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FK506-binding proteins (FKBPs) belong to the immunophilin family and are linked to various disease states, including the inflammatory response. The inhibition of cytokine and chemokine expression i...

Peroxisome proliferator-activated receptor gamma (PPARγ) is a master transcription factor in adipocyte differentiation, while distal-less homeobox 5 (Dlx5) is essential for initiating osteoblast differentiation by driving Runt-related transcription factor 2 expression. Considering that adipocytes and osteoblasts share common progenitors, there is a reciprocal correlation between bone and fat formation. However, the mechanism by which Dlx5 controls PPARγ remains unclear. We elucidated that Dlx5 physically binds to PPARγ during immunoprecipitation; in particular, the ligand-binding and DNA-binding domains of PPARγ were involved in the interaction. Transcriptional activity of PPARγ was significantly decreased by Dlx5 overexpression, whereas the opposite results were detected with Dlx5 knockdown. Rosiglitazone, a PPARγ agonist, further enhanced the PPARγ-induced transcriptional activity; however, Dlx5 overexpression effectively repressed the rosiglitazone-mediated increase in activity. Finally, DNA-binding affinity assay revealed that Dlx5 interrupts the interaction of PPARγ with the PPARγ response element promoter. In conclusion, our findings indicate that Dlx5 impedes PPARγ-induced activity, and it may be useful for managing diabetes drug-mediated obesity.

Alcohol consumption causes metabolic disorders and is a known risk factor for cardiovascular disease. However, some studies suggested that low level alcohol consumption improves insulin resistance. We evaluated the effects of alcohol consumption on insulin resistance using the homeostatic model assessment for insulin resistance (HOMA-IR).This study included 280,194 people without diabetes who underwent comprehensive health examinations more than twice between 2011 and 2018. The levels of alcohol intake were obtained through a self-questionnaire. All subjects were divided into two groups based on the Korean standard cut-off value of HOMA-IR, 2.2. Cox proportional hazard analysis was used to assess the risk of insulin resistance according to alcohol consumption. The mean age of the study subjects was 38.2 years and 55.7% were men. During the follow-up period (median 4.13 years), HOMA-IR progressed from2.2 to ≥2.2 in 64,443 subjects (23.0%) and improved from ≥2.2 to2.2 in 21,673 subjects (7.7%). In the parametric survival analysis, alcohol consumption was associated with improvement of HOMA-IR (HR [95% CI], 1.09[1.03-1.14], 1.11[1.06-1.17] and 1.20[1.13-1.26], respectively). In the analysis classified according to changes in alcohol consumption amounts, increased alcohol consumption tended to prevent the progression of HOMA-IR (0.97[0.96-0.99]; p = 0.004). However, the association between the changes in alcohol consumption amounts and improvement of HOMA-IR was not statistically significant.This retrospective observational study has shown that alcohol consumption can improve insulin resistance and increased alcohol consumption amounts may have preventive effects on the progression of HOMA-IR compared to the baseline level.

BackgroundPostoperative atrial fibrillation (POAF) is related to mortality after non-cardiac surgery. Left atrial volume index (LAVI) is known to be associated with prognosis and development of atrial fibrillation, but it has not been fully investigated in patients undergoing non-cardiac surgery.Materials and methodsA total of 203,787 consecutive adult patients underwent non-cardiac surgery at our institution between January 2011 and June 2019. After identifying those with available LAVI estimated during preoperative echocardiography, we divided them into those with LAVI higher and lower than 34 mL/m2. The primary outcome was incidence of POAF.ResultsA total of 83,097 patients were enrolled in this study. The study patients were divided into the low (57,838 [69.6%]) and high (25,259 [30.4%]) LAVI groups. After an adjustment, higher LAVI was associated with increased incidence of POAF (5.1% vs. 8.1%; odds ratio [OR], 1.33; 95% confidence interval [CI], 1.25–1.41; p < 0.001). In 24,549 pairs of propensity-score-matched population, the result was similar (6.2% vs. 7.9%; OR, 1.30; 95% CI, 1.21–1.39; p < 0.001). The estimated threshold of LAVI associated with POAF was 36.4 mL/m2 with an area under the curve of 0.571. Subgroup analysis in non-thoracic and thoracic surgery showed that the association between preoperative LAVI and POAF significantly interacted with diastolic dysfunction (p for interaction < 0.001), and the observed association was valid in patients without diastolic dysfunction.ConclusionPreoperative LAVI was shown to be associated with POAF in non-cardiac surgery. Our result needs verification in further studies.

