Genome-wide association study identifies novel susceptibilities to adult moyamoya disease.

Genome-wide association study has limited to discover single-nucleotide polymorphisms (SNPs) in several ethnicities. Here, we investigated an initial GWAS to identify genetic modifiers predicting with adult moyamoya disease (MMD) in Koreans. GWAS was performed in 216 patients with MMD and 296 controls using the large-scale Asian-specific Axiom Precision Medicine Research Array. A subsequent fine-mapping analysis was conducted to assess the causal variants associated with adult MMD. A total of 489,966 out of 802,688 SNPs were subjected to quality control analysis. Twenty-one SNPs reached a genome-wide significance threshold (p = 5 × 10-8) after pruning linkage disequilibrium (r2 < 0.8) and mis-clustered SNPs. Among these variants, the 17q25.3 region including TBC1D16, CCDC40, GAA, RNF213, and ENDOV genes was broadly associated with MMD (p = 3.1 × 10-20 to 4.2 × 10-8). Mutations in RNF213 including rs8082521 (Q1133K), rs10782008 (V1195M), rs9913636 (E1272Q), rs8074015 (D1331G), and rs9674961 (S2334N) showed a genome-wide significance (1.9 × 10-8 < p < 4.3 × 10-12) and were also replicated in the East-Asian populations. In subsequent analysis, RNF213 mutations were validated in a fine-mapping outcome (log10BF > 7). Most of the loci associated with MMD including 17q25.3 regions were detected with a statistical power greater than 80%. This study identifies several novel and known variations predicting adult MMD in Koreans. These findings may good biomarkers to evaluate MMD susceptibility and its clinical outcomes.

N-Feruloylserotonin inhibits lipopolysaccharide-induced inflammation via SIRT1-stimulated FOXO1 and NF-κB signaling pathways in RAW 264.7 cells.

Macrophages become activated by a variety of stimuli such as lipopolysaccharide (LPS) and participate in the process of immune responses. Activated macrophages produce various inflammatory mediators. In the present study, we investigated the anti-inflammatory mechanism of a serotonin derivative, N-feruloylserotonin, isolated from safflower seeds in RAW 264.7 macrophages. N-Feruloylserotonin treatment significantly attenuated these effects on LPS-induced reactive oxygen species, nitric oxide, and prostaglandin E2 production in RAW 264.7 macrophages. Furthermore, N-feruloylserotonin significantly decreased the abnormal expression of mitogen-activated protein kinase, such as phosphor (p)-c-Jun N-terminal kinase and p-extracellular-signal regulated kinase activation. Further research revealed that N-feruloylserotonin could stimulate sirtuin1 (SIRT1), then promote the forkhead box protein O1 (FOXO1), and suppress nuclear factor-kappa B (NF-kB) signaling pathways. The present study suggests that N-feruloylserotonin may be a new anti-inflammatory component and a promising candidate for anti-inflammatory therapeutic agents through the regulation of SIRT1-stimulated FOXO1 and NF-kB signaling pathways.

Oxiracetam alleviates anti-inflammatory activity and ameliorates cognitive impairment in the early phase of traumatic brain injury.

BACKGROUND: We aimed to investigate the effects of oxiracetam on cognitive impairment in the early phase of traumatic brain injury (TBI), for which no specific treatment is currently available. METHODS: The in vitro study used a cell injury controller to damage SH-SY5Y cells and evaluate the effect of oxiracetam at a dosage of 100 nM. The in vivo study used a stereotaxic impactor to induce a TBI model in C57BL/6 J mice and analyzed immunohistochemical changes and cognitive function after an intraperitoneal injection of oxiracetam (30 mg/kg/day) for 5 days. The number of mice used in this study was 60. They were divided into three groups (sham, TBI, and TBI with oxiracetam treatment) (20 mice in each group). RESULTS: The in vitro study showed that oxiracetam treatment resulted in increased superoxide dismutase (SOD)1 and SOD2 mRNA expression. The mRNA and protein expression of COX-2, NLRP3, caspase-1, and interleukin (IL)-1 ß were decreased after oxiracetam treatment, along with decreases in intracellular reactive oxygen species production and apoptotic effects. TBI mice treated with oxiracetam exhibited the loss of fewer cortical damaged lesions, less brain edema, and fewer Fluoro-Jade B (FJB)-positive and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL)-positive cells compared to those without oxiracetam treatment. The mRNA and protein expression of COX-2, NLRP3, caspase-1, and IL-1ß were decreased significantly after oxiracetam treatment. These inflammation-related markers, which colocalized with Iba-1-positive or GFAP-positive cells after TBI, were also decreased after oxiracetam treatment. TBI mice treated with oxiracetam had a smaller decrease in preference and more latency time than those not treated with oxiracetam, suggesting the amelioration of impaired cognitive impairment. CONCLUSIONS: Oxiracetam may be helpful in restoring cognitive impairment by ameliorating neuroinflammation in the early phase of TBI.

