Bailout intracranial angioplasty or stenting following thrombectomy for acute large vessel occlusion in China (ANGEL-REBOOT): a multicentre, open-label, blinded-endpoint, randomised controlled trial.

BACKGROUND: Unsuccessful recanalisation or reocclusion after thrombectomy is associated with poor outcomes in patients with large vessel occlusion (LVO) acute ischaemic stroke (LVO-AIS). Bailout angioplasty or stenting (BAOS) could represent a promising treatment for these patients. We conducted a randomised controlled trial with the aim to investigate the safety and efficacy of BAOS following thrombectomy in patients with LVO. METHODS: ANGEL-REBOOT was an investigator-initiated, multicentre, prospective, randomised, controlled, open-label, blinded-endpoint clinical trial conducted at 36 tertiary hospitals in 19 provinces in China. Participants with LVO-AIS 24 h after symptom onset were eligible if they had unsuccessful recanalisation (expanded Thrombolysis In Cerebral Infarction score of 0-2a) or risk of reocclusion (residual stenosis >70%) after thrombectomy. Eligible patients were randomly assigned by the minimisation method in a 1:1 ratio to undergo BAOS as the intervention treatment, or to receive standard therapy (continue or terminate the thrombectomy procedure) as a control group, both open-label. In both treatment groups, tirofiban could be recommended for use during and after the procedure. The primary outcome was the change in modified Rankin Scale score at 90 days, assessed in the intention-to-treat population. Safety outcomes were compared between groups. This trial was completed and registered at ClinicalTrials.gov (NCT05122286). FINDINGS: From Dec 19, 2021, to March 17, 2023, 706 patients were screened, and 348 were enrolled, with 176 assigned to the intervention group and 172 to the control group. No patients withdrew from the trial or were lost to follow-up for the primary outcome. The median age of patients was 63 years (IQR 55-69), 258 patients (74%) were male, and 90 patients (26%) were female; all participants were Chinese. After random allocation, tirofiban was administered either intra-arterially, intravenously, or both in 334 [96%] of 348 participants. No between-group differences were observed in the primary outcome (common odds ratio 0·86 [95% CI 0·59-1·24], p=0·41). Mortality was similar between the two groups (19 [11%] of 176 vs 17 [10%] of 172), but the intervention group showed a higher risk of symptomatic intracranial haemorrhage (eight [5%] of 175 vs one [1%] of 169), parenchymal haemorrhage type 2 (six [3%] of 175 vs none in the control group), and procedure-related arterial dissection (24 [14%] of 176 vs five [3%] of 172). INTERPRETATION: Among Chinese patients with unsuccessful recanalisation or who are at risk of reocclusion after thrombectomy, BAOS did not improve clinical outcome at 90 days, and incurred more complications compared with standard therapy. The off-label use of tirofiban might have affected our results and their generalisability, but our findings do not support the addition of BAOS for such patients with LVO-AIS. FUNDING: Beijing Natural Science Foundation, National Natural Science Foundation of China, National Key R&D Program Beijing Municipal Administration of Hospitals Incubating Program, Shanghai HeartCare Medical Technology, HeMo (China) Bioengineering, Sino Medical Sciences Technology.

The diagnosis of acute intermittent porphyria combined with seizures: Case report.

RATIONALE: Acute intermittent porphyria (AIP) is a rare metabolic disorder affecting heme production due to enzyme porphobilinogen deaminase deficiency. Diagnosing acute intermittent porphyria is difficult because its symptoms interrelate with those of other common diseases. When AIP is combined with seizures, the diagnosis process is more complicated. This case report shows all tests and criteria used to arrive at the final stage of diagnosis. PATIENT CONCERNS: The patient complained of severe abdominal pain, nausea, vomiting, and intermittent convulsions. Her medical history shows she had abdominal pain, mainly dull pain in the left upper abdomen. DIAGNOSES: Different symptomatic tests were done, and the cause of her symptoms was uncertain. A urine sun drying test was then done and confirmed the presence of porphyrin used to diagnose AIP. A genetic test was done after the patient was discharged, and AIP diagnosis was confirmed. INTERVENTIONS: Acute intermittent porphyria treatment was administered. OUTCOMES: The patent recovered fully. LESSONS: It is essential to consider acute intermittent porphyria diagnosis in patients having unexplained severe abdominal pain associated with neurological and psychiatric symptoms. Since AIP is a rare disease with a high mortality rate when not treated early, Clinical practices should include AIP as one of the tests done on patients showing these symptoms at an early stage. The fastest way to identify this is to conduct a urine test. The change of color from brown to reddish color is a diagnostic indicator of AIP. This strategy helps reduce misdiagnoses and delayed treatment of the right disease.

Upregulation of miR-489-3p Attenuates Cerebral Ischemia/Reperfusion Injury by Targeting Histone Deacetylase 2 (HDAC2).

