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Stroke is the most prevalent cardiovascular disease worldwide, and is still one of the leading causes of death and disability. Stem cell-based therapy is actively being investigated as a new potential treatment for certain neurological disorders, including stroke. Various types of cells, including bone marrow mononuclear cells, bone marrow mesenchymal stem cells, dental pulp stem cells, neural stem cells, inducible pluripotent stem cells, and genetically modified stem cells have been found to improve neurological outcomes in animal models of stroke, and there are some ongoing clinical trials assessing their efficacy in humans. In this review, we aim to summarize the recent advances in cell-based therapies to treat stroke.

Stroke-associated infection (SAI) is a common and serious complication of stroke. This study aimed to assess the effects of SAI on patient mortality and functional outcome at 3 months after stroke onset. We retrospectively analyzed 809 consecutive patients with acute stroke (517 men and 292 women; median age, 72 years) who were admitted to our department between September 2014 and June 2016. SAI was defined as an infection diagnosed during the hospitalization period. Poor outcome was defined as a modified Rankin Scale (mRS) score of 3–5 or death (mRS score of 6). The effect of SAI on functional outcome was evaluated using a multivariate logistic regression analysis. SAI occurred in 169 patients (20.9%); of these, 106 (62.7%) had pneumonia, 23 (13.6%) had a urinary-tract infection, and 40 (23.7%) had other types of infection. Patients with SAI were older, more likely to be female, had lower body mass indices, had higher stroke severity, and were more likely to have atrial fibrillation and a history of ischemic heart disease than patients without SAI. Poor functional outcome and mortality were more common in patients with SAI than in patients without SAI (poor functional outcome 41.8 vs. 4.8%, mortality 24.3 vs. 3.9%, respectively). After adjusting for age, sex, stroke severity, and various comorbidities, SAI was independently associated with poor functional outcome [odds ratio (OR) 6.88; 95% confidence interval (CI) 3.72–12.73] and mortality (OR 4.45, 95% CI 2.27–8.72) at 3 months after stroke onset. Our results suggest that SAI during the hospitalization period is independently associated with 3-month poor functional outcome and mortality.

ObjectiveSeveral studies have investigated the predictors of functional outcome in patients with ischemic stroke after mechanical thrombectomy (MT). However, it is not clear whether pre-stroke cognitive (PSC) impairment is associated with the functional outcome of patients treated with MT.MethodsWe enrolled 113 patients treated with MT from December 2016 to November 2018. PSC was evaluated using the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). Poor outcome was defined as a modified Rankin Scale score of 3–6. We compared the clinical characteristics between the groups with poor outcome (n = 61) and good outcome (n = 52) to determine if PSC could be a predictor of poor outcome.ResultsIQCODE was significantly higher in the group with poor outcome than good outcome (3.34 vs. 3.13, P = 0.017). Moreover, the following metrics differed between those two groups: age (75.9 vs. 71.6 years old, P = 0.010), the percentage of females (39.9% vs. 17.3%, P = 0.009), the percentage with hypertension (72.1% vs. 44.2%, P = 0.003), National Institutes of Health Stroke Scale (NIHSS) score on admission (20 vs. 11, P < 0.001), and no successful recanalization (24.5% vs. 7.7%; P = 0.025). Multivariable logistic regression analysis demonstrated that PSC (OR: 5.59; 95% CI: 1.55–23.47), history of hypertension (OR: 3.33; 95% CI: 1.29–9.11), no successful recanalization (OR: 5.51; 95% CI: 1.49–25.03), and NIHSS score on admission (OR: 1.14; 95% CI: 1.07–1.22) were associated with poor outcome 3 months after stroke onset.ConclusionsPSC was significantly and independently associated with poor functional outcome in patients treated with MT.

As the goal of mechanical thrombectomy is shifting toward mTICI-3 rather than mTICI-2b, we sought to clarify the limitation of the effect of mTICI-3. A post-hoc analysis of a registry of large-vessel occlusion stroke from 46 centers was conducted. Among 2,420 registered patients, 725 patients with anterior circulation occlusion who achieved successful reperfusion were analyzed. We compared outcomes between patients with mTICI-3 and mTICI-2b, and investigated how the effect of mTICI-3 changed according to baseline characteristics and time course. The proportion of patients with favorable outcomes (mRS 0–2 at day 90) was higher among patients with mTICI-3 compared to those with mTICI-2b (adjusted OR, 2.10; 95% CI, 1.49–2.97). There was no heterogeneity in the effect of mTICI-3 with respect to age, neurological deficit, alteplase use, occluded vessels, or infarct size. mTICI-3 was associated with favorable outcomes when the puncture-to-reperfusion time was <80 minutes (adjusted OR, 2.28; 95% CI, 1.52–3.41), but not when the puncture-to-reperfusion time was ≥80 minutes. A significant heterogeneity was found in the effect of mTICI-3 reperfusion across the puncture-to-reperfusion time subgroups (P for interaction = 0.025). Until when operators should continue the procedure after mTICI-2b has been achieved, needs to be studied.