Human embryonic stem cell-derived cerebral organoids for treatment of mild traumatic brain injury in a mouse model.

OBJECTIVE: There are no effective treatments for relieving neuronal dysfunction after mild traumatic brain injury (TBI). Here, we evaluated therapeutic efficacy of human embryonic stem cell-derived cerebral organoids (hCOs) in a mild TBI model, in terms of repair of damaged cortical regions, neurogenesis, and improved cognitive function. METHODS: Male C57BL/6 J mice were randomly divided into sham-operated, mild TBI, and mild TBI with hCO groups. hCOs cultured at 8 weeks were used for transplantation. Mice were sacrificed at 7 and 14 days after transplantation followed by immunofluorescence staining, cytokine profile microarray, and novel object recognition test. RESULTS: 8W-hCOs transplantation significantly reduced neuronal cell death, recovered microvessel density, and promoted neurogenesis in the ipsilateral subventricular zone and dentate gyrus of hippocampus after mild TBI. In addition, increased angiogenesis into the engrafted hCOs was observed. Microarray results of hCOs revealed neuronal differentiation potential and higher expression of early brain development proteins associated with neurogenesis, angiogenesis and extracellular matrix remodeling. Ultimately, 8W-hCO transplantation resulted in reconstruction of damaged cortex and improvement in cognitive function after mild TBI. CONCLUSION: hCO transplantation may be feasible for treating mild TBI-related neuronal dysfunction via reconstruction of damaged cortex and neurogenesis in the hippocampus.

Influence of renal impairment on neurologic outcomes following mechanical thrombectomy in acute vertebrobasilar stroke.

PURPOSE: Renal impairment (RI) has been regarded as a risk factor for unfavorable neurologic outcomes after mechanical thrombectomy (MT) in acute ischemic stroke. However, most of the previous studies were conducted on patients with anterior circulation stroke. Accordingly, the influence of RI on MT outcomes has not been well elucidated in detail in acute vertebrobasilar stroke. METHODS: Consecutive stroke patients with MT due to acute vertebrobasilar artery occlusion between March 2015 and December 2020 at four institutions were included. Multivariable logistic regression analysis was conducted to assess the associations between RI and outcomes and mortality at 3 months, and the development of intracerebral hemorrhage (ICH) after the procedure. Additionally, the multivariable Cox proportional hazards model was performed to determine the influence of RI on survival probability after patient discharge. RESULTS: A total of 110 patients were included in the final analysis. The presence of RI (OR = 0.268, 95% CI: 0.077-0.935), National Institute of Health Stroke Scale scores (OR = 0.849, 95% CI: 0.791-0.910), and puncture-to-recanalization time (OR = 0.981, 95% CI: 0.966-0.997) were related to outcomes. There was no significant association between RI and 3-month mortality or ICH. The cumulative survival probability after adjusting for relevant risk factors demonstrated that RI remained significantly associated with poorer survival after MT compared to patients without RI (HR = 2.111, 95% CI: 0.919-4.847). CONCLUSION: RI was an independent risk factor for poor 3-month neurologic outcomes and survival probability after MT in patients with acute vertebrobasilar stroke.

Application of Near-Infrared Spectroscopy for the Detection of Delayed Cerebral Ischemia in Poor-Grade Subarachnoid Hemorrhage.