Objective: The aim of this study was to develop, compare, and validate models for predicting cardiovascular disease (CVD) mortality and hospitalization with hypertension using a conventional statistical model and a deep learning model. Methods: Using the database of Korean National Health Insurance Service, 2,037,027 participants with hypertension were identified. Among them, CVD (myocardial infarction or stroke) death and/or hospitalization that occurred within one year after the last visit were analyzed. Oversampling was performed using the synthetic minority oversampling algorithm to resolve imbalances in the number of samples between case and control groups. The logistic regression method and deep neural network (DNN) method were used to train models for assessing the risk of mortality and hospitalization. Findings: Deep learning-based prediction model showed a higher performance in all datasets than the logistic regression model in predicting CVD hospitalization (accuracy, 0.863 vs. 0.655; F1-score, 0.854 vs. 0.656; AUC, 0.932 vs. 0.655) and CVD death (accuracy, 0.925 vs. 0.780; F1-score, 0.924 vs. 0.783; AUC, 0.979 vs. 0.780). Interpretation: The deep learning model could accurately predict CVD hospitalization and death within a year in patients with hypertension. The findings of this study could allow for prevention and monitoring by allocating resources to high-risk patients.

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.

Background A single‑lead implantable cardioverter-defibrillator (ICD) with a floating atrial dipole has been developed to enhance the diagnostic capability of atrial arrhythmias and to facilitate adjudication of arrhythmic events without the additional effort required for atrial lead insertion. However, there have been concerns about the long-term reliability of atrial sensing. Methods We enrolled patients with the single-chamber ICD with atrial-sensing electrodes from 4 tertiary university hospitals in Korea. Minimal, maximal, and mean P wave amplitudes were collected at 3–6 months, 6–12 months, and 12–24 months after implantation. The difference between the minimal and maximal sensing amplitudes was calculated as an indicator of the variability of atrial sensing, while the atrial sensing stability was assessed using the mean amplitude. Results A total of 86 patients were included for analysis. The variability of atrial sensing amplitudes significantly decreased at 12–24 months compared to 3–6 months (p = 0.01), while mean atrial amplitudes were stable throughout the mean follow-up duration of 17.4 months. Nine patients (10.5%) experienced inappropriate ICD therapy mostly due to misclassification of supraventricular tachycardia. Conclusions Under the hypothesis that sensing stability can be guaranteed as the variability decreases with time, we suggest that the concern about long-term sensing stability of a floating dipole can be abated with an ICD that has been implanted for over 2 years.

Endovascular treatment of fenestration-related aneurysms (FAs) is prone to technical challenges, given the inherent complexities. Herein, we have analyzed FAs in terms of angioarchitectural characteristics and outcomes achieved through endovascular intervention. Data accrued prospectively between January 2002 and July 2020 were productive of 105 FAs in 103 patients, each classifiable by the nature of incorporated vasculature as proximal portion, fenestrated limb, or distal end. Our investigation focused on clinical and morphological outcomes, with emphasis on technical aspects of treatment. The FAs selected for study originated primarily in anterior communicating artery (AcomA: 88/105, 83.8%), followed by basilar (7/105, 6.7%), anterior cerebral (4/105, 3.8%), and internal carotid (3/105, 2.8%) arteries. In nearly all locations, proximally situated aneurysms (43/105, 41%) were more frequent than aneurysms arising at distal ends (3/105, 2.8%), but the majority of AcomA lesions involved fenestrated segments (58/88, 65.9%); and most fenestrated channels (90/105, 85.7%) were asymmetric in size. Orifices of smaller fenestrated limbs were intentionally compromised during coil embolization in 23 aneurysms (21.9%), achieving complete (n = 19) or incomplete (n = 4) compromise, without resultant symptomatic ischemia. Saccular occlusion proved satisfactory in 77 lesions (73.3%). In follow-up monitoring of 100 patients for a mean period of 35.3 ± 26.5 months, 17 instances of recanalization (17.0%) occurred (minor, 9; major, 8). There was no recanalization of aneurysms with compromised limbs. Coil embolization of FAs is safe and effective, enabling tailored procedures that accommodate aberrant angioanatomic configurations. Compromise of a single limb during coiling also appears safe, conferring long-term protection from recanalization.

