Effectiveness of endovascular treatment for in-hospital stroke vs. community-onset stroke: a propensity score-matched analysis.

BACKGROUND: The effectiveness of endovascular treatment for in-hospital stroke remains debatable. We aimed to compare the outcomes between patients with in-hospital stroke and community-onset stroke who received endovascular treatment. METHODS: This prospective registry-based cohort study included consecutive patients who underwent endovascular treatment from January 2013 to December 2022 and were registered in the Selection Criteria in Endovascular Thrombectomy and Thrombolytic Therapy study and Yonsei Stroke Cohort. Functional outcomes at day 90, radiological outcomes, and safety outcomes were compared between the in-hospital and community-onset groups using logistic regression and propensity score-matched analysis. RESULTS: Of 1,219 patients who underwent endovascular treatment, 117 (9.6%) had in-hospital stroke. Patients with in-hospital onset were more likely to have a pre-stroke disability and active cancer than those with community-onset. The interval from the last known well to puncture was shorter in the in-hospital group than in the community-onset group (155 vs. 355 min, p<0.001). No significant differences in successful recanalization or safety outcomes were observed between the groups; however, the in-hospital group exhibited worse functional outcomes and higher mortality at day 90 than the community-onset group (all p<0.05). After propensity score matching including baseline characteristics, functional outcomes after endovascular treatment did not differ between the groups (OR: 1.19, 95% CI 0.78-1.83, p=0.4). Safety outcomes did not significantly differ between the groups. CONCLUSION: Endovascular treatment is a safe and effective treatment for eligible patients with in-hospital stroke. Our results will help physicians in making decisions when planning treatment and counseling caregivers or patients.

Improvement in Delivery of Ischemic Stroke Treatments but Stagnation of Clinical Outcomes in Young Adults in South Korea.

BACKGROUND: There is limited information on the delivery of acute stroke therapies and secondary preventive measures and clinical outcomes over time in young adults with acute ischemic stroke. This study investigated whether advances in these treatments improved outcomes in this population. METHODS: Using a prospective multicenter stroke registry in Korea, young adults (aged 18-50 years) with acute ischemic stroke hospitalized between 2008 and 2019 were identified. The observation period was divided into 4 epochs: 2008 to 2010, 2011 to 2013, 2014 to 2016, and 2017 to 2019. Secular trends for patient characteristics, treatments, and outcomes were analyzed. RESULTS: A total of 7050 eligible patients (mean age, 43.1; men, 71.9%) were registered. The mean age decreased from 43.6 to 42.9 years (Ptrend=0.01). Current smoking decreased, whereas obesity increased. Other risk factors remained unchanged. Intravenous thrombolysis and mechanical thrombectomy rates increased over time from 2008 to 2010 to 2017 to 2019 (9.5%-13.8% and 3.2%-9.2%, respectively; Ptrend<0.01). Door-to-needle time improved (Ptrend <.001), but onset-to-door and door-to-puncture times remained constant. Secondary prevention, including dual antiplatelets for noncardioembolic minor stroke (26.7%-47.0%), direct oral anticoagulants for atrial fibrillation (0.0%-56.2%), and statins for large artery atherosclerosis (76.1%-95.3%) increased (Ptrend<0.01). Outcome data were available from 2011. One-year mortality (2.5% in 2011-2013 and 2.3% in 2017-2019) and 3-month modified Rankin Scale scores 0 to 1 (68.3%-69.1%) and 0 to 2 (87.6%-86.2%) remained unchanged. The 1-year stroke recurrence rate increased (4.1%-5.5%; Ptrend=0.04), although the difference was not significant after adjusting for sex and age. CONCLUSIONS: Improvements in the delivery of acute stroke treatments did not necessarily lead to better outcomes in young adults with acute ischemic stroke over the past decade, indicating a need for further progress.

TAZ stimulates exercise-induced muscle satellite cell activation via Pard3-p38 MAPK-TAZ signalling axis.