γδ T cells facilitate the CD4 + T helper 1 (Th1) cell response against Plasmodium infection by activating conventional dendritic cells (cDCs), although the underlying mechanism remains elusive. Our study revealed that γδ T cells promote the complete maturation and production of interleukin-12 and CXCR3-ligands specifically in type 1 cDCs (cDC1), with minimal impact on cDC2 and monocyte derived DCs (Mo-DCs). During the initial infection phase, γδ T cell activation and temporal accumulation in the splenic white pulp, alongside cDC1, occur via CCR7-signaling. Furthermore, cDC1/γδ T cell interactions in the white pulp are amplified through CXCR3 signaling in γδ T cells, optimizing Th1 cell priming by cDC1. We also demonstrated how transitional Th1 cells arise in the white pulp before establishing their presence in the red pulp as fully differentiated Th1 cells. Additionally, we elucidate the reciprocal activation between γδ T cells and cDC1s. These findings suggest that Th1 cell priming is orchestrated by this reciprocal activation in the splenic white pulp during the early phase of blood-stage Plasmodium infection.

Interleukin (IL)-10 is a contributing factor to neuroprotection of mesenchymal stem cell (MSC) transplantation after ischemic stroke. Our aim was to increase therapeutic effects by combining MSCs and ex vivo IL-10 gene transfer with an adeno-associated virus (AAV) vector using a rat transient middle cerebral artery occlusion (MCAO) model. Sprague-Dawley rats underwent 90 min MCAO followed by intravenous administration of MSCs alone or IL-10 gene-transferred MSCs (MSC/IL-10) at 0 or 3 hr after ischemia reperfusion. Infarct lesions, neurological deficits, and immunological analyses were performed within 7 days after MCAO. 0-hr transplantation of MSCs alone and MSC/IL-10 significantly reduced infarct volumes and improved motor function. Conversely, 3-hr transplantation of MSC/IL-10, but not MSCs alone, significantly reduced infarct volumes (p < 0.01) and improved motor function (p < 0.01) compared with vehicle groups at 72 hr and 7 days after MCAO. Immunological analysis showed that MSC/IL-10 transplantation significantly inhibits microglial activation and pro-inflammatory cytokine expression compared with MSCs alone. Moreover, overexpressing IL-10 suppressed neuronal degeneration and improved survival of engrafted MSCs in the ischemic hemisphere. These results suggest that overexpressing IL-10 enhances the neuroprotective effects of MSC transplantation by anti-inflammatory modulation and thereby supports neuronal survival during the acute ischemic phase.

The ankle-brachial index (ABI), brachial-ankle pulse wave velocity (baPWV) and cardio-ankle vascular index (CAVI) are surrogate markers of arteriosclerosis. However, their roles in patients with acute ischemic stroke remain unclear. From October 2003 to September 2011, we enrolled patients with arteriosclerotic ischemic stroke (AIS) exhibiting large infarcts attributed to large-artery atherosclerosis (LAA) or deep subcortical infarcts (mainly lacunar infarcts) attributed to small-artery disease (SAD). Outpatients without a history of stroke served as controls (CTL). We divided the study period into two terms and assessed patients using two different oscillometric devices (Form PWV/ABI, Omron Colin; and VaSera VS-1500, Fukuda Denshi) in each term. One-way analysis of variance and age- and sex-adjusted analysis of covariance were used to compare the three groups. We analyzed 842 patients. The ABI was significantly lower in the LAA (n = 102) group than in the SAD (n = 280) and CTL (n = 460) groups. The baPWV was significantly higher in the LAA and SAD groups than in the CTL group. The CAVI gradually increased in the order of CTL, SAD and LAA. The cutoff values of baPWV and CAVI for detection of AIS were 18.3 m s(-1) (odds ratio (OR): 6.09, 95% confidence interval (CI): 3.97-9.62, P < 0.01) and 9.5 (OR: 1.44, 95% CI: 1.24-1.70, P < 0.001), respectively. Among the three indicators, a lower ABI indicated advanced atherosclerosis associated with LAA, and an increased baPWV more closely indicated AIS. An increased CAVI may indicate the degree of vessel stiffness due to arteriosclerosis.