The present study was performed to investigate the effect of maternal hypothyroidism and puberty onset in female rat pups. To do this, we employed propylthiouracil (PTU) to prepare a hypothyroid rat model. Pregnant rats were treated with PTU (0.025%) in drinking water from gestational day 14 to postnatal day 21 of offspring. Comparison of general indices such as body and tissue weights and puberty indices such as vaginal opening (VO) and tissue histology between control and PTU-treated rats were conducted. There was no significant difference in the date of VO between control and PTU group. The body weights of the PTU group were significantly lower, only 36.8% of the control group (p

To compare femoral sagittal axis between navigated total knee arthroplasty (TKA) and conventional TKA. A total of 136 cases were assigned to group 1 (navigated TKA) and 77 cases were assigned to group 2 (conventional TKA). Specifically, this study targeted patients with degenerative osteoarthritis. Only patients with primary TKA were analyzed. Hip knee ankle angle and lateral femoral bowing were measured using preoperative scanogram. Anterior femoral bowing was measured using preoperative femoral lateral X rays. The presence of anterior femoral notching and the insertion angle of the femoral implant with respect to the anatomical sagittal plane of the distal femur were checked using postoperative lateral knee X rays. Student t-test was used to compare the difference in the position of the sagittal plane of the femoral implant between the navigated TKA group and the conventional TKA group. When comparing the 2 groups, the sagittal axis of the femoral implant was more extended than the anatomical sagittal plane axis of the distal femur in group 1 than in group 2 (P = .01). There was a significant negative correlation between the value of anterior femoral bowing and the degree of flexion to the sagittal plane of the femoral implant in group 1 (correlation coefficient: -0.40, P = .01). The occurrence of anterior femoral notching was significantly higher in group 1 than in group 2. During navigated TKA, imageless navigation does not consider the anatomical variation of the femoral shaft. Therefore, surgeons should take into consideration that when performing navigated TKA, a femoral implant could be inserted more extended for the anatomical sagittal axis of the distal femur than for the conventional TKA. Also, surgeon should know that the degree of extension insertion of the femoral implant increases as femoral anterior bowing increases.

Neurally mediated syncope (NMS) is a common clinical problem. The underlying genetic factors of NMS remain controversial. We hypothesized that cardiac syncope-related genes may contribute to NMS in patients with previous frequent syncopal episodes and/or a family history of syncope. A total of 54 consecutive patients diagnosed with NMS were prospectively enrolled between 2013 and 2016. Inclusion criteria were more than five syncopal episodes with a family history of syncope (n = 17) or more than five syncopal episodes with no family history of syncope (n = 37). Ninety-eight cardiac syncope-related genes (channelopathy: 43 genes, cardiomyopathy: 50 genes, primary pulmonary hypertension: 5 genes) were screened by exome sequencing. All identified variants were classified according to the standards and guidelines by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Of the 54 patients, 17 patients (31.5%) had a family history of syncope. Two patients (3.7%) had pathogenic and likely pathogenic variants (PV/LPV) in cardiac syncope-related genes TTN and MYH7. We investigated genetic variation in patients with frequent NMS with a positive family history of syncope in Korea. PV/LPVs in genes related to cardiomyopathy were associated with recurrent NMS in Korean patients. Closer follow-up of these patients might be needed.

Cyclophilin A (CypA) is a ubiquitously expressed and highly conserved protein with peptidyl-prolyl cis-trans isomerase activity that is involved in various biological activities by regulating protein folding and trafficking. Although CypA has been reported to positively regulate osteoblast differentiation, the mechanistic details remain largely unknown. In this study, we aimed to elucidate the mechanism of CypA-mediated regulation of osteoblast differentiation. Overexpression of CypA promoted osteoblast differentiation in bone morphogenic protein 4 (BMP4)-treated C2C12 cells, while knockdown of CypA inhibited osteoblast differentiation in BMP4-treated C2C12. CypA and Runx2 were shown to interact based on immunoprecipitation experiments and CypA increased Runx2 transcriptional activity in a dose-dependent manner. Our results indicate that this may be because CypA can increase the DNA binding affinity of Runx2 to Runx2 binding sites such as osteoblast-specific cis-acting element 2. Furthermore, to identify factors upstream of CypA in the regulation of osteoblast differentiation, various kinase inhibitors known to affect osteoblast differentiation were applied during osteogenesis. Akt inhibition resulted in the most significant suppression of osteogenesis in BMP4-induced C2C12 cells overexpressing CypA. Taken together, our results show that CypA positively regulates osteoblast differentiation by increasing the DNA binding affinity of Runx2, and Akt signaling is upstream of CypA.