BACKGROUND: The objective of this study was to investigate the clinical feasibility of near-infrared spectroscopy (NIRS) for the detection of delayed cerebral ischemia (DCI) in patients with poor-grade subarachnoid hemorrhage (SAH) treated with coil embolization. METHODS: Cerebral regional oxygen saturation (rSO2) was continuously monitored via two-channel NIRS for 14 days following SAH. The rSO2 levels according to DCI were analyzed by using the Mann-Whitney U-test. A receiver operating characteristic curve was generated on the basis of changes in rSO2 by using the rSO2 level on day 1 as a reference value to determine the optimal cutoff value for identifying DCI. RESULTS: Twenty-four patients with poor-grade SAH were included (DCI, n = 8 [33.3%]; non-DCI, n = 16 [66.7%]). The rSO2 levels of patients with DCI were significantly lowered from 6 to 9 days compared with those in without DCI. The rSO2 level was 62.55% (58.30-63.40%) on day 6 in patients with DCI versus 65.40% (60.90-68.70%) in those without DCI. By day 7, it was 60.40% (58.10-61.90%) in patients with DCI versus 64.25% (62.50-67.10%) those without DCI. By day 8, it was 58.90% (56.50-63.10%) in patients with DCI versus 66.05% (59.90-69.20%) in those without DCI, and by day 9, it was 60.85% (58.40-65.20%) in patients with DCI versus 65.80% (62.70-68.30%) in those without DCI. A decline of greater than 14.5% in the rSO2 rate yielded a sensitivity of 92.86% (95% confidence interval: 66.1-99.8%) and a specificity of 88.24% (95% confidence interval: 72.5-96.7%) for identifying DCI. A decrease by more than 14.7% of the rSO2 level indicates a sensitivity of 85.7% and a specificity of 85.7% for identifying DCI. CONCLUSIONS: Near-infrared spectroscopy shows some promising results for the detection of DCI in patients with poor-grade SAH. Further studies involving a large cohort of the SAH population are required to confirm our results.

Extracellular Mitochondrial Dysfunction in Cerebrospinal Fluid of Patients with Delayed Cerebral Ischemia after Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Mitochondrial dysfunction is related to brain ischemic injury and neural cell death. However, little is known about the association between mitochondrial dysfunction of cerebrospinal fluid (CSF) and delayed cerebral ischemia (DCI) following subarachnoid hemorrhage (SAH). The objective of this study was to investigate whether extracellular CSF mitochondria might serve as a potential biomarker for DCI. METHODS: CSF samples were serially collected at 1, 3, and 5 days following SAH in 33 patients (DCI, n = 12; and non-DCI, n = 21) who underwent coil embolization. To monitor mitochondrial membrane potentials, JC-1 dye was used. The ratio (red/green) of JC-1 was considered as an indicator of intact mitochondrial membrane potential. Flow cytometry was done to analyze extracellular mitochondria particles and their possible cellular origins. RESULTS: DCI patients had lower JC-1 red/green ratios than non-DCI patients at 1 day (3.35 [3.20-3.75] vs. 3.70 [3.40-3.95] in non-DCI) and 3 days (4.65 [4.45-5.00] vs. 5.10 [4.65-5.30] in non-DCI) after SAH. At 5 days after SAH, JC-1 red/green ratio was significantly lower in DCI than that in non-DCI (3.05 [2.90-3.35] vs. 4.20 [4.10-4.50]; p < 0.01) patients. DCI patients had a higher percentage of vWF-positive mitochondria (40.10% [38.25%-44.90%] vs. 30.20% [25.70%-36.68%]) and a lower percentage of GLAST-positive mitochondria particles (26.85% [17.10%-30.00%] vs. 31.60% [26.70%-35.00%]) than non-DCI patients. However, there was no significant difference in CD45-positive (p = 0.369) or CD41/61-positive mitochondrial particles (p = 0.155) between the two groups of patients. CONCLUSIONS: Mitochondrial membrane potential could be a marker of DCI. JC-1 ratios seemed to be able to predict future DCI onset. Further studies are needed to determine detailed mechanisms of extracellular mitochondria-mediated cell-to-cell signals in DCI.

