Surgical Outcomes of Low-Flow Bypass Surgery in Intracranial Atherosclerotic Steno-Occlusive Diseases.

BACKGROUND AND OBJECTIVES: The role of bypass surgery in intracranial atherosclerotic steno-occlusive diseases (ICADs) remains controversial. We aimed to analyze the surgical outcomes of bypass surgery in patients with the ICADs in a single tertiary institution. METHODS: Among 1018 cases of low-flow bypass surgery between 2003 and 2022, 215 patients with the ICAD refractory to medical treatment were finally enrolled in this study. Clinical and radiological outcomes were retrospectively evaluated, with survival analyses. RESULTS: All strokes, cerebral infarctions, and intracranial hemorrhages occurred in 12.1% (n = 26), 9.8% (n = 21), and 2.3% (n = 5), respectively, during the clinical follow-up of 54.6 ± 47.6 months (range, 0.6-237.8 months). Among all stroke events, 84.6% (n = 22) occurred within 30 postoperative days. The 2-year and 5-year cumulative risks of all strokes were 12.1% each. The mean modified Rankin Scale scores were 1.6 ± 1.1 (range, 0-5) preoperatively and 0.8 ± 1.2 (range, 0-6) at last (P < .01). The patency of direct bypass was 99.1% (n = 213) just before discharge and 96.3% (n = 184 of 191 patients with available tests) at the last angiographic follow-up of 27.0 ± 27.3 months (range, 2.3-97.3 months). All the patients with available data (n = 190) showed hemodynamic improvement on acetazolamide-challenged single-photon emission computed tomography with 99mTc-hexamethylpropyleneamine oxime during the follow-up of 38.6 ± 36.7 months (range, 2.3-158.6 months). CONCLUSION: Low-flow bypass surgery showed acceptable treatment outcomes in the prevention of recurrent stroke.

Association between body mass index and results of cryoballoon ablation in Korean patients with atrial fibrillation: an analysis from the Korean Heart Rhythm Society Cryoablation registry.

AIMS: Pulmonary vein isolation using cryoablation is effective and safe in patients with atrial fibrillation (AF). Although both obesity and underweight are associated with a higher risk for incident AF, there is limited data on the efficacy and safety following cryoablation according to body mass index (BMI) especially in Asians. METHODS AND RESULTS: Using the Korean Heart Rhythm Society Cryoablation registry, a multicentre registry of 12 tertiary hospitals, we analysed AF recurrence and procedure-related complications after cryoablation by BMI (kg/m2) groups (BMI < 18.5, underweight, UW; 18.5-23, normal, NW; 23-25, overweight, OW; 25-30, obese Ⅰ, OⅠ; ≥30, obese Ⅱ, OⅡ). A total of 2648 patients were included (median age 62.0 years; 76.7% men; 55.6% non-paroxysmal AF). Patients were categorized by BMI groups: 0.9% UW, 18.7% NW, 24.8% OW, 46.1% OI, and 9.4% OII. Underweight patients were the oldest and had least percentage of non-paroxysmal AF (33.3%). During a median follow-up of 1.7 years, atrial arrhythmia recurred in 874 (33.0%) patients (incidence rate, 18.9 per 100 person-years). After multivariable adjustment, the risk of AF recurrence was higher in UW group compared with NW group (adjusted hazard ratio, 95% confidence interval; 2.55, 1.18-5.50, P = 0.02). Procedure-related complications occurred in 123 (4.7%) patients, and the risk was higher for UW patients (odds ratio, 95% confidence interval; 2.90, 0.94-8.99, P = 0.07), mainly due to transient phrenic nerve palsy. CONCLUSION: Underweight patients showed a higher risk of AF recurrence after cryoablation compared with NW patients. Also, careful attention is needed on the occurrence of phrenic nerve palsy in UW patients.

Ginseng Berry Juice (GBJ) Regulates the Inflammation in Acute Ulcerative Mouse Models and the Major Bioactive Substances Are Ginsenosides Rb3, Rc, Rd, and Re.