Chronic subdural hematomas (cSDHs) are generally known to result from traumatic tears of bridging veins. However, the causes of repeat spontaneous cSDHs are still unclear. We investigated the changes in vasculature in the human dura mater and outer membrane (OM) of cSDHs to elucidate the cause of their spontaneous repetition. The dura mater was obtained from a normal control participant and a patient with repeat spontaneous cSDHs. The pathological samples from the patient included the dura mater and OM tightly adhered to the inner dura. The samples were analyzed with a particular focus on blood and lymphatic vessels by immunohistochemistry, 3-dimensional imaging using a transparent tissue clearing technique, and electron microscopy. The dural border cell (DBC) layer of the dura mater and OM were histologically indistinguishable. There were 5.9 times more blood vessels per unit volume of tissue in the DBC layer and OM in the patient than in the normal control. The DBC layer and OM contained pathological sinusoidal capillaries not observed in the normal tissue; these capillaries were connected to the middle meningeal arteries via penetrating arteries. In addition, marked lymphangiogenesis in the periosteal and meningeal layers was observed in the patient with cSDHs. Neovascularization in the OM seemed to originate from the DBC layer; this is a potential cause of repeat spontaneous cSDHs. Embolization of the meningeal arteries to interrupt the blood supply to pathological capillaries via penetrating arteries may be an effective treatment option.

This paper presents a new design and fabrication method of flexible neural microprobes for deep brain stimulations (DBS) and neurological treatment applications. The developed new flexible microprobes are compatible with functional magnetic resonance imaging (fMRI) and can be used for neurological studies of brain functions under functional imaging such as fMRI for a long period of time. In this paper, the materials of the flexible neural microprobes are comprehensively selected to minimize the magnetic resonance imaging (MRI) artifacts, which limits many conventional feasible manufacturing processes to be used. Polyimide was adopted for the substrate of the neural microprobe, which has good biocompatibility and a relatively lower Young’s modulus. A 200 nm chromium reinforcement layer was embedded in the microprobe to attenuate its implantation stiffness while remaining flexible. Gold electroplating was employed to modify the electrode sites to improve the signal quality and sensitivity. The designed new neural microprobes were successfully fabricated at our NCSU Nanofabrication Facility (NNF) and bonded to a customized PCB. After the fabrication, the developed neural microprobes were characterized to validate their effectiveness. In vivo simultaneous DBS-fMRI experiments were conducted in surgery rooms on a rat’s deep brain targets, demonstrating the potential applications of our neural microprobe for neuroscience studies, medical diagnosis, and treatment applications. In vivo electrophysiology results show the effectiveness of our fabricated neural microprobes.

The salience network (SN) and default mode network (DMN) play a crucial role in cognitive function. The SN, anchored in the anterior insular cortex (AI), has been hypothesized to modulate DMN activity during stimulus-driven cognition. However, the causal neural mechanisms underlying changes in DMN activity and its functional connectivity with the SN are poorly understood. Here we combine feedforward optogenetic stimulation with fMRI and computational modeling to dissect the causal role of AI neurons in dynamic functional interactions between SN and DMN nodes in the rat brain. Optogenetic stimulation of Chronos-expressing AI neurons in rats suppressed DMN activity, and decreased AI-DMN and intra-DMN functional connectivity. Our findings demonstrate that feedforward optogenetic stimulation of AI neurons induces dynamic suppression and decoupling of the DMN and elucidates previously unknown features of rodent brain network organization. Our study advances foundational knowledge of causal mechanisms underlying dynamic cross-network interactions and brain network switching.TeaserInsular cortex stimulation reveals causal mechanisms underlying default mode network suppression by the salience network

Chamaecyparis obtusa (Siebold & Zucc.) Endl. (Cupressaceae) is known to produce a variety of antimicrobial substances. In the present study, components of three lots of essential oil from C. obtusa were analyzed by GCMS. It was confirmed that thujopsene and pinene were common markers. In addition, we report indoor space disinfectant effects of products containing C. obtusa essential oil (PO100, PO500, PO1000). It was confirmed that PO100 and PO500 could effectively remove airborne microorganisms in indoor spaces. Results of our study suggest that C. obtusa essential oil is effective in reducing contamination by infectious microorganisms in confined spaces.

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.

Backgrounds/aims Despite advances in surgical techniques and perioperative supportive care, radical resection of hilar cholangiocarcinoma is the only modality that can achieve long-term survival. We chronologically investigated surgical and oncological outcomes of hilar cholangiocarcinoma and analyzed the factors affecting overall survival. Methods We retrospectively enrolled 165 patients with hilar cholangiocarcinoma who underwent liver resection with a curative intent. The patients were divided into groups based on the period when the surgery was performed: period I (2005-2011) and period II (2012-2018). The clinicopathological characteristics, perioperative outcomes, and survival outcomes were analyzed. Results The patients' age, serum CA19-9 levels, and serum bilirubin levels at diagnosis were significantly higher in the period I group. There were no differences in pathological characteristics such as tumor stage, histopathologic status, and resection status. However, perioperative outcomes, such as estimated blood loss (1528.8 vs. 1034.1 mL, p=0.020) and postoperative severe complication rate (51.3% vs. 26.4%, p=0.022), were significantly lower in the period II group. Regression analysis demonstrated that period I (hazard ratio [HR]=1.591; 95% confidence interval [CI]=1.049-2.414; p=0.029), preoperative serum bilirubin at diagnosis (HR=1.585; 95% CI=1.058-2.374; p=0.026), and tumor stage (III, IV) (HR=1.671; 95% CI: 1.133-2.464; p=0.010) were significantly associated with poor prognosis. The 5-year survival rate was better in the period II patients than in the period I patients (35.1% vs. 21.0%, p=0.0071). Conclusions The surgical and oncological outcomes were better in period II. Preoperative serum bilirubin and advanced tumor stage were associated with poor prognosis in patients with hilar cholangiocarcinoma.