BACKGROUND: Exercise stimulates the activation of muscle satellite cells, which facilitate the maintenance of stem cells and their myogenic conversion during muscle regeneration. However, the underlying mechanism is not yet fully understood. This study shows that the transcriptional co-activator with PDZ-binding motif (TAZ) stimulates muscle regeneration via satellite cell activation. METHODS: Tazf/f mice were crossed with the paired box gene 7 (Pax7)creERT2 mice to generate muscle satellite cell-specific TAZ knockout (sKO) mice. Mice were trained in an endurance exercise programme for 4 weeks. Regenerated muscles were harvested and analysed by haematoxylin and eosin staining. Muscle tissues were also analysed by immunofluorescence staining, immunoblot analysis and quantitative reverse transcription PCR (qRT-PCR). For the in vitro study, muscle satellite cells from wild-type and sKO mice were isolated and analysed. Mitochondrial DNA was quantified by qRT-PCR using primers that amplify the cyclooxygenase-2 region of mitochondrial DNA. Quiescent and activated satellite cells were stained with MitoTracker Red CMXRos to analyse mitochondria. To study the p38 mitogen-activated protein kinase (MAPK)-TAZ signalling axis, p38 MAPK was activated by introducing the MAPK kinase 6 plasmid into satellite cells and also inhibited by treatment with the p38 MAPK inhibitor, SB203580. RESULTS: TAZ interacts with Pax7 to induce Myf5 expression and stimulates mammalian target of rapamycin signalling for satellite cell activation. In sKO mice, TAZ depletion reduces muscle satellite cell number by 38% (0.29 ± 0.073 vs. 0.18 ± 0.034, P = 0.0082) and muscle regeneration. After muscle injury, TAZ levels (2.59-fold, P < 0.0001) increase in committed cells compared to self-renewing cells during asymmetric satellite cell division. Mechanistically, the polarity protein Pard3 induces TAZ (2.01-fold, P = 0.008) through p38 MAPK, demonstrating that the p38 MAPK-TAZ axis is important for muscle regeneration. Physiologically, endurance exercise training induces muscle satellite cell activation and increases muscle fibre diameter (1.33-fold, 43.21 ± 23.59 vs. 57.68 ± 23.26 µm, P = 0.0004) with increased TAZ levels (1.76-fold, P = 0.017). However, sKO mice had a 39% reduction in muscle satellite cell number (0.20 ± 0.03 vs. 0.12 ± 0.02, P = 0.0013) and 24% reduction in muscle fibre diameter compared to wild-type mice (61.07 ± 23.33 vs. 46.60 ± 24.29 µm, P = 0.0006). CONCLUSIONS: Our results demonstrate a novel mechanism of TAZ-induced satellite cell activation after muscle injury and exercise, suggesting that activation of TAZ in satellite cells may ameliorate the muscle ageing phenotype and may be an important target protein for the drug development in sarcopenia.

Regulation of myogenesis and adipogenesis by the electromagnetic perceptive gene.

Obesity has been increasing in many regions of the world, including Europe, USA, and Korea. To manage obesity, we should consider it as a disease and apply therapeutic methods for its treatment. Molecular and therapeutic approaches for obesity management involve regulating biomolecules such as DNA, RNA, and protein in adipose-derived stem cells to prevent to be fat cells. Multiple factors are believed to play a role in fat differentiation, with one of the most effective factor is Ca2+. We recently reported that the electromagnetic perceptive gene (EPG) regulated intracellular Ca2+ levels under various electromagnetic fields. This study aimed to investigate whether EPG could serve as a therapeutic method against obesity. We confirmed that EPG serves as a modulator of Ca2+ levels in primary adipose cells, thereby regulating several genes such as CasR, PPARγ, GLU4, GAPDH during the adipogenesis. In addition, this study also identified EPG-mediated regulation of myogenesis that myocyte transcription factors (CasR, MyoG, MyoD, Myomaker) were changed in C2C12 cells and satellite cells. In vivo experiments carried out in this study confirmed that total weight/ fat/fat accumulation were decreased and lean mass was increased by EPG with magnetic field depending on age of mice. The EPG could serve as a potent therapeutic agent against obesity.

Prevalence of Mutations in Mendelian Stroke Genes in Early Onset Stroke Patients.