Characterization of the TCR ß Chain CDR3 Repertoire in Subarachnoid Hemorrhage Patients with Delayed Cerebral Ischemia.

Little is known of the adaptive immune response to subarachnoid hemorrhage (SAH). This study was the first to investigate whether T cell receptor (TCR) immune repertoire may provide a better understanding of T cell immunology in delayed cerebral ischemia (DCI). We serially collected peripheral blood in five SAH patients with DCI. High-throughput sequencing was used to analyze the TCR ß chain (TCRB) complimentary determining regions (CDR) 3 repertoire. We evaluated the compositions and variations of the repertoire between admission and the DCI period, for severe DCI and non-severe DCI patients. Clonality did not differ significantly between admission and DCI. Severe DCI patients had significantly lower clonality than non-severe DCI patients (p value = 0.019). A read frequency of 0.005% ≤ - < 0.05% dominated the clonal expansion in non-severe DCI patients. Regarding repertoire diversity, severe DCI had a higher diversity score on admission than non-severe DCI. The CDR3 lengths were similar between admission and DCI. Among 728 annotated V-J gene pairs, we found that the relative frequencies of two V-J pairs were different at the occurrence of DCI than at admission, with T cells increasing by over 15%. TCRB CDR3 repertoires may serve as biomarkers to identify severe DCI patients.

Ultrasonographic optic nerve sheath diameter to detect increased intracranial pressure in adults: a meta-analysis.

BACKGROUND: The optimal optic nerve sheath diameter (ONSD) cut-off for identifying increased intracranial pressure (IICP) remains unclear in adult patients. PURPOSE: To validate the diagnostic accuracy of ultrasonographic (US) ONSD > 5.0 mm as a cut-off for detecting IICP by computed tomographic (CT) through a meta-analysis. MATERIAL AND METHODS: A systemic literature review was performed of online databases from January 1990 to September 2017. A bivariate random-effects model was used to estimate pooled sensitivity, specificity, and diagnostic odds ratio (DOR) with 95% confidence intervals (CIs). A summary receiver operating characteristic (SROC) graph was used to provide summary points for sensitivity and specificity. Meta-regression tests were performed to estimate the influence of the study characteristics on DOR. Publication bias was assessed using Deeks' funnel plot asymmetry test. RESULTS: Six studies with 352 patients were included in the meta-analysis. US ONSD > 5.0 mm revealed pooled sensitivity of 99% (95% CI = 96-100) and specificity of 73% (95% CI = 65-80) for IICP detection. DOR was 178. The area under the SROC curve was 0.981, indicating a good level of accuracy. Meta-regression studies showed no significant associations between DOR and study characteristics such as probe mode (relative DOR [RDOR] = 0.60; P = 0.78), study quality (RDOR = 0.52; P = 0.67), IICP prevalence (RDOR = 0.04; P = 0.17), or pathology at admission (RDOR = 1.30; P = 0.87). CONCLUSION: US ONSD > 5.0 mm can be used to rapidly detect IICP in adults in emergency departments and intensive care units. Further meta-analysis based on individual patient-level databases is needed to confirm these results.

Intra-arterial thrombolysis of central retinal artery occlusion following percutaneous atrial septal defect closure.

Use of percutaneous devices for atrial septal defect (ASD) closure is growing, given the minimally invasive nature and the long-term durability of this approach. The reported rate of thrombus formation after catheter closure is 1.2%. Thrombotic risk varies according to closure device and Dacron-covered nitinol Amplatzer devices carry a 0-0.3% rate of thrombus formation; but central retinal artery occlusion (CRAO) is rarely implicated as an adverse event. Herein, we report the first successful intra-arterial thrombolytic treatment of CRAO developing after ASD closure via Amplatzer device. © 2015 Wiley Periodicals, Inc.

Extended monitoring of coiled aneurysms completely occluded at 6-month follow-up: late recanalization rate and related risk factors.

