fractionated stereotactic radiosurgery using Novalis. Eighteen months after the stereotactic radiosurgery, the tumor volume decreased although the patient lost vision. This report presents an extremely rare case of optic nerve hemangioblastoma, which is the first case treated with stereotactic radiosurgery.

[Chondroblastoma of the Temporal Bone Removed Using a Middle Cranial Fossa Approach].

We report a case of chondroblastoma of the middle cranial fossa, probably arising from the (infra) mandibular fossa, and expanding to the attic and external auditory canal that was successfully removed using a middle cranial fossa approach. No recurrences occurred during an 8-year postoperative follow-up period. Initial biopsy findings suggested a pathological diagnosis of giant cell tumor that was later confirmed to be a chondroblastoma based on an immunohistochemical study of S-100. This case study suggests a profound understanding of the clinical features, histopathological characteristics, and possible treatment. of chondroblastoma.

[The present state and view of the cerebrospinal fluid hypovolemia research].

Spontaneous intracranial hypotension is a rare disease characterized by orthostatic headache, low cerebrospinal fluid pressure and diffuse dural enhancement in brain MRI. German neurologist Schaltenbrand reported that orthostatic headache by low cerebrospinal fluid pressure in 1938. This disease came to be known after development of radiological diagnosis in 1990'. The author reported that cerebrospinal fluid leak is induced in the whiplash sequelae after traffic accident in 2003. Cerebrospinal fluid hypovolemia got into the news social. A lot of doctors deny the cerebrospinal fluid leak after mild traffic accident. The Cerebrospinal Fluid Hypovolemia Society is started up in 2003 and 11 research meeting held until today. The research group of Ministry of Health, Labour and Welfare was made in 2007. The image diagnostic criteria of cerebrospinal fluid leakage syndrome model were made in 2012. Neither the mechanism of the cerebrospinal fluid leak nor the mechanism of symptoms are understood well. The pathophysiology of cerebrospinal fluid hypovolemia is expected by researching the cerebrospinal fluid circulation.

Conservative treatment of ruptured vertebrobasilar dissecting aneurysm.

Ruptured vertebrobasilar dissecting aneurysm is usually treated surgically because rebleeding negatively affects outcome. However, the risk of rebleeding decreases markedly once several hours have passed from the initial bleeding. Moreover, surgery-related complications are not rare. We describe seven patients with ruptured vertebrobasilar dissecting aneurysm. To prevent rebleeding during the acute stage, we treated all seven patients conservatively with fentanyl instead of emergency surgery. During the follow-up period (mean 20 months), no patient suffered rebleeding. Conservative treatment with fentanyl administration may be a good option for management of ruptured vertebrobasilar dissecting aneurysm during the acute stage.

Brain abscess caused by Nocardia nova.

Nocardia nova is a newly identified species of the Nocardia asteroides group and has recently been characterized as a human pathogen. To date, a few cases of N. nova pneumonia or subcutaneous abscess have been reported. We describe a patient with a brain abscess caused by N. nova in a patient receiving prednisolone and cyclophosphamide for nephrosis. Surgical excision and antibiotic treatment of the brain abscess were successful. This is the first detailed report of central nervous system infection due to N. nova.

Three-dimensional computed tomographic angiography with low loads of contrast agent in acute subarachnoid hemorrhage.

In the pre-operative evaluation of aneurysmal subarachnoid hemorrhage (SAH), three-dimensional computed tomographic angiography (3D-CTA) is very helpful. However, it is usually difficult to perform 3D-CTA following four-vessel cerebral angiography in the setting of acute SAH because of high loads of contrast agent. The present report is designed to enable 3D-CTA following catheter angiography for surgical planning. Fourteen consecutive patients with acute SAH underwent four-vessel cerebral angiography. After identification of the aneurysm, all patients were moved to the CT room next to the angiography room under catheterization. Contrast agent (10 ml) was diluted with 40 ml of heparinized saline. This diluted contrast agent was then injected through intra-arterial catheter for 3D-CTA. 3D-CTA with diluted contrast agent which was injected through intra-arterial catheter revealed sufficiently clear images. In addition, this method could provide anatomical information that was not readily available from catheter angiography. 3D-CTA with additional low dose of contrast agent can immediately follow four-vessel cerebral angiography in the setting of acute SAH. No complications were noted throughout the procedures. It has been our experience that the imaging modality in combination with not only catheter angiography but also 3D-CTA is advantageous in case of acute SAH and provides better detail for surgical planning.