Evaluating cardiovascular disease risk stratification using multiple-polygenic risk scores and pooled cohort equations: insights from a 17-year longitudinal Korean cohort study.

Cardiovascular disease (CVD) remains the leading cause of mortality worldwide, caused by a complex interplay of genetic and environmental factors. This study aimed to evaluate the combined efficacy of multi-polygenic risk scores and pooled cohort equations (PCE) for predicting future CVD risks in the Korean population. In this longitudinal study, 7,612 individuals from the Ansan and Ansung cohorts were analyzed over a 17-year follow-up period. The participants were genotyped using the Korea Biobank Array, and quality-controlled genetic data were subjected to imputation analysis. The weighted sum of the PRSs (wPRSsum) was calculated using PRS-CS with summary statistics from myocardial infarction, ischemic stroke, coronary artery disease, and hypertension genome-wide association studies. The recalibrated PCE was used to assess clinical risk, and the participants were stratified into risk groups based on the wPRSsum and PCE. Associations between these risk scores and incident CVD were evaluated using Cox proportional hazards models and Kaplan-Meier analysis. The wPRSsum approach showed a significant association with incident CVD (HR = 1.15, p = 7.49 × 10-5), and the top 20% high-risk genetic group had an HR of 1.50 (p = 5.04 × 10-4). The recalibrated PCE effectively differentiated between the low and high 10-year CVD risk groups, with a marked difference in survival rates. The predictive models constructed using the wPRSsum and PCE demonstrated a slight improvement in prediction accuracy, particularly among males aged <55 years (C-index = 0.640). We demonstrated that while the integration of wPRSsum with PCE did not significantly outperform the PCE-only model (C-index: 0.703 for combined and 0.704 for PCE-only), it provided enhanced stratification of CVD risk. The highest risk group, identified through the combination of high wPRSsum and PCE scores, exhibited an HR of 4.99 for incident CVD (p = 1.45 × 10-15). These findings highlight the potential of integrating genetic risk assessments with traditional clinical tools for effective CVD risk stratification. Although the addition of wPRSsum to the PCE provided a marginal predictive improvement, it proved valuable in identifying high-risk individuals and supporting personalized treatment strategies. This study reinforces the utility of multi-PRS in conjunction with clinical risk assessment tools, paving the way for more tailored approaches for CVD prevention and management in diverse populations.

A Revision of the Phylogeny of Helicotylenchus Steiner, 1945 (Tylenchida: Hoplolaimidae) as Inferred from Ribosomal and Mitochondrial DNA.

Identification of Helicotylenchus species is very challenging due to phenotypic plasticity and existence of cryptic species complexes. Recently, the use of rDNA barcodes has proven to be useful for identification of Helicotylenchus. Molecular markers are a quick diagnostic tool and are crucial for discriminating related species and resolving cryptic species complexes within this speciose genus. However, DNA barcoding is not an error-free approach. The public databases appear to be marred by incorrect sequences, arising from sequencing errors, mislabeling, and misidentifications. Herein, we provide a comprehensive analysis of the newly obtained, and published DNA sequences of Helicotylenchus, revealing the potential faults in the available DNA barcodes. A total of 97 sequences (25 nearly full-length 18S-rRNA, 12 partial 28S-rRNA, 16 partial internal transcribed spacer [ITS]-rRNA, and 44 partial cytochrome c oxidase subunit I [COI] gene sequences) were newly obtained in the present study. Phylogenetic relationships between species are given as inferred from the analyses of 103 sequences of 18S-rRNA, 469 sequences of 28S-rRNA, 183 sequences of ITS-rRNA, and 63 sequences of COI. Remarks on suggested corrections of published accessions in GenBank database are given. Additionally, COI gene sequences of H. dihystera, H. asiaticus and the contentious H. microlobus are provided herein for the first time. Similar to rDNA gene analyses, the COI sequences support the genetic distinctness and validity of H. microlobus. DNA barcodes from type material are needed for resolving the taxonomic status of the unresolved taxonomic groups within the genus.

Diagnosis of atrial fibrillation based on AI-detected anomalies of ECG segments.

Early detection of atrial fibrillation (AF) is crucial for its effective management and prevention. Various methods for detecting AF using deep learning (DL) based on supervised learning with a large labeled dataset have a remarkable performance. However, supervised learning has several problems, as it is time-consuming for labeling and has a data dependency problem. Moreover, most of the DL methods do not provide any clinical evidence to physicians regarding the analysis of electrocardiography (ECG) for classification or detection of AF. To address these limitations, in this study, we proposed a novel AF diagnosis system using unsupervised learning for anomaly detection with three segments, PreQ, QRS, and PostS, based on the normal ECG. Two independent datasets, PTB-XL and China, were used in three experiments. We used a long short-term memory (LSTM)-based autoencoder to train the segments of the normal ECG. Based on the threshold of anomaly scores using mean squared error (MSE), it distinguished between normal and AF segments. In Experiment A, the best score was that of PreQ, which detected AF with an AUROC score of 0.96. In Experiment B and C for cross validation of each dataset, the best scores were also of PreQ, with AUROC scores of 0.9 and 0.95, respectively. To verify the significance of the anomaly score in distinguishing between AF and normal segments, we utilized an XG-Boosted model after generating anomaly scores in the three segments. The XG-Boosted model achieved an AUROC score of 0.98 and an F1 score of 0.94. AF detection using DL has been controversial among many physicians. However, our study differentiates itself from previous studies in that we can demonstrate evidence that distinguishes AF from normal segments based on the anomaly score.

Genetic variation in TAS2R38 bitterness receptor is associated with body composition in Korean females.