Panax ginseng fruit is known to have various biological effects owing to its large amount of saponins such as ginsenosides. In the present study, ginseng berry juice was confirmed to be effective against acute inflammation. Ginseng berry juice was used for analysis of active constituents, antioxidant efficacy, and in vivo inflammation. A high-performance liquid chromatography method was used for analysis of ginsenosides. In an HCl/ethanol-induced acute gastric injury model, microscopic, immunofluorescent, and immunohistochemical techniques were used for analysis of inhibition of gastric injury and mechanism study. In a mouse model of acute gastritis induced with HCl/ethanol, ginseng berry juice (GBJ, 250 mg/kg) showed similar gastric injury inhibitory effects as cabbage water extract (CB, 500 mg/kg, P.O). GBJ dose-dependently modulated the pro-inflammatory cytokines such as Tumor Necrosis Factor-α (TNF-α), Interleukin-6 (IL-6), and Interleukin-13 (IL-13). GBJ inhibited the activation of Nuclear Factor kappa bB (NF-κB) and suppressed the expressions of cyclooxigenase-2 (COX-2) and prostaglandin 2 (PGE2). The anti-inflammatory effect of GBJ is attributed to ginsenosides which have anti-inflammatory effects. Productivity as an effective food source for acute gastritis was analyzed and showed that GBJ was superior to CB. In addition, as a functional food for suppressing acute ulcerative symptoms, it was thought that the efficacy of gastric protection products would be higher if GBJ were produced in the form of juice rather than through various extraction methods.

Natural course of hemodynamically stable hemispheres contralateral to operated hemispheres in adult patients with ischemic moyamoya diseases.

The necessity of bilateral bypass in adult moyamoya disease (MMD) remains unclear despite its recommendation for pediatric and hemorrhagic cases. We aimed to investigate the natural course of hemodynamically stable unoperated hemispheres after bypass surgery for symptomatic and hemodynamically unstable hemispheres in adult patients with ischemic MMD. Among 288 patients, the mean age at the first operation of the unstable hemispheres was 40.8 ± 12.2 years. The mean follow-up period was 62.9 ± 46.5 months. 45 patients (15.6%) experienced stroke events in the unoperated hemisphere, consisting of hemorrhagic stroke in 8 (2.8%) and ischemic stroke in 37 (12.8%), including progressive transient ischemic attack in 25 (8.7%) and infarction in 12 (4.2%). Among them, 39 patients (13.5%) underwent bypass surgery. The annual risk of total stroke is 3.0%/patient-year, with 2.5% for ischemic stroke and 0.5% for hemorrhagic stroke. The 5- and 10-year cumulative risks of ischemic stroke were 13.4% and 18.3%, respectively, and those of hemorrhagic stroke were each 3.2%. The natural course of hemodynamically stable hemispheres contralateral to the operated ones appeared fairly good. Additional bypass surgery on the unoperated hemispheres should be considered for symptomatic and hemodynamically unstable hemispheres in adult patients with ischemic MMD during the follow-up.

Anti-inflammatory potential via the MAPK signaling pathway of Lactobacillus spp. isolated from canine feces.

Two probiotic candidates, Lactobacillus reuteri C1 (C1) and Lactobacillus acidophilus C5 (C5), which were previously isolated from canines, were evaluated in the present study. L. reuteri and L. acidophilus have anti-oxidant, anti-inflammatory, immune-enhancing, and anti-cancer properties and exhibit various probiotic effects in humans and animals. The strains C1 and C5 demonstrated good tolerance to acid and bile salt exposure, exhibited effective adhesion to HT-29 cell monolayer, and displayed sensitivity to antibiotics, thus affirming their probiotic characteristics. Moreover, C1 and C5 exhibited the ability to downregulate the expression of inducible NO synthase (iNOS), an immunomodulatory factor, leading to a reduction in NO production in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. These strains also demonstrated potent anti-inflammatory effects in LPS-stimulated RAW 264.7 cells, achieved through the augmentation of anti-inflammatory cytokine IL-10 expression and the inhibition of pro-inflammatory cytokine IL-1ß expression. These anti-inflammatory effects of C1 and C5 were closely associated with the mitogen-activated protein kinase (MAPK) signaling pathway. The results of the present study suggest that the C1 and C5 probiotic candidates attenuate LPS-induced inflammation via the MAPK signaling pathway and the strains can be used as probiotics considering their anti-inflammatory potential.

Blood-brain barrier disruption imaging in postoperative cerebral hyperperfusion syndrome using DCE-MRI.