Perampanel inhibits AMPA-induced increases in intracellular Ca2+, with no obvious effects against kainate- and NMDA-induced Ca2+ responses, and has a much longer terminal half-life (approximately 105 hours) in human, as well as good bioavailability. [...]perampanel may have advantages, since a less-frequent dosing regimen could be possible, resulting in a smoother drug concentration profile and potentially improved tolerability and fewer adverse events (Hanada et al., 2011). Phosphorylated Akt directly influences glycogen synthase kinase-3b, Bcl-2-associated apoptosis promoter/Bcl-2, caspase-9, IκB kinase, and Forkhead-related transcription factor 1. [...]strategies that involve suppressing oxidative and inflammatory injury of brain cells as well as upregulating the PI3K/Akt pathway could have a marked impact in improving the outcomes of cerebral ischemia. Interestingly, the protective effect might be mediated by preservation of claudin-5 protein expression, but does not involve glutamate receptor expression and intracellular Ca2+ regulation (Lv et al., 2016). [...]perampanel reduced apoptosis of oligodendrocyte precursor cells, accompanied with reduction of microglia infiltration and production of proinflammatory cytokines, including TNF-α, IL-1β, and IL-6, and enhanced oligodendrocyte precursor cell maturation. [...]in a previous study using a rat cortical impact model for TBI, oral perampanel administration (5 mg/kg) improved spatial working memory in the Morris water-maze test (Chen et al., 2017).

Background: Increasing evidence suggests improved time metrics leading to better clinical outcomes when stroke patients with suspected large vessel occlusion (LVO) are transferred directly to the angiography suite (DTAS) compared with cross-sectional imaging followed by transfer to the angiography suite. We performed a systematic review and meta-analysis on the efficacy and safety of DTAS approaches. Methods: We searched Embase, Medline, Scopus, and clinicaltrials.gov for studies comparing outcomes of DTAS and conventional triage. Eligible studies were assessed for risk of bias. We performed a random-effects meta-analysis on the differences of median door-to-groin and door-to-reperfusion times between intervention and control group. Secondary outcomes included good outcome at 90 days (modified Rankin Scale ⩽ 2) rate of symptomatic intracranial hemorrhage (sICH) and mortality within 90 days. Results: Eight studies (one randomized, one cluster-randomized trial and six observational studies) with 1938 patients were included. Door-to-groin and door-to-reperfusion times in the intervention group were on median 29.0 min [95% confidence interval (CI): 14.3–43.6; p < 0.001] and 32.1 min (95% CI: 15.1–49.1; p < 0.001) shorter compared with controls. Prespecified subgroup analyses for transfer (n = 1753) and mothership patients (n = 185) showed similar reductions of the door-to-groin and door-to-reperfusion times in response to the intervention. The odds of good outcome did not differ significantly between both groups but were numerically higher in the intervention group (odds ratio: 1.38, 95% CI: 0.97–1.95; p = 0.07). There was no significant difference for mortality and sICH between the groups. Conclusion: DTAS approaches for the triage of suspected LVO patients led to a significant reduction in door-to-groin and door-to-reperfusion times but an effect on functional outcome was not detected. The subgroup analysis showed similar results for transfer and mothership patients. Registration: This study was registered in PROSPERO (CRD42020213621).

Background: Autoimmune autonomic ganglionopathy (AAG) is characterized by serum autoantibodies against the ganglionic acetylcholine receptor (gAChR). Immunomodulatory treatments may alleviate AAG symptoms, but the most appropriate treatment strategy is unclear. Objective: This study aimed to confirm the effectiveness of treatments, particularly immunotherapy, in patients with seropositive AAG in Japan, as well as to determine the most effective treatment and the best assessment method for clinical response to treatment. Methods: We collected data from a previous cohort study of patients with seropositive AAG. The clinical autonomic and extra-autonomic symptoms were objectively counted and subjectively assessed using the modified Composite Autonomic Symptom Score. Post-treatment changes in the gAChR antibody level were evaluated. Results: Thirty-one patients received immunotherapy. Among them, 19 patients received intravenous methylprednisolone; 27, intravenous immunoglobulin; 3, plasma exchange; 18, oral steroids; 2, tacrolimus; 1, cyclosporine; and 1, mycophenolate mofetil. Patients who received immunotherapy showed improvements in the total number of symptoms (from 6.2 ± 2.0 to 5.1 ± 2.0) and modified Composite Autonomic Symptom Score (from 37.4 ± 15.3 to 26.6 ± 12.8). Orthostatic intolerance, sicca, and gastrointestinal symptoms were ameliorated by immunotherapy. Immunotherapy decreased the antibody levels (gAChRα3 antibodies, from 2.2 ± 0.4 to 1.9 ± 0.4, p = 0.08; gAChRβ4 antibodies, from 1.6 ± 0.1 to 1.0 ± 0.2, p = 0.002), but antibody levels increased in 10 patients despite immunotherapy. The rate of improvement in the total number of symptoms was higher in patients with combined therapy than in patients with non-combined therapy (70.7% vs 28.6%). Conclusions: The scores in many items on the rating scale decreased after immunotherapy in patients with seropositive AAG, particularly in the combined immunotherapy group. However, more accurate assessment scales for clinical symptoms and multicenter randomized, placebo-controlled prospective studies are warranted to establish future treatment strategies.