Sublingual Edaravone Dexborneol for the Treatment of Acute Ischemic Stroke: The TASTE-SL Randomized Clinical Trial.

Importance: Sublingual edaravone dexborneol, which can rapidly diffuse and be absorbed through the oral mucosa after sublingual exposure, is a multitarget brain cytoprotection composed of antioxidant and anti-inflammatory ingredients edaravone and dexborneol. Objective: To investigate the efficacy and safety of sublingual edaravone dexborneol on 90-day functional outcome in patients with acute ischemic stroke (AIS). Design, Setting, and Participants: This was a double-blind, placebo-controlled, multicenter, parallel-group, phase 3 randomized clinical trial conducted from June 28, 2021, to August 10, 2022, with 90-day follow-up. Participants were recruited from 33 centers in China. Patients randomly assigned to treatment groups were aged 18 to 80 years and had a National Institutes of Health Stroke Scale score between 6 and 20, a total motor deficit score of the upper and lower limbs of 2 or greater, a clinically diagnosed AIS symptom within 48 hours, and a modified Rankin Scale (mRS) score of 1 or less before stroke. Patients who did not meet the eligibility criteria or declined to participate were excluded. Intervention: Patients were assigned, in a 1:1 ratio, to receive sublingual edaravone dexborneol (edaravone, 30 mg; dexborneol, 6 mg) or placebo (edaravone, 0 mg; dexborneol, 60 µg) twice daily for 14 days and were followed up until 90 days. Main Outcomes and Measures: The primary efficacy outcome was the proportion of patients with mRS score of 1 or less on day 90 after randomization. Results: Of 956 patients, 42 were excluded. A total of 914 patients (median [IQR] age, 64.0 [56.0-70.0] years; 608 male [66.5%]) were randomly allocated to the edaravone dexborneol group (450 [49.2%]) or placebo group (464 [50.8%]). The edaravone dexborneol group showed a significantly higher proportion of patients experiencing good functional outcomes on day 90 after randomization compared with the placebo group (290 [64.4%] vs 254 [54.7%]; risk difference, 9.70%; 95% CI, 3.37%-16.03%; odds ratio, 1.50; 95% CI, 1.15-1.95, P = .003). The rate of adverse events was similar between the 2 groups (89.8% [405 of 450] vs 90.1% [418 of 464]). Conclusion and Relevance: Among patients with AIS within 48 hours, sublingual edaravone dexborneol could improve the proportion of those achieving a favorable functional outcome at 90 days compared with placebo. Trial Registration: ClinicalTrials.gov Identifier: NCT04950920.

EGR1 and EGR2 positively regulate plant ABA signaling by modulating the phosphorylation of SnRK2.2.

During abscisic acid (ABA) signaling, reversible phosphorylation controls the activity and accumulation of class III SNF1-RELATED PROTEIN KINASE 2s (SnRK2s). While protein phosphatases that negatively regulate SnRK2s have been identified, those that positively regulate ABA signaling through SnRK2s are less understood. In this study, Arabidopsis thaliana mutants of Clade E Growth-Regulating 1 and 2 (EGR1/2), which belong to the protein phosphatase 2C family, exhibited reduced ABA sensitivity in terms of seed germination, cotyledon greening, and ABI5 accumulation. Conversely, overexpression increased these ABA-induced responses. Transcriptomic data revealed that most ABA-regulated genes in egr1 egr2 plants were expressed at reduced levels compared with those in Col-0 after ABA treatment. Abscisic acid up-regulated EGR1/2, which interact directly with SnRK2.2 through its C-terminal domain I. Genetic analysis demonstrated that EGR1/2 function through SnRK2.2 during ABA response. Furthermore, SnRK2.2 de-phosphorylation by EGR1/2 was identified at serine 31 within the ATP-binding pocket. A phospho-mimic mutation confirmed that phosphorylation at serine 31 inhibited SnRK2.2 activity and reduced ABA responsiveness in plants. Our findings highlight the positive role of EGR1/2 in regulating ABA signaling, they reveal a new mechanism for modulating SnRK2.2 activity, and provide novel insight into how plants fine-tune their responses to ABA.