Little has been reported about the association between cerebral hyperperfusion syndrome (CHS) and blood-brain barrier (BBB) disruption in human. We aimed to investigate the changes in permeability after bypass surgery in cerebrovascular steno-occlusive diseases using dynamic contrast-enhanced MRI (DCE-MRI) and to demonstrate the association between CHS and BBB disruption. This retrospective study included 36 patients (21 hemispheres in 18 CHS patients and 20 hemispheres in 18 controls) who underwent combined bypass surgery for moyamoya and atherosclerotic steno-occlusive diseases. DCE-MRI and arterial spin labeling perfusion-weighted imaging (ASL-PWI) were obtained at the baseline, postoperative state, and discharge. Perfusion and permeability parameters were calculated at the MCA territory (CBF(territorial), Ktrans(territorial), Vp(territorial)) and focal perianastomotic area (CBF(focal), Ktrans(focal), Vp(focal)) of operated hemispheres. As compared with the baseline, both CBF(territorial) and CBF(focal) increased in the postoperative period and decreased at discharge, corresponding well to symptoms in the CHS group. Vp(focal) was lower in the postoperative period and at discharge, as compared with the baseline. In the control group, no parameters significantly differed among the three points. In conclusion, Vp at the focal perianastomotic area significantly decreased in patients with CHS during the postoperative period. BBB disruption may be implicated in the development of CHS after bypass surgery.

The impact of early cryoballoon ablation on clinical outcome in patients with atrial fibrillation: From the Korean cryoballoon ablation registry.

INTRODUCTION: Influence of early atrial fibrillation (AF) ablation, particularly cryoballoon ablation (CBA), on clinical outcome during long-term follow-up has not been clarified. The objective was to determine whether an early CBA (diagnosis-to-ablation of ≤6 months) strategy could affect freedom from AF recurrence after index CBA. METHODS: The study included 2605 patients from Korean CBA registry data with follow-up >12 months after de novo CBA. The primary outcome was recurrence of atrial tachyarrhythmias (ATs) of ≥30-s after a 3-month blanking period. RESULTS: Compared to patients in early CBA group, patients in late CBA group had higher prevalence of diabetes, congestive heart failure, and chronic kidney disease, and higher mean CHA2 DS2 -VAS score. During mean follow-up of >21 months, ATs recurrence was detected in 839 (32.2%) patients. The early CBA group showed a significantly lower 2-year recurrence rate of ATs than the late CBA group (26.1% vs. 31.7%, p = 0.043). In subgroup analysis, the early CBA group showed significantly higher 1-year and 2-year freedom from ATs recurrence than the late CBA group only in paroxysmal atrial fibrillation (PAF) patients in overall and propensity score matched cohorts. Multivariate analysis showed that early CBA was an independent factor for preventing ATs recurrence in PAF (hazard ratio: 0.637; 95% confidence intervals: 0.412-0.984). CONCLUSION: Early CBA strategy, resulting in significantly lower ATs recurrence during 2-year follow-up after index CBA, might be considered as an initial rhythm control therapy in patients with paroxysmal AF.

Pelargonium sidoides extract mediates nephrotoxicity through mitochondrial malfunction and cytoskeleton destabilization.

We investigated the cytotoxic effect of Pelargonium sidoides extract on Madin-Darby canine kidney (MDCK) cells. P. sidoides extract decreased the cell viability in a dose dependent manner (> 0.2%). The extract of P. sidoides decreased the mitochondrial action potential, increased the number of reactive oxygen species (ROS) inside the cell, and caused nicotinamide adenine dinucleotide hydride (NADH) to be released, all of which are signs of mitochondrial dysfunction. The results of unbiased mRNA sequencing showed that 0.3% P. sidoides extract upregulates the apoptosis-related gene (BBC3). This finding was supported by immunoblot analysis of apoptosis signal pathways, which included Bcl-2, Bax, cytochrome C (CytC), cleaved caspase 3 (CC3), cleaved caspase 7 (CC7), cleaved caspase 9 (CC9) and cleaved PARP (CP). It is interesting to note that the elevated levels of Bax, CytC, CC3, CC7, and CC9, as well as CP, were suppressed by N-acetyl-L-cysteine (NAC) pretreatment, which points to ROS-mediated apoptosis. The small GTPases, RhoA, and Rac1/cdc42-GTP-bound active form were all lowered when P. sidoides extract was used. Also, RhoA-related cytoskeleton signals (ROCK, p-LIMK1/2, p-cofilin) and Rac1/cdc42-related signals (N-WASP, WAVE-2) were inhibited by P. sidoides extract. NAC or RhoA/Rac1/cdc42 activator pretreatment reduced P. sidoides extract-induced actin destabilization. In this work, P. sidoides extract promotes apoptosis by causing mitochondrial dysfunction and cytoskeleton disassembly.