This review gives an account on the fast expanding field of monomeric (or molecular) heptazines, at the exclusion of their various polymeric forms, often referred to as carbon nitrides. While examp...

The proper administration of melatonin has well been documented to induce testicular regression in seasonal breeding animals. The subcutaneous injections of melatonin in the afternoon, not in the morning, consistently occurred testicular involution in the male Syrian (golden) hamsters whose reproductive activity is regulated by the photoperiod. But the effects of daily melatonin via gavage have not been estimated. Golden hamsters housed in long photoperiod (LP) were divided into 5 groups: the control animals housed in LP or in short photoperiod (SP) and animals treated daily with low (15 μg), middle (150 μg), and high dosages (1,500 μg) of pure melatonin by using gavage in the evening for 8 weeks. As results, LP control animals had large testes and SP controls displayed small and entirely regressed testes. The animals treated with various dosages of melatonin showed collectively degenerating effects on the weights of testes, epididymides, and seminal vesicles in the middle and high dosage groups, with the individual differences as well. The high dosages induced testicular regression in more proportion than the middle dosages did. The low dosage had large testes like the LP control animals. The small and inactive testes shown in some animals of both middle and high groups presented the complete regression as those of the animals maintained in SP. These results strongly suggest that the administrations of melatonin lead to testicular involution in the male golden hamsters when it is administered through gavage.

Spermatogonial stem cells (SSCs) have stemness characteristics, including germ cell-specific imprints that allow them to form gametes. Spermatogenesis involves changes in gene expression such as a transition from expression of somatic to germ cell-specific genes, global repression of gene expression, meiotic sex chromosome inactivation, highly condensed packing of the nucleus with protamines, and morphogenesis. These step-by-step processes finally generate spermatozoa that are fertilization competent. Dynamic epigenetic modifications also confer totipotency to germ cells after fertilization. Primordial germ cells (PGCs) in embryos do not enter meiosis, remain in the proliferative stage, and are referred to as gonocytes, before entering quiescence. Gonocytes develop into SSCs at about 6 days after birth in rodents. Although chromatin structural modification by Polycomb is essential for gene silencing in mammals, and epigenetic changes are critical in spermatogenesis, a comprehensive understanding of transcriptional regulation is lacking. Recently, we evaluated the expression profiles of Yin Yang 1 (YY1) and CP2c in the gonads of E14.5 and 12-week-old mice. YY1 localizes at the nucleus and/or cytoplasm at specific stages of spermatogenesis, possibly by interaction with CP2c and YY1-interacting transcription factor. In the present article, we discuss the possible roles of YY1 and CP2c in spermatogenesis and stemness based on our results and a review of the relevant literature.

Atrial fibrillation (AF) patients with low to intermediate risk, defined as non-gender CHAThis multi-center cohort study retrospectively analyzed AF patients with non-gender CHAOverall, 2694 patients [56.3±9.5 years; female, 726 (26.9%)] were followed-up for 4.0±2.8 years. The overall stroke rate was 0.84/100 person-years (P-Y), stratified as follows: 0.46/100 P-Y for an ABCD score of 0; 1.02/100 P-Y for an ABCD score ≥1. The ABCD score was superior to non-gender CHAThe biomarker-based ABCD score demonstrated improved stroke risk stratification in AF patients with non-gender CHA

The default mode network (DMN) of the brain is involved in cognition, emotion regulation, impulsivity, and balancing between internally and externally focused states. DMN dysregulation has been implicated in several neurological and neuropsychiatric disorders. In this study, we used functional magnetic resonance imaging (fMRI), positron emission tomography (PET), and spectral fiber-photometry to investigate the selective neuromodulatory effect of norepinephrine (NE)-releasing noradrenergic neurons in the locus coeruleus (LC) on the DMN in mice. Chemogenetic-induced tonic LC-NE activity decreased cerebral blood volume (CBV) and glucose uptake, and increased synchronous low frequency fMRI activity within the frontal cortices of the DMN. Fiber-photometry results corroborated these findings, showing that LC-NE activation induced NE release, enhanced calcium-weighted neuronal spiking, and reduced CBV in the anterior cingulate cortex. These data suggest that LC-NE alters conventional stimulus-evoked coupling between neuronal activity and CBV in the frontal DMN. We also demonstrated that chemogenetic activation of LC-NE neurons strengthened functional connectivity within the frontal DMN, and this effect was causally mediated by reduced modulatory inputs from retrosplenial and hippocampal regions to the association cortices of the DMN.