OBJECTIVE: Heritability of stroke is assumed not to be low, especially in the young stroke population. However, most genetic studies have been performed in highly selected patients with typical clinical or neuroimaging characteristics. We investigated the prevalence of 15 Mendelian stroke genes and explored the relationships between variants and the clinical and neuroimaging characteristics in a large, unselected, young stroke population. METHODS: We enrolled patients aged ≤55 years with stroke or transient ischemic attack from a prospective, nationwide, multicenter stroke registry. We identified clinically relevant genetic variants (CRGVs) in 15 Mendelian stroke genes (GLA, NOTCH3, HTRA1, RNF213, ACVRL1, ENG, CBS, TREX1, ABCC6, COL4A1, FBN1, NF1, COL3A1, MT-TL1, and APP) using a customized, targeted next generation sequencing panel. RESULTS: Among 1,033 patients, 131 (12.7%) had 28 CRGVs, most frequently in RNF213 (n = 59), followed by ABCC6 (n = 53) and NOTCH3 (n = 15). The frequency of CRGVs differed by ischemic stroke subtypes (p < 0.01): the highest in other determined etiology (20.1%), followed by large artery atherosclerosis (13.6%). It also differed between patients aged ≤35 years and those aged 51 to 55 years (17.1% vs 9.3%, p = 0.02). Only 27.1% and 26.7% of patients with RNF213 and NOTCH3 variants had typical neuroimaging features of the corresponding disorders, respectively. Variants of uncertain significance (VUSs) were found in 15.4% patients. INTERPRETATION: CRGVs in 15 Mendelian stroke genes may not be uncommon in the young stroke population. The majority of patients with CRGVs did not have typical features of the corresponding monogenic disorders. Clinical implications of having CRGVs or VUSs should be explored. ANN NEUROL 2023;93:768-782.

Frequency, management, and outcomes of early neurologic deterioration due to stroke progression or recurrence.

OBJECTIVE: The frequency, management, and outcomes of early neurologic deterioration (END) after ischemic stroke specifically due to stroke progression or stroke recurrence have not been well delineated. MATERIALS AND METHODS: In a multicenter, nationwide registry, data on END due to stroke progression or recurrence confirmed by imaging were collected prospectively between January 2019 and July 2020. Patient characteristics, management strategies, and clinical outcomes were analyzed. RESULTS: Among 14,828 consecutive ischemic stroke patients, 1717 (11.6%) experienced END, including 1221 (8.2%) with END due to stroke progression (SP) or stroke recurrence (SR). Active management after END was implemented in 64.2% of patients. Active management strategies included volume expansion (29.2%), change in antithrombotic regimen (26.1%), induced hypertension (8.6%), rescue reperfusion therapy (6.8%), intracranial pressure lowering with hyperosmolar agents (1.5%), bypass surgery (0.6%), and hypothermia (0.1%). Active management strategies that varied with patient features included volume expansion and induced hypertension, used more often in large artery atherosclerosis and small vessel occlusion, and rescue endovascular thrombectomy, more common in other (dissection), cardioembolism, and large artery atherosclerosis. Active management was associated with higher rates of freedom from disability (modified Rankin Scale, mRS, 0-1; 24.3% vs. 16.6%) and functional independence (mRS, 0-2; 41.6% vs. 27.7%) at 3 months. CONCLUSION: END specifically due to stroke progression or recurrence occurs in 1 in 12 acute ischemic stroke patients. In this observational study, active management, undertaken in two-thirds of patients, was most often hemodynamic or antithrombotic and was associated with improved functional outcomes.

CD133-Src-TAZ signaling stimulates ductal fibrosis following DDC diet-induced liver injury.

Chronic liver injury follows inflammation and liver fibrosis; however, the molecular mechanism underlying fibrosis has not been fully elucidated. In this study, the role of ductal WW domain-containing transcription regulator 1 (WWTR1)/transcriptional coactivator with PDZ-binding motif (TAZ) was investigated after liver injury. Ductal TAZ-knockout (DKO) mice showed decreased liver fibrosis following a Diethyl 1,4-dihydro-2,4,6-trimethyl-3,5-pyridinedicarboxylate (DDC) diet compared to wild-type (WT) mice, as evidenced by decreased expression levels of fibrosis inducers, including connective tissue growth factor (Ctgf)/cellular communication network factor 2 (CCN2), cysteine-rich angiogenic inducer 61 (Cyr61/CCN1), and transforming growth factor beta 1 (Tgfb1), in DKO mice. Similarly, TAZ-knockout (KO) cholangiocyte organoids showed decreased expression of fibrosis inducers. Additionally, the culture supernatant of TAZ-KO cholangiocyte organoids decreased the fibrogenic gene expression in liver stellate cells. Further studies revealed that prominin 1 (PROM1/CD133) stimulated TAZ for fibrosis. After the administration of DDC diet, fibrosis was decreased in CD133-KO (CD133-KO) mice compared to that in WT mice. Similarly, CD133-KO cholangiocyte organoids showed decreased Ctgf, Cyr61, and Tgfb1 expression levels compared to WT cholangiocyte organoids. Mechanistically, CD133 stabilized TAZ via Src activation. Inhibition of Src decreased TAZ levels. Similarly, CD133-knockdown HCT116 cells showed decreased TAZ levels, but reintroduction of active Src recovered the TAZ levels. Taken together, our results suggest that TAZ facilitates liver fibrosis after a DDC diet via the CD133-Src-TAZ axis.