Inhibitory Effects of Ehretia tinifolia Extract on the Excessive Oxidative and Inflammatory Responses in Lipopolysaccharide-Stimulated Mouse Kupffer Cells.

Ehretia tinifolia (E. tinifolia) L., an evergreen tree with substantial biological activity, including antioxidant and anti-inflammatory effects, has been used in many herbal and traditional medicines. To elucidate its antioxidant and anti-inflammatory activity and the underlying mechanisms, we applied a methanol extract of E. tinifolia (ETME) to lipopolysaccharide (LPS)-stimulated mouse immortalized Kupffer cells. ETME suppressed the LPS-induced increase in nitric oxide, a mediator for oxidative stress and inflammation, and restored LPS-mediated depletion of total glutathione level by stabilizing antioxidative nuclear factor erythroid 2-related factor 2 (Nrf2) and the subsequent increase in heme oxygenase-1 levels. Furthermore, ETME inhibited the LPS-induced production of pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin (IL)-1ß, and IL-6. The inhibitory effects of ETME on pro-inflammatory responses were regulated by ETME-mediated dephosphorylation of mitogen-activated protein kinases (MAPKs: p38, p44/p42, and stress-associated protein kinase/c-Jun N-terminal kinase) and inhibition of nuclear localization of nuclear factor kappa B (NF-κB). These results suggest that ETME is a possible candidate for protecting Kupffer cells from LPS-mediated oxidative stress and excessive inflammatory responses by activating antioxidant Nrf2/HO-1 and inhibiting pro-inflammatory NF-κB and MAPKs, respectively.

Is Thyroid Dysfunction Associated with Unruptured Intracranial Aneurysms? A Population-Based, Nested Case-Control Study from Korea.

Background: Few risk factors for the development of intracranial aneurysms (IAs) are known. We investigated the potential role of thyroid diseases in IA development using nationwide real-world data. Methods: A nested case-control study within the National Health Insurance Service-National Sample Cohort data from 2002 to 2019 was performed. A total of 5335 patients with unruptured IA were matched by age and sex with 80,025 controls at a ratio of 1:15. We estimated the odds ratios (ORs) and corresponding confidence intervals [CIs] between thyroid diseases and unruptured IA using a multivariable conditional logistic regression model. Results: Tobacco smoking, use of antihypertensive medication, and hypothyroidism were significantly associated with an elevated risk for unruptured IA in univariate analysis. In multivariable analysis, a history of hypothyroidism was associated with unruptured IA (adjusted OR: 1.46 [CI: 1.26-1.69]). Among patients with hypothyroidism, long-term use of thyroid hormone for >5 years was associated with a reduced risk for unruptured IA (adjusted OR: 0.69 [CI: 0.48-0.99]). A history of hyperthyroidism was associated with a reduced risk for unruptured IAs (adjusted OR: 0.71 [CI: 0.54-0.93]). In secondary analyses of the data according to sex, the respective observed associations between hypothyroidism and hyperthyroidism and the risk of IAs were found to be statistically significant in females but not in males. Conclusions: Hypothyroidism is associated with an increased risk of unruptured IAs, whereas hyperthyroidism is associated with a reduced risk. Overall, the findings suggest that thyroid hormones may play a protective role in the development of unruptured IAs. Further studies are needed to clarify potential direct causality and the biologic mechanisms relating thyroid dysfunction and unruptured IA.

Phonozen-mediated photodynamic therapy comparing two wavelengths in a mouse model of peritoneal carcinomatosis.

