Clinical Features and Treatment of Patients Infected With SARS-CoV-2 Omicron Variant While Hospitalized Due to Stroke: A Single Center Study in Japan.

BACKGROUND AND OBJECTIVE: In December 2019, COVID-19 spread rapidly across the globe. Throughout the pandemic, SARS-CoV-2 repeatedly mutated, transitioning from the alpha variant to the omicron variant. The severity and mortality of COVID-19 have been linked to age, sex, and the presence of underlying diseases (respiratory, cerebrovascular, cardiovascular, metabolic, and immune diseases, as well as cancer). The clinical features of patients infected with COVID-19 following a stroke, however, are fully unknown. Therefore, it is significant to explore the appropriate treatment for these patients based on their clinical features. METHODS: Of the 6175 patients who visited Asahi Hospital (Tokyo, Japan) between November 2022 and February 2023, 206 were admitted. Of these 206 patients, the 44 that contracted COVID-19 while hospitalized for strokes were retrospectively analyzed. RESULTS: Six (13.6%) of these patients died; four expired due to coagulopathy associated with ischemic heart failure and recurrent ischemic cerebrovascular disease. The mean D-dimer level increased to 3.53 in the deceased patients, while it was 1.64 in all patients. The platelet count was low in three of the deceased patients, while it was high in two patients. The severity of COVID-19 was significantly correlated with a high modified Rankin Scale (mRS) score and a high National Institute of Health Stroke Scale (NIHSS) score. The timing of vaccination is inversely correlated with COVID-19 severity. CONCLUSION: Patients with COVID-19 after a stroke have high mortality rates due to coagulopathy. Stroke patients with high mRS scores and high NIHSS scores are more likely to develop severe COVID-19. Anticoagulant therapy should be administered to COVID-19 patients with high mRS scores following a stroke.

Role of SOCS and VHL Proteins in Neuronal Differentiation and Development.

The basic helix-loop-helix factors play a central role in neuronal differentiation and nervous system development, which involve the Notch and signal transducer and activator of transcription (STAT)/small mother against decapentaplegic signaling pathways. Neural stem cells differentiate into three nervous system lineages, and the suppressor of cytokine signaling (SOCS) and von Hippel-Lindau (VHL) proteins are involved in this neuronal differentiation. The SOCS and VHL proteins both contain homologous structures comprising the BC-box motif. SOCSs recruit Elongin C, Elongin B, Cullin5(Cul5), and Rbx2, whereas VHL recruits Elongin C, Elongin B, Cul2, and Rbx1. SOCSs form SBC-Cul5/E3 complexes, and VHL forms a VBC-Cul2/E3 complex. These complexes degrade the target protein and suppress its downstream transduction pathway by acting as E3 ligases via the ubiquitin-proteasome system. The Janus kinase (JAK) is the main target protein of the E3 ligase SBC-Cul5, whereas hypoxia-inducible factor is the primary target protein of the E3 ligase VBC-Cul2; nonetheless, VBC-Cul2 also targets the JAK. SOCSs not only act on the ubiquitin-proteasome system but also act directly on JAKs to suppress the Janus kinase-signal transduction and activator of transcription (JAK-STAT) pathway. Both SOCS and VHL are expressed in the nervous system, predominantly in brain neurons in the embryonic stage. Both SOCS and VHL induce neuronal differentiation. SOCS is involved in differentiation into neurons, whereas VHL is involved in differentiation into neurons and oligodendrocytes; both proteins promote neurite outgrowth. It has also been suggested that the inactivation of these proteins may lead to the development of nervous system malignancies and that these proteins may function as tumor suppressors. The mechanism of action of SOCS and VHL involved in neuronal differentiation and nervous system development is thought to be mediated through the inhibition of downstream signaling pathways, JAK-STAT, and hypoxia-inducible factor-vascular endothelial growth factor pathways. In addition, because SOCS and VHL promote nerve regeneration, they are expected to be applied in neuronal regenerative medicine for traumatic brain injury and stroke.

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.

Cerebral Infarction Due to Occlusion of Main Trunk of Middle Cerebral Artery in Patient with Accessory Middle Cerebral Artery.

The existence of an accessory middle cerebral artery (AMCA) usually has no pathological significance. Three patients developed cerebral infarction due to thromboembolic occlusion of the main trunk of the middle cerebral artery (MCA). In these patients, AMCA originating from the anterior cerebral artery was intact, and ran to the lateral side along the main MCA. Emergency endovascular treatment to remove the thrombus in the main MCA was performed, and MCA was recanalized. In one patient, the main MCA re-occluded and cerebral infarction developed on the next day. The diameter of AMCA is commonly smaller than that of the main MCA. Therefore, volume of ischemic region depends on the collateral blood flow to the left MCA territory by AMCA. Once an anomalous MCA is detected in a patient with cerebral infarction involving the MCA territory, close examinations to assess the anatomy of both the main and anomalous MCA are mandatory.