Task-free functional connectivity in animal models provides an experimental framework to examine connectivity phenomena under controlled conditions and allows comparison with invasive or terminal procedures. To date, animal acquisitions are performed with varying protocols and analyses that hamper result comparison and integration. We introduce StandardRat, a consensus rat functional MRI acquisition protocol tested across 20 centers. To develop this protocol with optimized acquisition and processing parameters, we initially aggregated 65 functional imaging datasets acquired in rats from 46 centers. We developed a reproducible pipeline for the analysis of rat data acquired with diverse protocols and determined experimental and processing parameters associated with a more robust functional connectivity detection. We show that the standardized protocol enhances biologically plausible functional connectivity patterns, relative to pre-existing acquisitions. The protocol and processing pipeline described here are openly shared with the neuroimaging community to promote interoperability and cooperation towards tackling the most important challenges in neuroscience.

We present the relationship between an aneurysm in adult moyamoya disease (MMD) patients and a future stroke event.One hundred forty-seven aneurysms were found in 118 adult MMD patients. To find risk factors for future hemorrhagic and ischemic stroke, Kaplan-Meier and Cox-regression analyses were performed on clinical and radiologic factors. In addition to the anatomical classification method based on the circle of Willis, aneurysms occurring in the collateral pathway were analyzed by reflecting the hemodynamic changes in MMD.The initial clinical presentations are divided into ischemia (n = 53, 44.9%), hemorrhage (n = 51, 43.2%), and asymptomatic (n = 14, 11.9%). The mean size of the aneurysms was 2.9 ± 1.67 mm. Thirty-four aneurysms were treated with coil (n = 24) and glue embolization (n = 10). One hundred thirteen aneurysms were conservatively managed. All of aneurysms did not cause recurrent hemorrhagic strokes by aneurysm rupture. The mean follow-up period duration was 78.3 ± 58.9 months. The overall estimated rate of hemorrhage was 10.5%/hemisphere at 5 years and 18.2%/hemisphere at 10 years after the initial angiography. The overall estimated rate of infarction was 2.8%/hemisphere at 5 years and 4.5%/hemisphere at 10 years after the initial angiography. A Cox regression analysis revealed that a collateral pathway aneurysm is a significant risk factor for hemorrhagic stroke (P = 0.045, hazard ratio = 2.366). However, less hemorrhaging occurred in MMD patients with hypertension (P = 0.018, hazard ratio = 0.364).The presence of a collateral pathway aneurysm appears to reflect the hemodynamic stress exerted on the cerebral hemispheres of MMD patients, suggesting an increased risk of future hemorrhagic strokes.

It is unclear which factors are associated with progressive sinus node dysfunction after cavotricuspid isthmus (CTI)-dependent atrial flutter (AFL) ablation. We sought to evaluate the incidence and predictors for permanent pacemaker (PPM) implantation after CTI-dependent AFL ablation. Between January 2011 and June 2021, 353 patients underwent CTI-dependent AFL ablation were studied. During a median follow-up of 31.6 months, 30 patients (8.5%) received PPM implantation, 24 for sick sinus syndrome and 6 for atrioventricular block. In multivariable model, prior atrial fibrillation (AF) (HR 3.570; 95% CI 1.034–12.325; P = 0.044), lowest previous sinus heart rate (HR 0.942; 95% CI 0.898–0.988; P = 0.015), and left atrial volume index (LAVI) (HR 1.067; 95% CI 1.024–1.112; P = 0.002) were independently associated with PPM implantation after CTI-dependent AFL ablation. The best cut-off points for predicting PPM implantation were 60.1 ml/m2 for LAVI and 46 beats per minute for lowest previous sinus heart rate. Among the patients discharged without PPM implantation after ablation, sinus pause over three seconds at AFL termination during ablation was an independent predictor of PPM implantation (HR 17.841; 95% CI 4.626–68.807; P