BACKGROUND: This study assessed the therapeutic efficacy of intraperitoneal photodynamic therapy (PDT) using photosensitizer activation at two different wavelengths, 405 and 664 nm, in a mouse model of peritoneal carcinomatosis. METHODS: The dark and light cytotoxicity of chlorin e6-polyvinylpyrrolidone (Phonozen) were measured in vitro under 402 ± 14 and 670 ± 18 nm LED activation in bioluminescent human gastric cancer cells, MKN45-luc. Cell viability was measured at 6 h after irradiation using the PrestoBlue assay. Corresponding in vivo studies were performed in athymic nude mice by intraperitoneal injection of 1 × 106 MKN45-luc cells. PDT was performed 10 d after tumor induction and comprised intraperitoneal injection of Phonozen followed by light irradiation at 3 h, delivered by a diffusing-tip optical fiber placed in the peritoneal cavity and coupled to a 405 or 664 nm diode laser to deliver a total energy of 50 J (20 mice per cohort). Whole-body bioluminescence imaging was used to track the tumor burden after PDT out to 130 days, and 5 mice in each cohort were sacrificed at 4 h post treatment to measure the acute tumor necrosis. RESULTS: Photosensitizer dose-dependent photocytotoxicity was higher in vitro at 405 than 664 nm. In vivo, PDT reduced the tumor growth rate at both wavelengths, with no statistically significant difference. There was substantial necrosis, and median survival was significantly prolonged at both wavelengths compared with controls (46 and 46 vs. 34 days). CONCLUSIONS: Phonozen-mediated PDT results in significant cytotoxicity in vitro as well as tumor necrosis and prolonged survival in vivo following intraperitoneal light irradiation. Blue light was more photocytotoxic than red in vitro and had marginally higher efficacy in vivo.

The ivy sign as a radiological marker for follow-up of postoperative cerebral perfusion status in adult moyamoya disease.

OBJECTIVE: Little is known about the relationship between postoperative changes in cerebral perfusion and the ivy sign representing leptomeningeal collateral burden in moyamoya disease (MMD). This study aimed to investigate the usefulness of the ivy sign in evaluating cerebral perfusion status following bypass surgery in patients with adult MMD. METHODS: Two hundred thirty-three hemispheres in 192 patients with adult MMD undergoing combined bypass between 2010 and 2018 were retrospectively enrolled. The ivy sign was represented as the ivy score on FLAIR MRI in each territory of the anterior, middle, and posterior cerebral arteries. Ivy scores, as well as clinical and hemodynamic states on SPECT, were semiquantitatively compared both preoperatively and at 6 months after surgery. RESULTS: Clinical status improved at 6 months after surgery (p < 0.01). On average, ivy scores in whole and individual territories were decreased at 6 months (all p values < 0.01). Cerebral blood flow (CBF) postoperatively improved in three individual vascular territories (all p values ≤ 0.03) except for the posterior cerebral artery territory (PCAt), and cerebrovascular reserve (CVR) improved in those areas (all p values ≤ 0.04) except for the PCAt. Postoperative changes in ivy scores and CBF were inversely correlated in all territories (p ≤ 0.02), except for the PCAt. Furthermore, changes in ivy scores and CVR were only correlated in the posterior half of the middle cerebral artery territory (p = 0.01). CONCLUSIONS: The ivy sign was significantly decreased after bypass surgery, which was well correlated with postoperative hemodynamic improvement in the anterior circulation territories. The ivy sign is believed to be a useful radiological marker for postoperative follow-up of cerebral perfusion status.

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.

A child who presented with cerebral infarction: Clipping combined with bypass surgery of a thrombosed giant aneurysm.

Background: Cerebral aneurysms are not common among children and most of them are presented with subarachnoid hemorrhage or mass effect. Here, we describe a rare case of a pediatric giant aneurysm presented with cerebral infarction. Case Description: A 38-month-old boy visited the emergency room due to left hemiparesis and left central type facial palsy. Initial magnetic resonance imaging showed acute cerebral infarction on the right basal ganglia and coronal radiata. Furthermore, a thrombosed aneurysm with a diameter of 30.57 mm at the frontal branch of the right middle cerebral artery was observed. A right pterional craniotomy with Sylvian dissection was performed. Superior and inferior divisions of the frontal branch originating from the aneurysm were identified. The superior division was cutoff from an aneurysm and clipping saving the inferior division was done. Subsequently, end-to-end anastomosis was done between a parietal branch of the superficial temporal artery and a superior division from the aneurysm. No acute complication from the operation was observed. Motor power of the left upper extremity recovered after rehabilitation, while fine motor impairment remained 6 months after the surgery. Conclusion: This case illustrates successful treatment of a pediatric giant aneurysm with extremely rare presentation of cerebral infarction, under a meticulous surgical plan and ad hoc modification.

Biomechanical microenvironmental stimulating effect of pulsed electromagnetic field on the regeneration of crush injured rat sciatic nerve.