Central role of Prominin-1 in lipid rafts during liver regeneration.

Prominin-1, a lipid raft protein, is required for maintaining cancer stem cell properties in hepatocarcinoma cell lines, but its physiological roles in the liver have not been well studied. Here, we investigate the role of Prominin-1 in lipid rafts during liver regeneration and show that expression of Prominin-1 increases after 2/3 partial hepatectomy or CCl4 injection. Hepatocyte proliferation and liver regeneration are attenuated in liver-specific Prominin-1 knockout mice compared to wild-type mice. Detailed mechanistic studies reveal that Prominin-1 interacts with the interleukin-6 signal transducer glycoprotein 130, confining it to lipid rafts so that STAT3 signaling by IL-6 is effectively activated. The overexpression of the glycosylphosphatidylinsositol-anchored first extracellular domain of Prominin-1, which is the domain that binds to GP130, rescued the proliferation of hepatocytes and liver regeneration in liver-specific Prominin-1 knockout mice. In summary, Prominin-1 is upregulated in hepatocytes during liver regeneration where it recruits GP130 into lipid rafts and activates the IL6-GP130-STAT3 axis, suggesting that Prominin-1 might be a promising target for therapeutic applications in liver transplantation.

Impact of Renal Function on Short-Term Outcome After Reperfusion Therapy in Patients With Ischemic Stroke.

BACKGROUND: A high and low estimated glomerular filtration rate (eGFR) could affect outcomes after reperfusion therapy for ischemic stroke. This study aimed to determine whether renal function based on eGFR affects mortality risk in patients with ischemic stroke within 6 months following reperfusion therapy. METHODS: This prospective registry-based cohort study included 2266 patients who received reperfusion therapy between January 2000 and September 2019 and were registered in the SECRET (Selection Criteria in Endovascular Thrombectomy and Thrombolytic Therapy) study or the Yonsei Stroke Cohort. A high and low eGFR were based on the Chronic Kidney Disease Epidemiology Collaboration equation and defined, respectively, as the 5th and 95th percentiles of age- and sex-specific eGFR. Occurrence of death within 6 months was compared among the groups according to their eGFR such as low, normal, or high eGFR. RESULTS: Of the 2266 patients, 2051 (90.5%) had a normal eGFR, 110 (4.9%) a low eGFR, and 105 (4.6%) a high eGFR. Patients with high eGFR were younger or less likely to have hypertension, diabetes, or atrial fibrillation than the other groups. Active cancer was more prevalent in the high-eGFR group. During the 6-month follow-up, there were 24 deaths (22.9%) in the high-eGFR group, 37 (33.6%) in the low-eGFR group, and 237 (11.6%) in the normal-eGFR group. After adjusting for variables with P<0.10 in the univariable analysis, 6-month mortality was independently associated with high eGFR (hazard ratio, 2.22 [95% CI, 1.36-3.62]; P=0.001) and low eGFR (HR, 2.29 [95% CI, 1.41-3.72]; P=0.001). These associations persisted regardless of treatment modality or various baseline characteristics. CONCLUSIONS: High eGFR as well as low eGFR were independently associated with 6-month mortality after reperfusion therapy. Kidney function could be considered a prognostic factor in patients with ischemic stroke after reperfusion therapy.

Systemic inflammatory markers of persistent cerebral edema after aneurysmal subarachnoid hemorrhage.