Cerebral ischemia/reperfusion (I/R) injury is the continuation and deterioration of ischemic injury, and there are no effective treatment strategies for this condition. It has been reported that microRNAs (miRNAs) are considered as potential targets to protect the brain against I/R injury. Previous studies have shown that miR-489-3p plays a vital role in regulating apoptosis of neurons. miR-489-3p is considered as a potential target to protect the brain against I/R injury-induced neuron apoptosis. This study aimed to explore the molecular mechanism of miR-489-3p in protection against cerebral I/R injury. A rat model with cerebral I/R injury was established using the MCAO method. The cell model was constructed using the oxygen­glucose deprivation (OGD) method. The expression of miR-489-3p was detected by qRT-PCR. The expression of HDAC2 was detected by Western blot assay and immunofluorescence assay. Cell apoptosis was evaluated by flow cytometry and TUNEL staining assay. The relationship between miR-489-3p and HDAC2 was determined by bioinformatics analysis and luciferase reporter assay. Rescue experiments were performed to investigate the mechanism of the miR-489-3p/HDAC2 axis. miR-489-39 was significantly downregulated, while HDAC2 was upregulated during cerebral I/R injury both in vitro and in vivo. Upregulation of miR-489-3p obviously attenuated cerebral I/R injury by increasing PC12 cell viability, reducing LDH release, and inhibiting cell apoptosis. HDAC2 was identified as a direct target of miR-489-3p. Silencing of HDAC2 showed a neuroprotective effect against OGD/R injury in vitro. Overexpression of HDAC2 significantly attenuated the protective effects of miR-489-3p mimics on cell injury in vitro. Our results revealed that the upregulation of miR-489-3p attenuated cerebral I/R injury by negatively regulating HDAC2.

Development of an UPLC-MS/MS Method for the Quantitative Analysis of Upadacitinib in Beagle Dog Plasma and Pharmacokinetics Study.

BACKGROUND: Upadacitinib, a novel selective Janus kinase 1 (JAK1) inhibitor, has been recently approved by the US FDA for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA). An ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method for the quantitative analysis of upadacitinib in beagle dog plasma was developed and validated. METHODS: Upadacitinib and fedratinib (internal standard, IS) were extracted with ethyl acetate under alkaline condition and then separated and detected. The chromatographic column was Waters Acquity UPLC BEH C18 column (2.1 mm × 50 mm, 1.7 µm), the mobile phase was acetonitrile and 0.1% formic acid in water with gradient elution procedure, and the flow rate was 0.40 mL/min. Under the positive ion mode, upadacitinib and IS were monitored by multiple reaction monitoring (MRM) as the following mass transition pairs: m/z 447.00 → 361.94 for upadacitinib and m/z 529.82 → 141.01 for IS. RESULTS: In the concentration range of 1-500 ng/mL, upadacitinib had good linearity, and the lower limit of quantification (LLOQ) was 1 ng/mL. The RSD of the intra- and inter-day precision was less than 10.03%, and the RE of accuracy was -3.79% to 2.58%. The extraction recovery of upadacitinib was more than 80%, the matrix effect was around 100%, and upadacitinib was found to be stable. CONCLUSION: The novel optimized UPLC-MS/MS assay was an effective tool for the determination of upadacitinib and had been successfully applied to the pharmacokinetic study of upadacitinib in beagle dogs, and this method would also be used to study DDIs.

Pharmacological Interventions for REM Sleep Behavior Disorder in Parkinson's Disease: A Systematic Review.

To review the therapeutic effects of drugs on REM sleep behavior disorder (RBD) in Parkinson's disease (PD) by searching the MEDLINE/PubMed, Embase, Cochrane, and CBM databases. According to the inclusion and exclusion criteria, studies were included after excluding duplicate data. We evaluated the safety and efficacy of pharmacological intervention to improve RBD in patients with Parkinson's disease (PD-RBD). This systematic review mainly describes the drugs that can be used to treat PD-RBD patients. The results have shown that melatonin can be used as the first-line drug for PD-RBD, and clonazepam provides significant improvement on PD-RBD, androtigotine can be used as an alternative drug. However, further large-scale clinical trial studies are still needed to provide the best guidelines for the pharmacological treatment of PD-RBD.

Long noncoding MIAT acting as a ceRNA to sponge microRNA-204-5p to participate in cerebral microvascular endothelial cell injury after cerebral ischemia through regulating HMGB1.

This study is applied to the investigation of the long noncoding RNA myocardial infarction associated transcript's (MIAT's) role in regulating the expression of high-mobility group box 1 (HMGB1) in cerebral microvascular endothelial cell (CMEC) injury after cerebral ischemia by serving as a competitive endogenous RNA (ceRNA) to sponge microRNA-204-5p (miR-204-5p). The cerebral ischemia model of middle cerebral artery occlusion (MCAO) in rats was established by the suture method, in which rats were injected with empty plasmids and MIAT siRNA plasmids. The cerebral ischemia injury model in vitro was established through oxygen glucose deprivation (OGD) in primary cultured CMECs in rats. The cells were transfected with empty plasmids and MIAT siRNA plasmids. The MIAT/miR-204-5p/HMGB1 axis' function in damage and angiogenesis of CMECs were explored. The binding site between MIAT and miR-204-5p along with that between miR-204-5p and HMGB1 was determined. MIAT was overexpressed in MCAO rats' brain tissue and inhibited MIAT attenuated the injury of brain tissue in MCAO rats. Inhibition of MIAT promoted angiogenesis, promoted miR-204-5p expression and inhibited HMGB1 expression in brain tissue of MCAO rats. Inhibition of MIAT reduced CMEC damage, induced angiogenesis of CMECs, increased the number of surviving neurons, promoted miR-204-5p expression and inhibited HMGB1 expression in CMECs treated with OGD. MIAT promoted HMGB1 expression by competitive binding to miR-204-5p to regulate the injury of CMECs after cerebral ischemia. Our study showed that MIAT promoted HMGB1 expression by competitively binding to miR-204-5p to regulate the injury of CMECs after cerebral ischemia.