Efficacy and safety of intravitreal HLX04-O, an anti-VEGF monoclonal antibody, for the treatment of wet age-related macular degeneration.

AIM: To evaluate the efficacy and safety of HLX04-O, an investigational ophthalmic formulation of HLX04 (bevacizumab biosimilar) for intravitreal injection, as a treatment for wet age-related macular degeneration (wAMD) in a phase 1/2 clinical trial (NCT04993352). METHODS: Eligible patients with wAMD were enrolled to receive HLX04-O intravitreal injections at a dose of 1.25 mg/0.05 mL every four weeks. Efficacy and adverse events were evaluated every month during study visits. RESULTS: A 76-year-old male with wAMD in his left eye participated in the trial and completed six cycles of HLX04-O intravitreal injections. Changes were observed in macular center point thickness (baseline vs last study visit, 437 vs 255 µm) and best-corrected visual acuity letter score (baseline vs last study visit, 36 vs 77) of the affected eye, which indicated an improvement in wAMD over treatment. No adverse events were reported by the data cutoff date. CONCLUSION: HLX04-O at 1.25 mg/0.05 mL every four weeks is well tolerated in this patient, demonstrating promising safety and efficacy in wAMD treatment. Large-scale studies are required to confirm the outcomes.

The Role of Nitric Oxide in Plant Responses to Salt Stress.

The gas nitric oxide (NO) plays an important role in several biological processes in plants, including growth, development, and biotic/abiotic stress responses. Salinity has received increasing attention from scientists as an abiotic stressor that can seriously harm plant growth and crop yields. Under saline conditions, plants produce NO, which can alleviate salt-induced damage. Here, we summarize NO synthesis during salt stress and describe how NO is involved in alleviating salt stress effects through different strategies, including interactions with various other signaling molecules and plant hormones. Finally, future directions for research on the role of NO in plant salt tolerance are discussed. This summary will serve as a reference for researchers studying NO in plants.

Diagnosis and differential diagnosis flow diagram of Chinese post-stroke aphasia types and treatment of post-stroke aphasia.

This review aimed to explore the concept, etiology, classification, classical cortical mapping, assessment, diagnosis and differential diagnosis, treatment, rehabilitation, mechanism, recovery, prognosis, and influencing factors for Chinese post-stroke aphasia (PSA). The review emphasized the necessity and significance of neuroimaging assessment of brain and blood vessels and neuropsychological assessment in diagnosis and differential diagnosis of Chinese PSA. In addition, it suggested and recommended to use "dichotomies of internal and external, and anterior and posterior" as a starting point, based on the anatomic location of brain and blood vessels and their relationship with language area and language disorder. As a result, the formulated Chinese PSA classification was more suitable to guide the clinical treatment of cerebral stroke. Diagnosis, classification, and differential diagnosis of Chinese PSA types were performed according to the "dichotomy" and "four elements." The formulated "flow diagram" enabled to determine the classification of Chinese PSA types. It was beneficial for patients to establish targeted and individualized rehabilitation training plans. This review introduced the use of memantine, piracetam, donepezil, etc. in PSA treatment, evaluated clinical studies conducted in China and abroad, investigated the mechanism of action related to the use of drugs in PSA treatment, and explored the therapeutic mechanism of rehabilitation training. It suggested the use drugs of memantine, piracetam, donepezil, etc. combine with non-pharmacotherapy and rehabilitation training in clinical studies on PSA treatment and also in practical settings.

Plastid-Localized EMB2726 Is Involved in Chloroplast Biogenesis and Early Embryo Development in Arabidopsis.