BACKGROUND: Cerebral edema (CE) at admission is a surrogate marker of 'early brain injury' (EBI) after subarachnoid hemorrhage (SAH). Only recently has the focus on the changes in CE after SAH such as delayed resolution or newly developed CE been examined. Among several factors, an early systemic inflammatory response has been shown to be associated with CE. We investigate inflammatory markers in subjects with early CE which does not resolve, i.e., persistent CE after SAH. METHODS: Computed tomography scans of SAH patients were graded at admission and at 7 days after SAH for CE using the 0-4 'subarachnoid hemorrhage early brain edema score' (SEBES). SEBES ≤ 2 and SEBES ≥ 3 were considered good and poor grade, respectively. Serum samples from the same subject cohort were collected at 4 time periods (at < 24 h [T1], at 24 to 48 h [T2]. 3-5 days [T3] and 6-8 days [T4] post-admission) and concentration levels of 17 cytokines (implicated in peripheral inflammatory processes) were measured by multiplex immunoassay. Multivariable logistic regression analyses were step-wisely performed to identify cytokines independently associated with persistent CE adjusting for covariables including age, sex and past medical history (model 1), and additional inclusion of clinical and radiographic severity of SAH and treatment modality (model 2). RESULTS: Of the 135 patients enrolled in the study, 21 of 135 subjects (15.6%) showed a persistently poor SEBES grade. In multivariate model 1, higher Eotaxin (at T1 and T4), sCD40L (at T4), IL-6 (at T1 and T3) and TNF-α (at T4) were independently associated with persistent CE. In multivariate model 2, Eotaxin (at T4: odds ratio [OR] = 1.019, 95% confidence interval [CI] = 1.002-1.035) and possibly PDGF-AA (at T4), sCD40L (at T4), and TNF-α (at T4) was associated with persistent CE. CONCLUSIONS: We identified serum cytokines at different time points that were independently associated with persistent CE. Specifically, persistent elevations of Eotaxin is associated with persistent CE after SAH.

Stroke of Other Determined Etiology: Results From the Nationwide Multicenter Stroke Registry.

BACKGROUND: Stroke of other determined etiology (OE) includes patients with an uncommon cause of stroke. We described the general characteristics, management, and outcomes of stroke in OE and its subgroups. METHODS: This study is a retrospective analysis of a prospective, multicenter, nationwide registry, the Clinical Research Center for Stroke-Korea-National Institutes of Health registry. We classified OE strokes into 10 subgroups according to the literature and their properties. Each OE subgroup was compared according to clinical characteristics, sex, age strata, lesion locations, and management. Moreover, 1-year composites of stroke and all-cause mortality were investigated according to the OE subgroups. RESULTS: In total, 2119 patients with ischemic stroke with OE types (mean age, 55.6±16.2 years; male, 58%) were analyzed. In the Clinical Research Center for Stroke-Korea-National Institutes of Health registry, patients with OE accounted for 2.8% of all patients with stroke. The most common subtypes were arterial dissection (39.1%), cancer-related coagulopathy (17.3%), and intrinsic diseases of the arterial wall (16.7%). Overall, strokes of OE were more common in men than in women (58% versus 42%). Arterial dissection, intrinsic diseases of the arterial wall and stroke associated with migraine and drugs were more likely to occur at a young age, while disorders of platelets and the hemostatic system, cancer-related coagulopathy, infectious diseases, and hypoperfusion syndromes were more frequent at an old age. The composite of stroke and all-cause mortality within 1 year most frequently occurred in cancer-related coagulopathy, with an event rate of 71.8%, but least frequently occurred in stroke associated with migraine and drugs and arterial dissection, with event rates of 0% and 7.2%, respectively. CONCLUSIONS: This study presents the different characteristics, demographic findings, lesion locations, and outcomes of OE and its subtypes. It is characterized by a high proportion of arterial dissection, high mortality risk in cancer-related coagulopathy and an increasing annual frequency of cancer-related coagulopathy in patients with stroke of OE.

TAZ links exercise to mitochondrial biogenesis via mitochondrial transcription factor A.