The wettability of surfaces can be manipulated using actuating micro/nanostructures, as in the manipulation of water droplets with magnetic forces. Controlling water droplets with magneto-responsive surfaces is limited to optical applications, however, because these surfaces are normally opaque. Herein, we introduce a magneto-responsive actuating surface that is capable of controlling not only the wettability but also the optical transmittance. The magneto-responsive actuating surface is fabricated using a composite of iron particles with polydimethylsiloxane (PDMS). Thanks to the elastic properties of PDMS, fabricated microstructures' bending is induced by applying magnetic force. Therefore, the static/dynamic water contact angle and the optical transmittance can be controlled. Furthermore, as a feasible application, a sliding angle control system that depends on the magnet location is implemented. On the basis of the interesting characteristics of not only wettability but also optical transmittance, this study is expected to be widely used in various fields such as optics, surface self-cleaning systems of solar cells, and smart windows.

The snare technique can be used to overcome unsuitable cardiac venous anatomies for left ventricular (LV) lead implantation in cardiac resynchronization therapy (CRT) procedures. However, limited data exist regarding performance of the snare technique. We classified 262 patients undergoing CRT procedure into the snare (n = 20) or conventional group (n = 242) according to the LV lead implantation method. We compared the safety, efficacy, and composite outcome (all-cause death and heart failure readmission) at 3 years post-implant between the snare and conventional groups. In the snare group, all LV leads were implanted safely using orthodromic (n = 15) or antidromic (n = 5) techniques, and no immediate complications occurred including vessel perforation, tamponade, and lead dislodgement. During follow-up, LV lead threshold and impedance remained stable without requiring lead revision in the snare group. There were no significant between-group differences regarding LV ejection fraction increase (12 ± 13% vs. 12 ± 13%, p = 0.929) and LV end-systolic volume reduction (18 ± 48% vs. 28 ± 31%, p = 0.501). Both groups exhibited comparable CRT-response rates (62.5% vs. 60.6%, p = 1.000). The risk of primary outcome was not significantly different between the two groups (25.9% vs. 30.9%, p = 0.817). In patients who failed conventional LV lead implantation for CRT, the snare technique could be a safe and effective solution to overcome difficult coronary venous anatomy.

OBJECTIVES The aim of this study was to evaluate the clinical implication of tumour spread through air spaces (STAS) as a prognostic factor in pathological stage I lung adenocarcinoma treated with lobectomy and to identify related parameters. METHODS Medical records of patients who underwent pulmonary lobectomy for stage I (American Joint Committee on Cancers eighth edition) lung adenocarcinomas between 2012 and February 2018 at our institutions were reviewed retrospectively. Patients with minimally invasive adenocarcinomas and tumours ≥3 cm in size were excluded. Included patients were classified into STAS (+) and STAS (−) groups. Clinical implications of STAS and recurrence in patients were investigated. RESULTS A total of 109 patients was analysed: 41 (37.6%) in the STAS (+) and 68 (62.4%) in the STAS (−) group. STAS was associated with larger consolidation diameter on chest tomography (≥1.5 cm; P = 0.006) or a higher invasive ratio (≥85%; P = 0.012) and presence of a micropapillary pattern in multivariable analysis (P = 0.003) The recurrence-free survival curve showed statistical difference (P = 0.008) with 3-year survival rates of 73.0% (9 patients) and 96.8% (2 patients) in the STAS (+) and STAS (−) group, respectively. However, no statistical significance was observed in the lung cancer-related survival curve (P = 0.648). The presence of STAS was an independent risk factor for recurrence in multivariable analysis (hazard ratio = 5.9, P = 0.031). CONCLUSIONS The presence of STAS could be an important risk factor for recurrence in patients with early-stage invasive lung adenocarcinoma treated with pulmonary lobectomy.

The present study investigated the terminal differentiation capacity into adipocytes and subsequent growth inhibition in A549 cancer cells treated with pioglitazone (PGZ), a PPARγ activator. The rate of cell growth in A549 cells was significantly (P