This study evaluated the biomechanical microenvironmental stimulating effect of pulsed electromagnetic field (PEMF) on the regeneration of crush-injured rat sciatic nerve, when combined with bone marrow mesenchymal stem cells (BMSCs) and recombinant human nerve growth factor (rhNGF-ß), in the form of an adenoviral vector-mediated NGF. Sprague-Dawley rats were equally distributed into six groups; PBS, BMSC, NGF-Ad + BMSC, PEMF + PBS, PEMF + BMSC and PEMF + NGF-Ad + BMSC. The PBS group received PBS (volume: 10µL/rat), the BMSC group with BMSCs (1 × 106 cell/10 µL/rat) and NGF-Ad group with the rhNGF-ß Ad infected BMSCs (1 × 106 cell/10 µL/rat) immediate after right sciatic nerve crush injury. The PEMF groups were exposed to PEMF of 1mT, 50 Hz, 1 h/day. The rats were observed for 3 weeks. PEMF alone did not showed the positive effect compared with negative control group. The groups transplanted with BMSCs showed higher axonal regeneration compared with the groups without transplantation of the cells whether BMSC was infected with NGF-Ad or not and whether the animals received PEMF. PEMF + NGF-Ad + BMSC group showed the significantly highest number of axons than the other groups. Functionally, all groups showed marked improvement at 3 weeks postoperatively although the difference was not statistically significant among the groups. PEMF showed the positive effect when combined with BMSC and NGF-ad in aspect of number of axons. Therefore, combining the microenvironment stimulation methods of PEMF and conventional methods such as transplantation of stem cells and growth factor could be considered for the regeneration methods in the nerve damage.

Aryl hydrocarbon receptor maintains hepatic mitochondrial homeostasis in mice.

OBJECTIVE: Mitophagy removes damaged mitochondria to maintain cellular homeostasis. Aryl hydrocarbon receptor (AhR) expression in the liver plays a crucial role in supporting normal liver functions, but its impact on mitochondrial function is unclear. Here, we identified a new role of AhR in the regulation of mitophagy to control hepatic energy homeostasis. METHODS: In this study, we utilized primary hepatocytes from AhR knockout (KO) mice and AhR knockdown AML12 hepatocytes. An endogenous AhR ligand, kynurenine (Kyn), was used to activate AhR in AML12 hepatocytes. Mitochondrial function and mitophagy process were comprehensively assessed by MitoSOX and mt-Keima fluorescence imaging, Seahorse XF-based oxygen consumption rate measurement, and Mitoplate S-1 mitochondrial substrate utilization analysis. RESULTS: Transcriptomic analysis indicated that mitochondria-related gene sets were dysregulated in AhR KO liver. In both primary mouse hepatocytes and AML12 hepatocyte cell lines, AhR inhibition strongly suppressed mitochondrial respiration rate and substrate utilization. AhR inhibition also blunted the fasting response of several essential autophagy genes and the mitophagy process. We further identified BCL2 interacting protein 3 (BNIP3), a mitophagy receptor that senses nutrient stress, as an AhR target gene. AhR is directly recruited to the Bnip3 genomic locus, and Bnip3 transcription was enhanced by AhR endogenous ligand treatment in wild-type liver and abolished entirely in AhR KO liver. Mechanistically, overexpression of Bnip3 in AhR knockdown cells mitigated the production of mitochondrial reactive oxygen species (ROS) and restored functional mitophagy. CONCLUSIONS: AhR regulation of the mitophagy receptor BNIP3 coordinates hepatic mitochondrial function. Loss of AhR induces mitochondrial ROS production and impairs mitochondrial respiration. These findings provide new insight into how endogenous AhR governs hepatic mitochondrial homeostasis.

Purification of phenoloxidase from Haliotis discus hannai and its anti-inflammatory activity in vitro.