Mitochondria are energy-generating organelles and mitochondrial biogenesis is stimulated to meet energy requirements in response to extracellular stimuli, including exercise. However, the mechanisms underlying mitochondrial biogenesis remain unknown. Here, we demonstrate that transcriptional coactivator with PDZ-binding motif (TAZ) stimulates mitochondrial biogenesis in skeletal muscle. In muscle-specific TAZ-knockout (mKO) mice, mitochondrial biogenesis, respiratory metabolism, and exercise ability were decreased compared to wild-type mice. Mechanistically, TAZ stimulates the translation of mitochondrial transcription factor A via Ras homolog enriched in brain (Rheb)/Rheb like 1 (Rhebl1)-mTOR axis. TAZ stimulates Rhebl1 expression via TEA domain family transcription factor. Rhebl1 introduction by adeno-associated virus or mTOR activation recovered mitochondrial biogenesis in mKO muscle. Physiologically, mKO mice did not stimulate exercise-induced mitochondrial biogenesis. Collectively, our results suggested that TAZ is a novel stimulator for mitochondrial biogenesis and exercise-induced muscle adaptation.

Intracranial non-occlusive intraluminal thrombus may indicate underlying etiology of large vessel occlusion in patients undergoing endovascular therapy.

BACKGROUND: The underlying etiology of intracranial non-occlusive intraluminal thrombus (iNOT) remains unknown. This study aimed to investigate whether the presence of iNOT can indicate the underlying etiology of large vessel occlusion (LVO) in patients undergoing endovascular therapy (EVT). METHODS: Among patients who underwent EVT at three comprehensive stroke centers, we included those with intracranial LVO in the anterior circulation. The presence of iNOT was determined by pretreatment DSA. We investigated the association between iNOT and intracranial atherosclerotic stenosis (ICAS) related LVO. RESULTS: Of 546 patients, 44 (8.1%) had iNOT. Patients with iNOT were younger, had less hypertension, atrial fibrillation, and a history of antiplatelet use. In addition, the involvement of the M1 segment of the middle cerebral artery (MCA) was more frequent. However, they had a lower National Institutes of Health Stroke Scale (NIHSS) score on admission and longer onset to recanalization time compared with patients with no iNOT. In a logistic regression model adjusting for age, sex, atrial fibrillation, smoking, prior antiplatelet and anticoagulant use, intravenous tissue plasminogen activator, NIHSS on admission, number of technical trials, intraprocedural re-occlusion, and the location of LVO (p<0.10 in the univariate analysis), the presence of iNOT was significantly associated with ICAS related LVO (adjusted OR 3.04; 95% CI 1.33 to 6.90; p=0.007). CONCLUSIONS: The presence of iNOT may reflect an underlying ICAS related LVO in patients undergoing EVT.

Immediate and Long-Term Outcomes of Reperfusion Therapy in Patients With Cancer.

Background and Purpose: Patients with acute stroke are often accompanied by comorbidities, such as active cancer. However, adequate treatment guidelines are not available for these patients. The purpose of this study was to evaluate the association between cancer and the outcomes of reperfusion therapy in patients with stroke. Methods: We compared treatment outcomes in patients who underwent reperfusion therapy, using a nationwide reperfusion therapy registry. We divided the patients into 3 groups according to cancer activity: active cancer, nonactive cancer, and without a history of cancer. We investigated reperfusion processes, 24-hour neurological improvement, adverse events, 3-month functional outcome, and 6-month survival and related factors after reperfusion therapy. Results: Among 1338 patients who underwent reperfusion therapy, 62 patients (4.6%) had active cancer, 78 patients (5.8%) had nonactive cancer, and 1198 patients (89.5%) had no history of cancer. Of the enrolled patients, 969 patients received intravenous thrombolysis and 685 patients underwent endovascular treatment (316 patients received combined therapy). Patients with active cancer had more comorbidities and experienced more severe strokes; however, they showed similar 24-hour neurological improvement and adverse events, including cerebral hemorrhage, compared with the other groups. Although the functional outcome at 3 months was poorer than the other groups, 36.4% of patients with active cancer showed functional independence. Additionally, 52.9% of the patients with determined stroke etiology showed functional independence despite active cancer. During the 6-month follow-up, 46.6% of patients with active cancer died, and active cancer was independently associated with poor survival (hazard ratio, 3.973 [95% CI, 2.528­6.245]). Conclusions: In patients with active cancer, reperfusion therapy showed similar adverse events and short-term outcomes to that of other groups. While long-term prognosis was worse in the active cancer group than the nonactive cancer groups, not negligible number of patients had good functional outcomes, especially those with determined stroke mechanisms.

The Clinical Usefulness of Targeted Temperature Management in Acute Ischemic Stroke with Malignant Trait After Endovascular Thrombectomy.