OBJECTIVES: To estimate long-term durability in coiled aneurysms completely occluded at 6-month follow-up imaging, focusing on late recanalization rate and the risk factors involved. METHODS: A cohort of 620 patients harbouring 698 completely occluded coiled aneurysms at 6-month follow-up was subjected to extended monitoring (mean, 24.5 ± 7.9 months). Cumulative recanalization rate and related risk factors were analysed using Cox proportional hazards regression and Kaplan-Meier product-limit estimator. RESULTS: Forty-three aneurysms (6.2 %) occluded completely at 6-months displayed recanalization (3.02 % per aneurysm-year) during continued surveillance (1425.5 aneurysm-years), with 26 (60.5 %) surfacing in another 6 months, 15 (34.9 %) within 18 months and 2 (4.6 %) within 30 months. Cumulative survival rates without recanalization were significantly lower in subjects with aneurysms >7 mm (p = 0.014), with bifurcation aneurysms (p = 0.009) and with subarachnoid haemorrhage (SAH) at presentation (p < 0.001). Multivariate analysis indicated that aneurysms >7 mm (HR = 2.37, p = 0.02) and bifurcation aneurysms (HR = 2.70, p = 0.03) were significant factors in late recanalization, whereas a link with SAH at presentation was marginal (HR = 1.92, p = 0.06) and stent placement fell short of statistical significance (HR = 0.47; p = 0.12). CONCLUSION: Most (93.8 %) coiled aneurysms showing complete occlusion at 6 months post-procedure were stable in long-term monitoring. However, aneurysms >7 mm and bifurcation aneurysms were predisposed to late recanalization. KEY POINTS: • Most coiled aneurysms showing complete occlusion at 6 months were stable. • Forty-three aneurysms (6.2 %) occluded completely at 6-month follow-up displayed late recanalization. • Late recanalization rate was 3.02 % per aneurysm-year during follow-up of 1425.5 aneurysm-years. • Aneurysms over 7 mm and bifurcation aneurysms were predisposed to late recanalization.

Modified coil protection for proper coil frame configuration in wide-necked aneurysms.

INTRODUCTION: Although various protective techniques for treating wide-necked intracranial aneurysms currently exist and continue to evolve, their utility may be limited in some lesions with complex configurations, small-caliber channels, or inherently tortuous vascular patterns. Described herein is a modified coil protection technique as a novel adjunct for proper coil frame configuration. METHODS: Initially, a microcatheter is passed into aneurysmal sac, and the first coil is inserted to build a frame. Inevitably, some coils may abut opposite poles of aneurysms and protrude into parent arteries. Should this happen, a second microcatheter may be placed at the site of coil protrusion, so that a separate and smaller coil may be partially deployed for protection. A framing coil may then be configured within aneurysmal sac, under protection of the secondary coil. Once the first coil is entirely in place, the remainder of second coil is carefully inserted, and additional coil may be inserted as needed via dual microcatheters. RESULTS: This technique was successfully applied to 23 saccular intracranial aneurysms of internal carotid (n = 8), middle cerebral (n = 6), anterior cerebral (n = 6), and superior cerebellar artery (n = 3), combining stent protection in two patients and balloon remodeling in one. Selective endovascular treatment was effective as a result. Excellent outcomes were achieved in all patients, with no morbidity or mortality directly related to the modified procedure. CONCLUSION: As suggested by outcomes of this small study, our modified coil protection method may be a safe option if traditional coiling strategies are not feasible, enabling stable coil frame configuration in wide-necked aneurysms.

Progressive thrombosis of small saccular aneurysms filled with contrast immediately after coil embolization: analysis of related factors and long-term follow-up.