Embryogenesis is a critical developmental process that establishes the body organization of higher plants. During this process, the biogenesis of chloroplasts from proplastids is essential. A failure in chloroplast development during embryogenesis can cause morphologically abnormal embryos or embryonic lethality. In this study, we isolated a T-DNA insertion mutant of the Arabidopsis gene EMBRYO DEFECTIVE 2726 (EMB2726). Heterozygous emb2726 seedlings produced about 25% albino seeds with embryos that displayed defects at the 32-cell stage and that arrested development at the late globular stage. EMB2726 protein was localized in chloroplasts and was expressed at all stages of development, such as embryogenesis. Moreover, the two translation elongation factor Ts domains within the protein were critical for its function. Transmission electron microscopy revealed that the cells in emb2726 embryos contained undifferentiated proplastids and that the expression of plastid genome-encoded photosynthesis-related genes was dramatically reduced. Expression studies of DR5:GFP, pDRN:DRN-GFP, and pPIN1:PIN1-GFP reporter lines indicated normal auxin biosynthesis but altered polar auxin transport. The expression of pSHR:SHR-GFP and pSCR:SCR-GFP confirmed that procambium and ground tissue precursors were lacking in emb2726 embryos. The results suggest that EMB2726 plays a critical role during Arabidopsis embryogenesis by affecting chloroplast development, possibly by affecting the translation process in plastids.

AtPFA-DSP3, an atypical dual-specificity protein tyrosine phosphatase, affects salt stress response by modulating MPK3 and MPK6 activity.

Protein phosphorylation, especially serine/threonine and tyrosine phosphorylation, plays significant roles in signalling during plant growth and development as well as plant responses to biotic or abiotic stresses. Dual-specificity protein tyrosine phosphatases dephosphorylate components of these signalling pathways. Here, we report that an atypical dual-specificity protein tyrosine phosphatase, AtPFA-DSP3 (DSP3), negatively affects the response of plants to high-salt conditions. A DSP3 loss-of-function mutant showed reduced sensitivity to salt treatment. DSP3 was primarily localized in nuclei and was degraded during salt treatment. Compared to wild type, the level of ROS was lower in the dsp3 mutant and higher in plants ectopically expressing DSP3, indicating that higher DSP3 level was associated with increased ROS production. DSP3 interacted with and dephosphorylated MPK3 and MPK6. Genetic analyses of a dsp3mpk3 double mutant revealed that DSP3's effect on salt stress depends on MPK3. Moreover, the phosphatase activity of DSP3 was required for its role in salt signalling. These results indicate that DSP3 is a negative regulator of salt responses in Arabidopsis by directly modulating the accumulation of phosphorylated MPK3 and MPK6.

Mild Encephalitis/Encephalopathy with a Reversible Isolated Splenial Lesion (MERS) in Adult Patients: A Small Case Series.

BACKGROUND: Mild encephalitis/encephalopathy with a reversible isolated splenial lesion (MERS) is a rare and complex clinico-radiological condition that aggregates various diseases. From a geographical point of view, most cases have been reported in Asia, especially in Japan. However, a very limited number of studies have properly evaluated Chinese patients diagnosed with MERS. METHODS: Putative encephalitis/encephalopathy patients affected by a reversible isolated SCC lesion, as detected by magnetic resonance imaging (MRI), were retrospectively evaluated. Specifically, we reviewed extensive patient data, including prodromal and neurologic symptoms, neurologic examinations, MRI and electroencephalography (EEG) findings, laboratory results, treatments, and prognosis. RESULTS: Six clinically mild encephalitis/encephalopathy patients, affected by a reversible isolated SCC lesion, were identified in a cohort of 22 patients. Six patients presented fever symptoms before the onset of neurological manifestations. Initial MRI data exhibited isolated SCC lesions with isointense or slightly hypointense on T1WI, hyperintense on T2WI, Flair, and DWI, as well as decreased ADC values, without contrast enhancement. EEG data indicated abnormalities (3/4), as well as elevated serum inflammatory markers (5/6) and hyponatremia (4/6). Cell content and protein yields were normal or slightly increased in the CSF of 6 patients, excluding one episode of significant increase in cell number. Patients were treated with corticosteroids, antivirals, and antibiotics, resulting in their full clinical recovery. SCC lesions mostly disappeared in all patients. CONCLUSION: In our study, the clinical features identified in all affected patients were mostly identical, which consisted of relatively mild CNS manifestations with a promising prognostic status.

