Intravenous Administration of Human Muse Cells Ameliorates Deficits in a Rat Model of Subacute Spinal Cord Injury.

Multilineage-differentiating stress-enduring (Muse) cells are newly established pluripotent stem cells. The aim of the present study was to examine the potential of the systemic administration of Muse cells as an effective treatment for subacute SCI. We intravenously administered the clinical product "CL2020" containing Muse cells to a rat model two weeks after mid-thoracic spinal cord contusion. Eight experimental animals received CL2020, and twelve received the vehicle. Behavioral analyses were conducted over 20 weeks. Histological evaluations were performed. After 20 weeks of observation, diphtheria toxin was administered to three CL2020-treated animals to selectively ablate human cell functions. Hindlimb motor functions significantly improved from 6 to 20 weeks after the administration of CL2020. The cystic cavity was smaller in the CL2020 group. Furthermore, larger numbers of descending 5-HT fibers were preserved in the distal spinal cord. Muse cells in CL2020 were considered to have differentiated into neuronal and neural cells in the injured spinal cord. Neuronal and neural cells were identified in the gray and white matter, respectively. Importantly, these effects were reversed by the selective ablation of human cells by diphtheria toxin. Intravenously administered Muse cells facilitated the therapeutic potential of CL2020 for severe subacute spinal cord injury.

Usefulness of Transcranial Motor Evoked Potential in Clipping Surgery for Cerebral Aneurysms-Introduction of a New Protocol for Stable Monitoring.

The usefulness of transcranial motor evoked potentials (Tc-MEPs) in clipping surgery has been reported. However, numerous false positive and false negative cases were reported. We report the usefulness of a new protocol compared with direct cortical MEP (Dc-MEP).Materials were 351 patients who underwent aneurysmal clipping under simultaneous monitoring of Tc- and Dc-MEPs. A total of 337 patients without hemiparesis and 14 with hemiparesis were separately analyzed. Intraoperative changes of Tc-MEP thresholds were examined in the first 50 patients without hemiparesis. The stimulation strength of Tc-MEP was set at +20% of the stimulation threshold. As thresholds changed intraoperatively, thresholds were examined every 10 min and changed stimulation strength.Stimulation thresholds of Tc-MEP were significantly decreased after craniotomy and significantly increased after CSF aspiration. The recording ratios of Tc- and Dc-MEPs were 98.8% and 90.5%, respectively. Out of 304 patients without MEP change, 5 patients developed transient or mild hemiparesis with infarction of the territory of the perforating artery arising from the posterior communicating artery. Out of 31 patients whose MEP transiently disappeared, 3 patients developed transient or mild hemiparesis. The other two patients without MEP recovery manifested persistent hemiparesis. In 14 patients with preoperative hemiparesis, 3 patients whose healthy/affected ratio of Tc-MEP was large developed severe persistent hemiparesis.We clarified the intraoperative changes of Tc-MEP thresholds for the first time. A new protocol of Tc-MEP that followed thresholds and changed stimulation strength to +20% of thresholds is useful for stable monitoring. The usefulness of Tc-MEP is the same as that or better than that of Dc-MEP.

Association of intravenous administration of human Muse cells with deficit amelioration in a rat model of spinal cord injury.

OBJECTIVE: Multilineage-differentiating stress-enduring (Muse) cells are pluripotent stem cells, which can be harvested from the bone marrow. After transplantation, Muse cells can migrate to an injured site of the body and exert repair effects. However, it remains unknown whether Muse cell transplantation can be an effective treatment in spinal cord injury (SCI). METHODS: The authors used a rat model of thoracic spinal cord contusion injury. For Muse cell transplantation, the clinical product CL2020 containing 300,000 Muse cells was administered intravenously 1 day after midthoracic SCI. Animals were divided into CL2020 (n = 11) and vehicle-treated (n = 15) groups. Behavioral and histological evaluations were conducted over a period of 8 weeks to see whether intravenous CL2020 administration provided therapeutic effects for SCI. The effects of human-selective diphtheria toxin on reversion of the therapeutic effects of CL2020 were also investigated. RESULTS: Hindlimb motor function significantly improved after CL2020 transplantations. Importantly, the effects were reverted by the human-selective diphtheria toxin. In immunohistochemical analyses, the cystic cavity formed after the injury was smaller in the CL2020 group. Furthermore, higher numbers of descending 5-hydroxytryptamine (5-HT) fibers were preserved distal to the injury site after CL2020 administration. Eight weeks after the injury, Muse cells in CL2020 were confirmed to differentiate most predominantly into neuronal cells in the injured spinal cord. CONCLUSIONS: Following SCI, Muse cells in CL2020 can reach the injured spinal cord after intravenous administration and differentiate into neuronal cells. Muse cells in CL2020 facilitated nerve fiber preservation and exerted therapeutic potential for severe SCI.

Limitations of median nerve somatosensory evoked potential monitoring during carotid endarterectomy.