INTRODUCTION: Although it is well-known that incomplete occlusion of aneurysms after coil embolization predisposes to later recanalization, not all aneurysms will be fully occluded by coiling. In follow-up, we evaluated outcomes of small aneurysms (<10 mm) that showed filling of the sac with contrast immediately after coil embolization and assessed factors implicated in subsequent progressive thrombosis. METHODS: Between January 2008 and December 2010, a total of 1035 aneurysms in 898 patients were treated by endovascular coiling. Of these, 210 small aneurysms displayed filling of the sac by contrast immediately after coil embolization. Time-of-flight magnetic resonance angiography (TOF-MRA; at 6, 12, 24, and 36 months) and digital subtraction angiography (as needed) were used for postoperative monitoring. Complete occlusion of these aneurysms at the 6-month follow-up point was attributed to progressive thrombosis. RESULTS: In 186 (88.5 %) of the 210 aneurysms that showed filling of the sac with contrast, complete occlusion was observed on follow-up imaging studies at 6 months. Multiple logistic regression analysis indicated that progressive thrombosis was linked to aneurysmal neck diameter ≤4 mm (p < 0.001) and packing density >30 % (p = 0.016). Aneurysms originating from non-branching vessels were of marginal statistical significance (p = 0.056). In 179 progressively thrombosed aneurysms with follow-up evaluations of ≥12 months (mean, 31.9 ± 7.6 months), 168 aneurysms (93.9 %) exhibited stable occlusion, whereas minor recanalization was observed in 6 (3.3 %) instances, and major recanalization occurred in 5 (2.8 %). CONCLUSIONS: In aneurysms where filling of the sac with contrast was demonstrable after coil embolization, aneurysms with small neck diameters or high coil packing density, and non-branching aneurysms seem predisposed to progressive intra-aneurysmal thrombosis over the course of time.

Intravenous flat-detector computed tomography angiography for symptomatic cerebral vasospasm following aneurysmal subarachnoid hemorrhage.

The study evaluated the diagnostic accuracy of intravenous flat-detector computed tomography (IV FDCT) angiography in assessing hemodynamically significant cerebral vasospasm in patients with subarachnoid hemorrhage (SAH) with digital subtraction angiography (DSA) as the reference. DSA and IV FDCT were conducted concurrently in patients suspected of having symptomatic cerebral vasospasm postoperatively. The presence and severity of vasospasm were estimated according to location (proximal versus distal). Vasospasm >50% was defined as having hemodynamic significance. Vasospasms <30% were excluded from this analysis to avoid spectrum bias. Twenty-nine patients (311 vessel segments) were measured. The intra- and interobserver agreements were excellent for depicting vasospasm (k = 0.84 and 0.74, resp.). IV FDCT showed a sensitivity of 95.7%, specificity of 92.3%, positive predictive value of 93.6%, and negative predictive value of 94.7% for detecting vasospasm (>50%) with DSA as the reference. Bland-Altman plots revealed good agreement of assessing vasospasm between the two tests. The discrepancy of vasospasm severity was more noted in the distal location with high-severity. However, it was not statistically significant (Spearman's rank test; r = 0.15, P = 0.35). Therefore, IV FDCT could be a feasible noninvasive test to evaluate suspected significant vasospasm in SAH.

Pulsed Radiofrequency Neuromodulation for Post-Stroke Shoulder Pain in Patients with Hemorrhagic Stroke.

Objective: Post-stroke shoulder pain (PSSP) is a common complication that limits the range of motion (ROM) of the shoulder, the patient's rehabilitation and in turn, affects the patients' quality of life (QOL). Several treatment modalities such as sling, positioning, strapping, functional electrical stimulation (FES), and nerve block have been suggested in literatures, however none of the treatments had long-term effects for PSSP. In this study, the authors evaluated clinical efficacy of pulsed radiofrequency (PRF) neuromodulation on the suprascapular nerve for PSSP, and suggested it as a potential treatment with long-term effect. Methods: This retrospective case series was conducted at a single center, a private practice institution. From 2013 to 2021, 13 patients with PSSP underwent PRF neuromodulation of the suprascapular nerve. The primary outcome measure was the visual analog scale (VAS) score. The secondary outcome measurements included the shoulder ROM, disability assessment scale (DAS), modified Ashworth scale (mAS), modified Rankin scale (mRS), and EuroQol-5 dimension-3L questionnaire (EQ-5D-3L) scores. These parameters were evaluated before PRF modulation, immediately after PRF modulation, and every three months until the final follow-up visit. Results: Six men and seven women were enrolled, and all patients were followed-up for a minimum of 12 months. The mean VAS score was 7.07 points before PRF neuromodulation and 2.38 points immediately post-procedure. Shoulder ROM for abduction and flexion, DAS for pain, mRS, and EQ-5D-3L demonstrated marked improvement. No complications were reported. Conclusion: PRF neuromodulation of the suprascapular nerve is an effective modality in patients with PSSP, and has long-term effect of pain relief, improvement of QOL.