Thrombolysis with alteplase 3-4.5 hours after acute ischaemic stroke: the first multicentre, phase III trial in China.

BACKGROUND AND PURPOSE: Data on the efficacy and safety of alteplase for acute ischaemic stroke (AIS) administered 3-4.5 hours after the onset of stroke symptoms in Chinese patients is limited. We sought to determine whether AIS patients would benefit from thrombolysis with alteplase between 3 and 4.5 hours after the onset of stroke symptoms in a prospective, multicentre, single-arm trial in China. MATERIALS AND METHODS: Eligible AIS patients were given 0.9 mg/kg alteplase intravenously. The primary efficacy endpoint was a favourable outcome at 3 months, defined as a score of 0 or 1 on the modified Rankin Scale. Thresholds for the primary efficacy endpoint were determined to be 40% based on the literature review. The primary safety endpoint was symptomatic intracranial haemorrhage (sICH) according to the European Cooperative Acute Stroke Study III (ECASS III) trial definition. Post hoc analysis between this study and the ECASS III trial were compared using the propensity score matching (PSM) method. RESULTS: A total of 120 eligible AIS patients from 11 sites in China received thrombolysis therapy in this study. The median time from onset of symptoms to needle was 3 hours 54 min. The percentage of patients with a favourable outcome was 63.3% (95% CI 54.4 to 71.4), significantly higher than the predefined threshold (p<0.0001). Three patients (2.5%, 95% CI 0.5 to 7.1) had sICH, including two fatal sICH. Six patients died within 3 months after treatment. The post hoc PSM analysis showed a numerically higher rate of the primary efficacy endpoint in this study (63.3%) than the matched placebo arm (56.7%) in the ECASS III trial. CONCLUSIONS: Intravenous alteplase with a standard dose administered between 3 and 4.5 hours after onset of symptoms is effective and safe for Chinese AIS patients. TRIAL REGISTRATION NUMBER: NCT02930837.

Efficacy of cattle encephalon glycoside and ignotin in patients with acute cerebral infarction: a randomized, double-blind, parallel-group, placebo-controlled study.

Cattle encephalon glycoside and ignotin (CEGI) injection is a compound preparation formed by a combination of muscle extract from healthy rabbits and brain gangliosides from cattle, and it is generally used as a neuroprotectant in the treatment of central and peripheral nerve injuries. However, there is still a need for high-level clinical evidence from large samples to support the use of CEGI. We therefore carried out a prospective, multicenter, randomized, double-blind, parallel-group, placebo-controlled study in which we recruited 319 patients with acute cerebral infarction from 16 centers in China from October 2013 to May 2016. The patients were randomized at a 3:1 ratio into CEGI (n = 239; 155 male, 84 female; 61.2 ± 9.2 years old) and placebo (n = 80; 46 male, 34 female; 63.2 ± 8.28 years old) groups. All patients were given standard care once daily for 14 days, including a 200 mg aspirin enteric-coated tablet and 20 mg atorvastatin calcium, both taken orally, and intravenous infusion of 250-500 mL 0.9% sodium chloride containing 40 mg sodium tanshinone IIA sulfonate. Based on conventional treatment, patients in the CEGI and placebo groups were given 12 mL CEGI or 12 mL sterile water, respectively, in an intravenous drip of 250 mL 0.9% sodium chloride (2 mL/min) once daily for 14 days. According to baseline National Institutes of Health Stroke Scale scores, patients in the two groups were divided into mild and moderate subgroups. Based on the modified Rankin Scale results, the rate of patients with good outcomes in the CEGI group was higher than that in the placebo group, and the rate of disability in the CEGI group was lower than that in the placebo group on day 90 after treatment. In the CEGI group, neurological deficits were decreased on days 14 and 90 after treatment, as measured by the National Institutes of Health Stroke Scale and the Barthel Index. Subgroup analysis revealed that CEGI led to more significant improvements in moderate stroke patients. No drug-related adverse events occurred in the CEGI or placebo groups. In conclusion, CEGI may be a safe and effective treatment for acute cerebral infarction patients, especially for moderate stroke patients. This study was approved by the Ethical Committee of Peking University Third Hospital, China (approval No. 2013-068-2) on May 20, 2013, and registered in the Chinese Clinical Trial Registry (registration No. ChiCTR1800017937).