BACKGROUND/OBJECTIVE: Targeted temperature management (TTM) may be more beneficial after endovascular treatment (EVT) in patients with a large ischemic core. Therefore, we assessed the usefulness of TTM for such patients from a multicenter endovascular registry. METHODS: Anterior circulation stroke patients who underwent endovascular recanalization were included; acute ischemic stroke with malignant traits was designated as (1) baseline Alberta Stroke Program Early CT Score (ASPECTS) below 6 and (2) diffusion-weighted imaging (DWI) lesion volume measurement (> 82 ml) or National Institutes of Health Stroke Scale score > 20 and item Ia > 0. TTM (34.5 °C) was maintained for at least 48 h. RESULTS: We evaluated baseline demographics, risk factors, EVT parameters, and clinical outcomes between the TTM and non-TTM groups. Among the 548 patients, the TTM group (n = 91) significantly had a lower baseline ASPECTS (p < 0.001) and a higher DWI volume (p < 0.001) than the non-TTM group (n = 457). TTM group had a lower prevalence of favorable outcome (0-2 of modified Rankin Scale at 3 months; p = 0.008) than the non-TTM group. In a subgroup analysis of malignant trait patients (n = 80), TTM patients (n = 28) had more favorable outcome (32.1% vs. 7.7% p = 0.009) and less hemorrhagic transformation (none vs. any hemorrhage, p = 0.007) than non-TTM patients (n = 52). After adjusting for potential outcome predictors, TTM (odds ratio [OR] 4.63; confidence interval [CI] 1.20-17.89; p = 0.026) and hypertension (OR 0.18; CI 0.04-0.74; p = 0.018) were found to be independent determinants. CONCLUSIONS: Our data suggest that TTM attenuates impending hemorrhagic transformation and leads to favorable clinical outcomes in EVT patients with malignant trait.

Transcriptional coactivator with PDZ-binding motif stimulates epidermal regeneration via induction of amphiregulin expression after ultraviolet damage.

Ultraviolet (UV) irradiation induces the proliferation and differentiation of keratinocytes in the basal layer of the epidermis, which increases epidermal thickness in skin regeneration. However, the mechanism underlying this phenomenon is not yet known in detail. In this study, we aimed to demonstrate that the transcriptional coactivator with PDZ-binding motif (TAZ) stimulates epidermal regeneration by increasing keratinocyte proliferation. During epidermal regeneration, TAZ is localized in the nucleus of keratinocytes of the basal layer and stimulates epidermal growth factor receptor (EGFR) signaling. TAZ depletion in keratinocytes decreased EGFR signaling activation, which delays epidermal regeneration. Interestingly, TAZ stimulated the transcription of amphiregulin (AREG), a ligand of EGFR, through TEAD-mediated transcriptional activation. Together, these results show that TAZ stimulates EGFR signaling through AREG induction, suggesting that it plays an important role in epidermal regeneration.

Transmission and regulation of biochemical stimulus via a nanoshell directly adsorbed on the cell membrane to enhance chondrogenic differentiation of mesenchymal stem cell.

A nanoscale artificial extracellular matrix (nanoshell) formed by layer-by-layer adsorption can enhance and modulate the function of stem cells by transferring biochemical stimulus to the cell directly. Here, the nanoshell composed of fibronectin (FN) and chondroitin sulfate (CS) is demonstrated to promote chondrogenic differentiation of mesenchymal stem cells (MSCs). The multilayer structure of nanoshell is formed by repeating self-assembly of FN and CS, and its thickness can be controlled through the number of layers. The expression of chondrogenic markers in MSCs coated with the FN/CS nanoshell was increased as the number of bilayers in the nanoshell increased until four, but when it exceeds five bilayers, the effect began to decrease. Finally, the MSCs coated with optimized four bilayers of FN/CS nanoshell have high chondrogenic differentiation efficiency and showed the potential to increase formation of cartilage tissue when it is transplanted into mouse kidney. So, the precise regulation of stem cell fate at single cell level can be possible through the cellular surface modification by self-assembled polymeric film.

In-Hospital and Post-Discharge Recovery after Acute Ischemic Stroke: a Nationwide Multicenter Stroke Registry-base Study.