Although chemotherapy is a key cancer treatment, many chemotherapeutic drugs produce chronic neuropathic pain, called chemotherapy-induced neuropathic pain (CINP), which is a dose-limiting adverse effect. To date, there is no medicine that prevents CINP in cancer patients and survivors. We determined whether blockers of the canonical Wnt signaling pathway prevent CINP. Neuropathic pain was induced by intraperitoneal injection of paclitaxel (PAC) on four alternate days in male Sprague-Dawley rats or male Axin2-LacZ knock-in mice. XAV-939, LGK-974, and iCRT14, Wnt/β-catenin blockers, were administered intraperitoneally as a single or multiple doses before or after injury. Mechanical allodynia, phosphoproteome profiling, Wnt ligands, and inflammatory mediators were measured by von Frey filament, phosphoproteomics, reverse transcription-polymerase chain reaction, and Western blot analysis. Localization of β-catenin was determined by immunohistochemical analysis in the dorsal root ganglia (DRGs) in rats and human. Our phosphoproteome profiling of CINP rats revealed significant phosphorylation changes in Wnt signaling components. Importantly, repeated systemic injections of XAV-939 or LGK-974 prevented the development of CINP in rats. In addition, XAV-939, LGK-974, and iCRT14 ameliorated CINP. PAC increased Wnt3a and Wnt10a, activated β-catenin in DRG, and increased monocyte chemoattractant protein-1 and interleukin-1β in DRG. PAC also upregulated rAxin2 in mice. Furthermore, β-catenin was expressed in neurons, including calcitonin gene–related protein-expressing neurons and satellite cells in rat and human DRG. In conclusion, chemotherapy increases Wnt3a, Wnt10a, and β-catenin in DRG and their pharmacological blockers prevent and ameliorate CINP, suggesting a target for the prevention and treatment of CINP. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13311-020-00956-w.

Hectorite nanoplatelets (HNPs) have intriguing surface properties such as high specific surface areas and high cation exchange capacities. Here, we introduce a facile but robust approach to fabricate attractive hectorite nanoplatelets (AHNPs), in which the surfaces of HNPs were hydrophobically modified by using a cationic surfactant, dimethyldioctadecylammonium chloride. The chemical and structural characterization, performed by X-ray diffraction, Fourier transform infrared spectroscopy, confocal laser scanning microscopy, and transmission electron microscopy, revealed that the edge of AHNPs was richly functionalized with hydroxy groups. We then prepared the organogels by finely dispersing the AHNPs in the silicone oil by repeated high-pressure homogenization. Suspension rheology studies suggested that the interaction between AHNPs led to the formation of a strong gel phase, which exhibited a reversible sol-gel transition in response to the applied shear stress. This was attributed to the weak, but long-ranged interaction between AHNPs in the silicone oil, which were induced by hydrogen bonding between the few hydroxyl groups that are present at the edges of the AHNPs. The AHNPs fabricated in this study are expected to be widely used as rheology modifiers in various oil-based complex fluids.

Tension pneumocephalus is a treatable emergency that is usually caused by trauma or surgery. We present a rare case of spontaneous tension pneumocephalus. A 64-year-old woman presented with a severe aggravating headache. Computed tomography revealed a large air collection in the brain parenchyma of the right frontal lobe, both lateral ventricles, and the subarachnoid space. Emergent craniotomy was performed because her headache got progressively worse. We found that an abnormal bony protrusion connected the frontal sinus mucosa and the intraparenchymal pneumocephalus. After removal of the bony mass and repair of the defect, the patient immediately recovered and there was no recurrence.

A method for the separation and quantification of acteoside by reverse-phase high-performance liquid chromatography (HPLC) was developed and validated. Hot water and ethanolic extracts of Osmanthus fragrans leaves and flowers were analyzed for acteoside content. Excellent linearity was obtained, with an r2 higher than 0.999. The precision, specificity, and accuracy of our method were excellent, suggesting that it can be conveniently used for the quantification of acteoside in the crude extract of O. fragrans. The hot water and ethanol extracts were analyzed, and their biological activities were tested. The extraction yields, marker (acteoside) contents, and antioxidant activities of the leaf and flower extracts were analyzed. The antioxidant activity was confirmed by measuring the 2,2-diphenyl-2-picrylhydrazyl radical scavenging activity, reducing power, and total phenolic content. The acteoside content tended to be higher in the 100% ethanol extract of O. fragrans compared to those with the other extraction conditions tested. Overall, almost all extracts prepared with ethanolic solvents tended to produce better antioxidant activity than those prepared with hot water. These results suggest that the ethanolic extract of O. fragrans could serve as a potential antioxidant and anti-inflammatory pharmaceutical source, and our validated method would be useful for the quality control of O. fragrans extracts.

Previously, we reported adverse effects of low-dose nonylphenol (NP) exposure on the reproductive parameters of F1 female mice. In the present study we further investigated the pathohistological effect of NP exposure on the reproductive organs in F1 female mice. NP exposures were continuously conducted from parental pre-mating period until the postnatal day (PND) 33 of F1 offspring for vaginal examination. Mice were sacrificed on PND 30 and the reproductive tissue weights were measured. The initial (at PND 21) body weights of the NP-50 group animals were significantly lower than those of control group animals, and the weight deficit were recovered when the terminal (PND 33) body weights were measured. Early vaginal opening was found in NP group animals (p