Superficial siderosis and nonobstructive hydrocephalus due to subependymoma in the ventricle: An illustrative case report.

Background: Intraventricular tumors can generally result in obstructive hydrocephalus as they grow. Rarely, however, some intraventricular tumors develop superficial siderosis (SS) and trigger hydrocephalus, even though the tumor has hardly grown. Here, we present an illustrative case of SS and nonocclusive hydrocephalus caused by subependymoma of the lateral ventricles. Case Description: A 78-year-old man with an intraventricular tumor diagnosed 7 years ago had been suffering from gait disturbance for 2 years. He also developed cognitive impairment. Intraventricular tumors showed little growth on annual magnetic resonance imaging (MRI). MRI T2-star weighted images (T2*WI) captured small intratumoral hemorrhages from the beginning of the follow-up. Three years before, at the same time as the onset of ventricular enlargement, T2*WI revealed low intensity in the whole tumor and cerebral surface. Subsequent follow-up revealed that this hemosiderin deposition had spread to the brain stem and cerebellar surface, and the ventricles had expanded further. Cerebrospinal fluid (CSF) examination revealed xanthochromia. The tumor was completely removed en bloc. Histopathological findings were consistent with those of subependymoma. Although CSF findings improved, SS and hydrocephalus did not improve. Therefore, the patient underwent a lumboperitoneal shunt for CSF diversion after tumor resection. Conclusion: Some intraventricular tumors cause SS and nonobstructive hydrocephalus due to microbleeding, even in the absence of tumor growth. T2*WI and, if necessary, timely CSF examination can allow identification of presymptomatic SS. This follow-up strategy may provide a favorable course by facilitating early intervention in patients with intraventricular lesions, not just subependymomas.

Morphological Change of Cerebral Aneurysm with Possible Pseudoaneurysm at A2/3 of the Anterior Cerebral Artery on Three-dimensional Computed Tomographic Angiography.

Intracranial pseudoaneurysm formation due to a ruptured nontraumatic aneurysm is rare. We describe a case of ruptured aneurysm, which showed morphological change on radiological examinations. An 83-year-old woman developed subarachnoid hemorrhage (SAH) with ventricular rupture and intracerebral hematoma in the corpus callosum. Contrast-enhanced computed tomography (CE-CT) demonstrated an aneurysm at the right A2/3 junction of the anterior cerebral artery. CE-CT repeated 17 h after the initial one showed shortening of the lesion on both three-dimensional and raw images. The aneurysm was surgically clipped. In cases of SAH with a hematoma or thick SAH, there is a possibility that a pseudoaneurysm will form at the tip of the true aneurysm in an adjacent thrombus or existence of intraluminal thrombus. The morphology may change during the period between initial radiological evaluation and the operation in these cases. We should be aware that the intraoperative findings or subsequent radiological findings might be different from those observed on preoperative radiological examinations.

Incision Edge "Lifting Method" in Cerebral Bypass Surgery: A Novel Optional Technique for Narrow or Thin Recipient Arteries.

BACKGROUND: Cerebral bypass surgery, such as the superficial temporal artery-middle cerebral artery bypass, is one of the essential procedures for cerebral revascularization. However, very narrow or thin blood vessels will increase the risk of anastomotic problems, such as occurs in Moyamoya disease. For such vessels, we have devised a "lifting method" in the recipient arteriotomy. In the present study, we have introduced this novel optional technique and evaluated its effects. METHODS: The lifting method is a procedure of lifting the incision edge of a linear incision on the recipient vessel to widen the ostium. We attempted the lifting method in 23 consecutive patients (41 arteries) and, as a historical control, compared the results with those from the conventional method in 25 consecutive patients (37 arteries) for the previous 3 years. We compared patient age, years of surgical experience, recipient vessel diameter, anastomotic events, and final patency. As a subanalysis, the same evaluations were performed separately for patients with Moyamoya disease. Furthermore, the time required for the lifting procedure was measured retrospectively. RESULTS: The incidence of anastomotic events with the conventional method was 13.5% overall and 19% in those with Moyamoya disease. No adverse events occurred with the lifting method (P < 0.05). No statistically significant differences were found for the other factors, including final patency between the 2 groups. The time required for the lifting procedure averaged 1 minute, 15 seconds. CONCLUSIONS: Use of the lifting method widens and secures the ostium in a recipient vessel and greatly facilitates operability. We have found it to be a foolproof method enabling safe and reliable anastomosis even with narrow or thin vessels.