Analysis of risk factors for vascular cognitive impairment in patients with cerebral infarction.

This study aimed to identify risk factors for vascular cognitive impairment (VCI) in cerebral infarction patients. Associations between VCI and age, gender, blood pressure, lipid levels, glycosylated hemoglobin, atrial fibrillation, tobacco smoking, alcohol consumption, homocysteine (Hcy), and High-Sensitivity C-Reactive Protein (HS-CRP) were evaluated in patients with cerebral infarction (n = 300) using single factor analysis and multivariate logistic regression analysis. By single factor analysis, the age, glycosylated hemoglobin, atrial fibrillation, blood pressure, Hcy, HS-CRP, tobacco smoking, and alcohol consumption were significantly associated with VCI in these patients. By multivariate logistic regression analysis, the age, glycosylated hemoglobin, blood pressure, Hcy, and HS-CRP were revealed as independent risk factors. The age, glycosylated hemoglobin, blood pressure, Hcy, and HS-CRP can serve as predictive factors for VCI in patients with cerebral infarction.

Microcalorimetric investigation on effects of La(III) on metabolic activity of mitochondria isolated from hybrid rice.

Rare earth elements (REEs) have beneficial influence on plant growth and are widely used in agriculture practice, but little is known about the behavior of the REEs in mitochondria of plant cell. Thermogenic metabolic curves were determined by the ampoule method at 303 K using a TAM air isothermal microcalorimeter in mitochondria isolated from hybrid rice Liangyoupeijiu (Oryza sativa L.), and the effect of La(III) on its mitochondrial metabolism was investigated. From the obtained heat flux curves, the crucial parameters including as activity recovery rate constant (k) and maximum heat power (P(max)) were determined. Application of La(3+) in concentrations ranging from 0 to 120 microg/ml significantly increased k and P(max) values with the high point reaching 346 and 222% of the control, respectively. Concentrations from 140-150 microg/ml had the opposite effect. These results were consistent with previous reports on the effects of REEs on plant growth. It was concluded that the La-induced change of mitochondrial metabolic activity is a possible mechanism by which La(III) ions influences hybrid rice growth.

Bioenergetic investigation of the effects of La(III) and Ca(II) on the metabolic activity of Tetrahymena thermophila BF5.

The heat flux of Tetrahymena thermophila BF5 during growth and the effects of La(3+) and Ca(2+) on them were investigated with microcalorimetry; simultaneously, morphological changes of T. thermophila were obtained by light microscope. La(3+) in low concentration (0-5.0 x 10(-4) mol/l) remarkably stimulated T. thermophila metabolism, but high dose of La(3+) (5.8-8.6 x 10(-4) mol/l) restrained it in a linear manner with IC(50) being 7.2 x 10(-4) mol/l. In contrast, low concentration of Ca(2+) did not manifest obvious stimulation on T. thermophila metabolism; moreover, the IC(50) of Ca(2+) was much higher than that of La(3+). Low concentration of La(3+) did not lead to changes in appearance of T. thermophila, but low dose of Ca(2+) clearly promoted the cell proliferation. In addition, the morphological changes of T. thermophila evoked by high concentrations of La(3+) and Ca(2+) were consistent with relevant microcalorimetric results. It is concluded that La and Ca influence T. thermophila via different pathways, and La represents toxic action rather than Ca analogy.