BACKGROUND: Using data from a large national stroke registry, we aimed to investigate the incidence and determinants of in-hospital and post-discharge recovery after acute ischemic stroke and the independence of their occurrence. METHODS: In-hospital recovery was defined as an improvement of 4 points or > 40% in the National Institutes of Health Stroke Scale (NIHSS) score from admission to discharge. Post-discharge recovery was defined as any improvement in the modified Rankin Scale (mRS) score from discharge to 3 months after stroke onset. Two analytic methods (multivariate and multivariable logistic regression) were applied to compare the effects of 18 known determinants of 3-month outcome and to verify whether in-hospital and post-discharge recovery occur independently. RESULTS: During 54 months, 11,088 patients with acute ischemic stroke meeting the eligibility criteria were identified. In-hospital and post-discharge recovery occurred in 36% and 33% of patients, respectively. Multivariate logistic regression with an equality test for odds ratios showed that 7 determinants (age, onset-to-admission time, NIHSS score at admission, blood glucose at admission, systolic blood pressure, smoking, recanalization therapy) had a differential effect on in-hospital and post-discharge recovery in the way of the opposite direction or of the same direction with different degree (all P values < 0.05). Both in-hospital and post-discharge recovery occurred in 12% of the study population and neither of them in 43%. The incidence of post-discharge recovery in those with in-hospital recovery was similar to that in those without (33.8% vs. 32.7%, respectively), but multivariable analysis showed that these 2 types of recovery occurred independently. CONCLUSION: Our findings suggest that, in patients with acute ischemic stroke, in-hospital and post-discharge recovery may occur independently and largely in response to different factors.

TAZ stimulates liver regeneration through interleukin-6-induced hepatocyte proliferation and inhibition of cell death after liver injury.

In response to liver injury, the liver undergoes a regeneration process to retain its mass and function. However, the regeneration mechanism has not been fully clarified. This study investigated the role of transcriptional coactivator with PDZ-binding motif (TAZ), a Hippo-signaling effector, in liver regeneration. We observed that TAZ stimulates liver regeneration after liver injury. After partial hepatectomy (PHx) or carbon tetrachloride damage, TAZ was required for liver regeneration to increase hepatic cell proliferation and resist hepatic apoptosis, which were decreased in liver-specific TAZ knockout (LKO) mice. TAZ stimulated macrophage infiltration, resulting in IL-6 production, which induced liver regeneration. In LKO mice, IL-6-induced activation of signal transducer and activator of transcription 3, ERK, and PKB was decreased. We also observed that periductal fibrogenesis was significantly increased in LKO mice during liver regeneration after PHx, which was caused by increased hepatic apoptosis. Our results suggest that TAZ stimulates liver regeneration through IL-6-induced hepatocyte proliferation and inhibition of cell death after liver injury.-Kim, A. R., Park, J. I., Oh, H. T., Kim, K. M., Hwang, J.-H., Jeong, M. G., Kim, E.-H., Hwang, E. S., Hong, J.-H. TAZ stimulates liver regeneration through interleukin-6-induced hepatocyte proliferation and inhibition of cell death after liver injury.

Developing palatal bone using human mesenchymal stem cell and stem cells from exfoliated deciduous teeth cell sheets.

Cleft palate is one of the most common craniofacial defects in newborn babies. The characteristics of this genetic disease produce soft and hard tissue defects on the lip and maxilla, which cause not only aesthetic but also functional problems with speech, eating, and breathing. Bone grafts using autologous cancellous bone have been a standard treatment to repair the hard tissue defect in cleft palates. However, such grafts do not fully integrate into host bone and undergo resorption. To overcome engraftment problems, it is common to engineer new tissues with a combination of multipotent cells and biomaterial frameworks. Here, we manufactured cell sheets for bone repair of cleft palates derived from two osteogenic cell sources, human mesenchymal stem cells (hMSCs) and stem cells from human exfoliated deciduous teeth (SHEDs). Cell sheets made from hMSCs and SHEDs gave rise to in vitro calcification, which indicated the osteogenic potential of these cells. The cell sheets of hMSCs and SHEDs expressed the bone-specific osteogenic markers, osterix, osteocalcin, and osteopontin, following insertion into ex vivo-cultured embryonic palatal shelves and in ovo culture. In conclusion, we showed that osteogenic stem cell sheets have mineralization potential and might represent a new alternative to autologous bone transplantation in the reconstruction of cleft palates.