Longitudinal Genome-Wide Association Study of Cognitive Impairment after Subarachnoid Hemorrhage.

OBJECTIVES: The occurrence of cognitive deficits after subarachnoid hemorrhage (SAH) is highly possible, leading to vascular dementia. We performed a novel longitudinal genome-wide association study (GWAS) to identify genetic modifications associated with cognitive impairment following SAH in a long-term prospective cohort study. MATERIALS AND METHODS: This GWAS involved 153 patients with SAH sharing 5,971,372 markers after high-throughput imputation. Genome-wide Cox proportional hazard regression testing was performed to estimate the hazard ratio (HR) and 95% confidence interval (CI). Subsequently, a weighted polygenetic risk score (wPRS) was determined, based on GWAS-driven loci and risk stratification. RESULTS: Cognitive impairment was observed in 65 patients (42.5%) during a mean follow-up of 37.7 ± 12.4 months. Five genome-wide signals, including rs138753053 (PDCD6IP-LOC101928135, HR = 28.33, p = 3.4 × 10-8), rs56823384 (LINC00499, HR = 12.47, p = 2.8 × 10-9), rs145397166 (CASC15, HR = 11.16, p = 1.7 × 10-8), rs10503670 (LPL-SLC18A1, HR = 2.88, p = 4.0 × 10-8), and rs76507772 (IRS2, HR = 5.99, p = 3.5 × 10-8), were significantly associated with cognitive impairment following SAH. In addition, the well-constructed wPRS containing five markers showed nominal ability to predict cognitive impairment (AUROC = 0.745, 95% CI: 0.667-0.824). Tertile stratification showed a higher effectiveness in predicting cognitive impairment, especially in those with haptoglobin 2-1 (HR = 44.59, 95% CI: 8.61-231.08). CONCLUSIONS: Our study revealed novel susceptible loci for cognitive impairment, longitudinally measured in patients with SAH. The clinical utility of these loci will be evaluated in further follow-up studies.

Therapeutic Effect of Donepezil on Neuroinflammation and Cognitive Impairment after Moderate Traumatic Brain Injury.

BACKGROUND: Despite the important clinical issue of cognitive impairment after moderate traumatic brain injury (TBI), there is currently no suitable treatment. Here, we used in vitro and in vivo models to investigate the effect of Donepezil-an acetylcholinesterase (AChE) inhibitor-on cognitive impairment in the acute period following injury, while focusing on neuroinflammation and autophagy- and mitophagy-related markers. METHODS: The purpose of the in vitro study was to investigate potential neuroprotective effects in TBI-induced cells after donepezil treatment, and the in vivo study, the purpose was to investigate therapeutic effects on cognitive impairment in the acute period after injury by analyzing neuroinflammation and autophagy- and mitophagy-related markers. The in vitro TBI model involved injuring SH-SY5Y cells using a cell-injury controller and then investigating the effect of donepezil at a concentration of 80 µM. The in vivo TBI model was made using a stereotaxic impactor for male C57BL/6J mice. Immuno-histochemical markers and cognitive functions were compared after 7 days of donepezil treatment (1 mg/kg/day). Mice were divided into four groups: sham operation with saline treatment, sham operation with donepezil treatment, TBI with saline treatment, and TBI with donepezil treatment (18 mice in each group). Donepezil treatment was administered within 4 h post-TBI. RESULTS: In vitro, donepezil was found to lead to increased cell viability and 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimi-dazolylcarbocyanine iodide (JC-1), along with decreased reactive oxygen species (ROS), lactate-dehydrogenase (LDH), 2'-7'-dichlorodihydrofluorescein diacetate (DCFH-DA)-positive cells, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells. The mRNA and protein expressions of neuroinflammation (Cyclooxygenase-2, COX-2; NOD-like receptor protein 3, NLRP3; Caspase-1; and Interleukin-1 beta, IL-1ß), as well as autophagy- and mitophagy-related markers (death-associated protein kinase 1, DAPK1; PTEN-induced kinase 1, PINK1; BCL2/adenovirus E1B 19 kDa protein-interacting protein 3-like, BNIP3L; Beclin-1, BECN1; BCL2-associated X protein, BAX; microtubule-associated protein 1A/1B-light chain 3B (LC3B); Sequestosome-1; and p62) were all found to decrease after donepezil treatment. The in vivo study also showed that donepezil treatment resulted in decreased levels of cortical tissue losses and brain swelling in TBI compared to the TBI group without donepezil treatment. Donepezil treatment was also shown to decrease the mRNA and Western blotting expressions of all markers, and especially COX-2 and BNIP3L, which showed the most significant decreases. Moreover, TBI mice showed an decreased escape latency, increased alteration rate, and improved preference index, altogether pointing to better cognitive performance after donepezil treatment. CONCLUSIONS: Donepezil treatment may be beneficial in improving cognitive impairment in the early phase of moderate traumatic brain injury by ameliorating neuroinflammation, as well as autophagy and mitophagy.