Interleukin-17 receptor C gene polymorphism reduces treatment effect and promotes poor prognosis of ischemic stroke.

OBJECTIVE: To study the relationship between Interleukin-17 receptor C (IL-17RC) gene polymorphism and ischemic stroke (IS). METHODS: Three hundred cases of IS patients and 300 cases of the healthy controls were selected. Serum of IS patients and the controls was collected. The relative mRNA levels of IL-17, IL-17RC, IL-6, IL-8, G-CSF and granulocyte-macrophage colony stimulating factor (GM-CSF) by qRT-PCR. The protein expression of IL-17 and IL-17RC was determined by Western blotting. IL-17RC genotype was identified by PCR amplification. The proportion of IL-17RC, SNP and re37511 in IS and control group was determined. The treatment effect on IS and prognosis of patients with IL-17RC, SNP and re37511 was compared. RESULTS: The relative mRNA levels of IL-17, IL-17RC, IL-6, IL-8, G-CSF and GM-CSF in IS group were significantly higher than the control group. The protein expression of IL-17 and IL-17RC in IS group was also markedly higher than the control group. The proportion of IL-17RC re37511 in IS group was much larger than control group and proportion of IL-17RC much less. The percent of poor treatment effect in re37511 was much larger than IL-17RC. The percent of death and recrudescence in patients with IL-17RC re37511 was the highest. CONCLUSION: IS up-regulates the expression of IL-17 and IL-17RC. IL-17RC re37511 indicates the patients have a poorer treatment effect and prognosis.

Relationship between procalcitonin serum levels and functional outcome in stroke patients.

To determine whether serum procalcitonin (PCT) levels at admission were associated with short-term functional outcome after acute ischemic stroke (AIS) in a cohort Chinese sample. We prospectively studied 378 patients with AIS who were admitted within 24 h after the onset of symptoms. PCT and NIH stroke scale (NIHSS) were measured at the time of admission. Short-term functional outcome was measured by modified Rankin scale (mRS) 90 days after admission. The results indicated that the serum PCT levels were significantly higher in AIS patients as compared to normal controls (P < 0.0001). In the 114 patients with an unfavorable functional outcome, serum PCT levels were higher compared with those in patients with a favorable outcome (2.40 (IQR, 1.10-3.69) ng/mL and 0.42 (IQR, 0.10-1.05) ng/mL, respectively, P < 0.001). PCT was an independent prognostic marker of functional outcome [odds ratio (OR) 3.45 (2.29-4.77), adjusted for the NIHSS and other possible confounders] in patients with ischemic stroke, added significant additional predictive value to the clinical NIHSS score. In receiver operating characteristic curve analysis, the prognostic accuracy of PCT was higher compared to Hs-CRP and NIHSS score. PCT is an independent predictor of short-term functional outcome after ischemic stroke in Chinese sample even after correcting for possible confounding factors.

A natural flavonoid glucoside icariin inhibits Th1 and Th17 cell differentiation and ameliorates experimental autoimmune encephalomyelitis.

Multiple sclerosis (MS) is an autoimmune disease that is characterized by recurrent episodes of T cell-mediated immune attack on central nervous system (CNS) myelin, leading to axon damage and progressive disability. Icariin, a natural flavonoid glucoside isolated from plants in the Epimedium family, has been proved to have various pharmacological activities. However, the effect of icariin on experimental autoimmune encephalomyelitis (EAE) has never been investigated. In our current study, we found that icariin treatment leads to alleviated inflammatory infiltration and reduced blood-brain barrier leakage (BBB) of the paracellular tracer (FITC-dextran) in EAE. Mice that received icariin-treated T cells also displayed lower EAE scores and better clinical recovery from EAE. Icariin administration suppresses the frequencies of Th1 and Th17 cells in the splenocytes and lymph node cells. Icariin-treated mice also show lower frequency of Th17 cells in CNS mononuclear cells. The effect of icariin on Th1 and Th17 cell differentiation may be mediated via modulation of dendritic cells (DCs). Furthermore, icariin suppresses the proliferation of T cells and the differentiation of Th1 and Th17 cells in vitro. In conclusion, icariin ameliorates EAE and this was associated with suppressed Th1 and Th17 cell differentiation.