OBJECTIVE: Hypoperfusion during carotid artery cross-clamping (CC) for carotid endarterectomy (CEA) may result in the major complication of perioperative stroke. Median nerve somatosensory evoked potential (MNSSEP) monitoring, which is an established method for the prediction of cerebral ischemia, has low sensitivity in detecting such hypoperfusion. In this study the authors sought to explore the limitations of MNSSEP monitoring compared to tibial nerve somatosensory evoked potential (TNSSEP) monitoring for the detection of CC-related hypoperfusion. METHODS: The authors retrospectively analyzed data from patients who underwent unilateral CEA with routine shunt use. All patients underwent preoperative magnetic resonance angiography and were monitored for intraoperative cerebral ischemia by using MNSSEP, TNSSEP, and carotid stump pressure during CC. First, the frequency of MNSSEP and TNSSEP changes during CC were analyzed. Subsequently, variables related to stump pressure were determined by using linear analysis and those related to each of the somatosensory evoked potential (SSEP) changes were determined by using logistic regression analysis. RESULTS: A total of 94 patients (mean age 74 years) were included in the study. TNSSEP identified a greater number of SSEP changes during CC than MNSSEP (20.2% vs 11.7%; p < 0.05). Linear regression analysis demonstrated that hypoplasia of the contralateral proximal segment of the anterior cerebral artery (A1 hypoplasia) (p < 0.01) and hypoplasia of the ipsilateral precommunicating segment of the posterior cerebral artery (P1 hypoplasia) (p = 0.02) independently and negatively correlated with stump pressure. Both contralateral A1 hypoplasia (OR 26.25, 95% CI 4.52-152.51) and ipsilateral P1 hypoplasia (OR 8.75, 95% CI 1.83-41.94) were independently related to the TNSSEP changes. However, only ipsilateral P1 hypoplasia (OR 8.76, 95% CI 1.61-47.67) was independently related to MNSSEP changes. CONCLUSIONS: TNSSEP monitoring appears to be superior to MNSSEP in detecting CC-related hypoperfusion. Correlation with stump pressure and SSEP changes indicates that TNSSEP, and not MNSSEP monitoring, is a reliable indicator of cerebral ischemia in the territory of the anterior cerebral artery.

Patient with Recurrent Anterior Cerebral Artery Dissecting Aneurysm After Stent-Assisted Coil Embolization Successfully Treated with A3-A3 Anastomosis.

BACKGROUND: With recent advances in endovascular devices and techniques, the use of endovascular treatment has been reported for intracranial dissecting aneurysms. However, the efficacy of this endovascular approach for intracranial dissection is still unknown. We report the case of a patient with a recurrent anterior cerebral artery (ACA) dissecting aneurysm after endovascular treatment. CASE DESCRIPTION: A 67-year-old woman underwent stent-assisted coil embolization for a ruptured ACA dissecting aneurysm of the left A2 segment. Aneurysmal dilatation was completely occluded after embolization. However, follow-up angiography 40 days after treatment showed compaction of the coil mass and reenlargement of the aneurysm. Open surgery was performed, considering the risk of rebleeding from the recurrent dissecting aneurysm. A3-A3 anastomosis followed by trapping of the coiled aneurysm along with the stent was successfully performed through the interhemispheric approach. The postoperative course was uneventful, and angiography 6 months after surgery revealed disappearance of the aneurysm and patency of the A3-A3 anastomosis. CONCLUSIONS: Stent-assisted coil embolization for an ACA dissecting aneurysm may not be curative, and the coiled aneurysm may recur within a short time period. Microsurgical bypass trapping can be considered as the alterative or salvage treatment because of curability. Revascularization surgery, such as A3-A3 anastomosis, should be performed before trapping to avoid ischemic complications.

Chemoenzymatic synthesis, characterization, and application of glycopolymers carrying lactosamine repeats as entry inhibitors against influenza virus infection.

To control interspecies transmission of influenza viruses, it is essential to elucidate the molecular mechanisms of the interaction of influenza viruses with sialo-glycoconjugate receptors expressed on different host cells. Competitive inhibitors containing mimetic receptor carbohydrates that prevent virus entry may be useful tools to address such issues. We chemoenzymatically synthesized and characterized the glycopolymers that were carrying terminal 2,6-sialic acid on lactosamine repeats as influenza virus inhibitors. In vitro and in vivo infection experiments using these glycopolymers demonstrated marked differences in inhibitory activity against different species of viruses. Human viruses, including clinically isolated strains, were consistently inhibited by glycopolymers carrying lactosamine repeats with higher activity than those containing a single lactosamine. A swine virus also showed the same recognition properties as those from human hosts. In contrast, avian and equine viruses were not inhibited by any of the glycopolymers examined carrying single, tandem, or triplet lactosamine repeats. Hemagglutination inhibition and solid-phase binding analyses indicated that binding affinity of glycopolymers with influenza viruses contributes dominantly to the inhibitory activity against viral infection. Sequence analysis and molecular modeling of human viruses indicated that specific amino acid substitutions on hemagglutinin may affect binding affinity of glycopolymers carrying lactosamine repeats with viruses. In conclusion, glycopolymers carrying lactosamine repeats of different lengths are useful to define molecular mechanisms of virus recognition. The core carbohydrate portion as well as sialyl linkages on the receptor glycoconjugate may affect host cell recognition of human and swine viruses.