Modeling of the brain-lung axis using organoids in traumatic brain injury: an updated review.

Clinical outcome after traumatic brain injury (TBI) is closely associated conditions of other organs, especially lungs as well as degree of brain injury. Even if there is no direct lung damage, severe brain injury can enhance sympathetic tones on blood vessels and vascular resistance, resulting in neurogenic pulmonary edema. Conversely, lung damage can worsen brain damage by dysregulating immunity. These findings suggest the importance of brain-lung axis interactions in TBI. However, little research has been conducted on the topic. An advanced disease model using stem cell technology may be an alternative for investigating the brain and lungs simultaneously but separately, as they can be potential candidates for improving the clinical outcomes of TBI.In this review, we describe the importance of brain-lung axis interactions in TBI by focusing on the concepts and reproducibility of brain and lung organoids in vitro. We also summarize recent research using pluripotent stem cell-derived brain organoids and their preclinical applications in various brain disease conditions and explore how they mimic the brain-lung axis. Reviewing the current status and discussing the limitations and potential perspectives in organoid research may offer a better understanding of pathophysiological interactions between the brain and lung after TBI.

Therapeutic Potential of Two Derivative Prescriptions of Rokumijiogan, Hachimijiogan and Bakumijiogan against Renal Damage in Nephrectomized Rats.

Background: Hachimijiogan (HJG) and Bakumijiogan (BJG), two derivative prescriptions of Rokumijiogan (RJG), were selected to investigate their renoprotective potential in the 5/6 nephrectomized (5/6Nx) rat model. Methods: Rats were treated with HJG and BJG orally at 150 mg/kg body weight/day once daily for 10 weeks after resection of 5/6 of the renal volume, and their renoprotective effects were compared with 5/6Nx vehicle-treated and sham-operated control rats. Results: Improvements in renal lesions, glomerulosclerosis, tubulointerstitial injury, and arteriosclerotic lesions estimated by histologic scoring indices in the HJG-treated group were compared with those in the BJG-treated group. HJG- and BJG-treated groups ameliorated the renal function parameters. Elevated levels of renal oxidative stress-related biomarkers were reduced, while decreased antioxidant defence systems (superoxide dismutase and the glutathione/oxidized glutathione ratio) were increased in the HJG-treated group rather than the BJG-treated group. In contrast, BJG administration significantly reduced expression of the inflammatory response through oxidative stress. The HJG-treated group showed a decrease in inflammatory mediators through the JNK pathway. To gain a deeper understanding of their therapeutic action, the effects of the main components detected in HJG and BJG were evaluated using the LLC-PK1 renal tubular epithelial cell line, which is the renal tissue most vulnerable to oxidative stress. Corni Fructus and Moutan Cortex-originated compositions afforded important protection against oxidative stress induced by peroxynitrite. Conclusions: From our described and discussed analyses, it can be concluded that RJG-containing prescriptions, HJG and BJG are an excellent medicine for chronic kidney disease. In the future, appropriately designed clinical studies in people with chronic kidney disease are necessary to evaluate the renoprotective activities of HJG and BJG.