Haliotis discus hannai, a food with a high protein content, is widely consumed in Asian countries. It is known to have antioxidant, anticancer, and antibacterial effects. Since the biological significance of H. discus hannai hemolymph has not been widely studied, the objective of the present study was to purify phenoloxidase (PO) and investigate its immunological effects on human colonic epithelial cells. PO was purified through ammonium sulfate precipitation and one step column chromatography. The molecular weight of the protein was about 270 kDa. When PO was mixed with Gram-negative bacteria-derived lipopolysaccharide (LPS) at various ratios (10:1-1:10, w/w), the amount of residual LPS was reduced. PO at concentrations up to 200 µg/mL was not cytotoxic to HT-29 cells. The inflammatory response induced by LPS in HT-29 cells was regulated when the concentration of PO was increased. With increasing concentration of PO, production levels of pro-inflammatory cytokines, cytokines associated with hyperimmune responses such as IL4, IL-5, and INF-γ, and prostaglandin 2 (PGE2) were regulated. It was thought that simultaneous treatment with PO and LPS anti-inflammatory effects in HT-29 cells showed by regulating the ERK1/2-mediated NF-κB pathway. Results of this study suggest that H. discus hannai hemolymph is involved in the regulation of Gram-negative bacteria-related inflammatory immune responses in human colonic epithelial cells.

Population-Attributable Risk Fractions for Antiplatelets and Anticoagulants in Spontaneous Intracranial Hemorrhages.

INTRODUCTION: Concerns about spontaneous intracranial hemorrhages (sICHs) have increased over time with the increasing use of antithrombotic agents. Hence, we aimed to analyze the risk and risk fractions for antithrombotics in sICHs in South Korea. METHODS: From the National Health Insurance Service-National Sample Cohort including 1,108,369 citizens, 4,385 cases, aged 20 years or more and newly diagnosed as sICHs between 2003 and 2015, were included in this study. A total of 65,775 sICH-free controls were randomly selected at a ratio of 1:15 from individuals with the same birth year and sex according to a nested case-control study design. RESULTS: Although the incidence rate of sICHs started to decrease from 2007 onward, the use of antiplatelets, anticoagulants, and statins continued to increase. Antiplatelets (adjusted odds ratio [OR] 3.59, 95% confidence interval [CI] 3.18-4.05), anticoagulants (adjusted OR 7.46, 95% CI 4.92-11.32), and statins (adjusted OR 1.98, 95% CI 1.79-2.18) were significant risk factors for sICHs even after adjusting for hypertension, alcohol intake, and cigarette smoking. From 2003-2008 to 2009-2015, the population-attributable fractions changed from 28.0% to 31.3% for hypertension, from 2.0% to 3.2% for antiplatelets, and from 0.5% to 0.9% for anticoagulants. CONCLUSION: Antithrombotic agents are significant risk factors for sICHs, and their contribution is increasing over time in Korea. These findings are expected to draw the attention of clinicians to precautions to be taken when prescribing antithrombotic agents.

Role of surgery in management of intracranial dural arteriovenous fistulas.

Intracranial dural arteriovenous fistulas (DAVF) are abnormal connections between intracranial arterial and venous systems within the dural layers. Intracranial DAVFs are rare but can occur wherever dural components exist. The pathogenesis of DAVFs is controversial. Venous hypertension is considered as a main cause of clinical symptoms which are subclassified into asymptomatic, benign and aggressive manifestations. To date, several classification schemes have been proposed to stratify the natural course and risks of DAVFs. Currently, endovascular therapy is the main treatment modality. Moreover, the use of radiosurgery and radiotherapy has been limited. Open surgery is also selectively performed as a main treatment modality for specific types of DAVFs and an adjunctive modality for the endovascular approach. Herein, we present a review of the general perspectives of intracranial DAVFs with an emphasis on the role of surgery.

Public awareness of chronic venous disease in Korea.

OBJECTIVE: This study aimed to evaluate the current level of chronic venous disease (CVD) awareness and its relevant influencing factors. METHODS: Online and interview surveys were conducted in two distinct groups from May 14 to June 16, 2020. An online survey was conducted among 900 adults aged 20 to 64 years from the research database, whereas interviews were conducted among 124 patients who presented with CVD symptoms, which covered the awareness of such symptoms and their impact on quality of life. RESULTS: Most respondents reported low levels of CVD awareness by recognizing the disease only by an entity. In 53 respondents who visited the hospital with suspected venous symptoms, the actual diagnosis was made in only 30.2%. CVD diagnosis was associated with increased CVD awareness. Female sex, age of >29 years, higher educational level, and higher income were associated with increased CVD awareness. Approximately 60% of the patients with CVD responded that physical symptoms had a negative impact on their quality of life rather than emotion or appearance. CONCLUSIONS: The public is largely unaware of CVD but not in detail. Educational programs to improve CVD awareness should be implemented to enable appropriate CVD management.