Bitterness-receptor gene TAS2R38 is associated with taste sensitivity and dietary behaviour, and is known to play a critical role in adiposity. However, evidence regarding body composition from a large cohort is lacking. This study aimed to ascertain whether TAS2R38 rs10246939 C > T bitterness genetic variation is associated with body composition in Korean individuals. The TAS2R38 rs10246939 genotypes, anthropometric measurements, and body composition of 1,843 males and 1,801 females from the Korean Genome and Epidemiology Study were analysed. Findings suggested that there was a significant difference in body fat components by TAS2R38 genotype. Furthermore, the bitterness genotype exhibited a positive association with adiposity markers in females. The TT genotype showed greater body mass index, body fat percentage, and degree of obesity than those with the C allele. However, such an association was not observed in males. In conclusion, this study suggests that TAS2R38 rs10246939 is associated with fat tissue markers in Korean females.

Uric acid regulates α-synuclein transmission in Parkinsonian models.

Ample evidence demonstrates that α-synuclein (α-syn) has a critical role in the pathogenesis of Parkinson's disease (PD) with evidence indicating that its propagation from one area of the brain to others may be the primary mechanism for disease progression. Uric acid (UA), a natural antioxidant, has been proposed as a potential disease modifying candidate in PD. In the present study, we investigated whether UA treatment modulates cell-to-cell transmission of extracellular α-syn and protects dopaminergic neurons in the α-syn-enriched model. In a cellular model, UA treatment decreased internalized cytosolic α-syn levels and neuron-to-neuron transmission of α-syn in donor-acceptor cell models by modulating dynamin-mediated and clathrin-mediated endocytosis. Moreover, UA elevation in α-syn-inoculated mice inhibited propagation of extracellular α-syn which decreased expression of phosphorylated α-syn in the dopaminergic neurons of the substantia nigra leading to their increased survival. UA treatment did not lead to change in markers related with autophagolysosomal and microglial activity under the same experimental conditions. These findings suggest UA may control the pathological conditions of PD via additive mechanisms which modulate the propagation of α-syn.

What Is the Optimal Digoxin Level? Challenging Case of Fetal Atrial Flutter Treatment in a Monochorionic Diamniotic Twin.

Background: Atrial flutter is an infrequent yet potentially fatal arrhythmia. Digoxin is the preferred first-line treatment for fetal atrial flutter due to its efficacy and favorable safety profile. The optimal digoxin serum target level for neonatal atrial flutter management remains uncertain, with the standard target level ranging from 1.0 to 2.0 ng/mL due to potential toxicity concerns above this threshold. Case Presentation: We present a case of atrial flutter in a fetus within a monochorionic diamniotic (MCDA) twin pregnancy that was successfully managed using a higher-than-standard target level of digoxin. A 34-year-old nulliparous woman was referred to our institution at 31 + 3 weeks of gestation due to fetal distress in an MCDA twin pregnancy. Fetal echocardiography revealed a ventricular rate of 214 bpm in twin A, while twin B exhibited no abnormal findings. Conclusions: Our case highlights a distinct correlation between the serum digoxin level and its impact on atrial flutter. A higher target serum level of digoxin may be necessary to achieve sinus conversion due to the unique maternal and fetal circulatory characteristics in MCDA pregnancies.

Renoprotective Effect of Chrysanthemum coronarium L. Extract on Adenine-Induced Chronic Kidney Disease in Mice.

Chronic kidney disease (CKD) gradually leads to loss of renal function and is associated with inflammation and fibrosis. Chrysanthemum coronarium L., a leafy vegetable, possesses various beneficial properties, including anti-oxidative, anti-inflammatory, and antiproliferative effects. In this study, we investigated the renoprotective effect of Chrysanthemum coronarium L. extract (CC) on adenine (AD)-induced CKD in mice. CKD was induced by feeding mice with an AD diet (0.25% w/w) for 4 weeks. Changes in renal function, histopathology, inflammation, and renal interstitial fibrosis were analyzed. The adenine-fed mice were characterized by increased blood urea nitrogen, serum creatinine, and histological changes, including inflammation and fibrosis; however, these changes were significantly restored by treatment with CC. Additionally, CC inhibited the expression of the inflammatory markers, monocyte chemoattractant protein-1, interleukins-6 and -1ß, intercellular adhesion molecule-1, and cyclooxygenase 2. Moreover, CC suppressed the expression of the fibrotic markers, type IV collagen, and fibronectin. Furthermore, CC attenuated the expression of profibrotic genes (tumor growth factor-ß and α-smooth muscle actin) in AD-induced renal injury mice. Thus, our results suggest that CC has the potential to attenuate AD-induced renal injury and might offer a new option as a renoprotective agent or functional food supplement to manage CKD.

Mobile educational tool based on augmented reality technology for tooth carving: results of a prospective cohort study.

BACKGROUND: Augmented reality (AR) technology has been shown to be effective in displaying information and presenting three-dimensional objects. Although AR applications are commonly used by learners via mobile devices, plastic models or two-dimensional images are still commonly used in tooth carving practice. Learners practicing tooth carving face a challenge due to the three-dimensional features of teeth as there is a lack of tools available that provide sequential guidance. In this study, we developed an AR-based tooth carving practice tool (AR-TCPT) and compared it to a plastic model to evaluate its potential as a practice tool as well as its user experience. METHODS: To model tooth carving, we created a three-dimensional object from sequential steps that included the maxillary canines and maxillary first premolars (16 steps), mandibular first premolars (13 steps), and mandibular first molars (14 steps). Image markers, created using Photoshop software, were assigned to each tooth. An AR-based mobile application was developed using the Unity engine. For tooth carving, 52 participants were randomly assigned to a control group (n = 26; using a plastic tooth model) or an experimental group (n = 26; using the AR-TCPT). User experience was evaluated using a 22-item questionnaire. Data were comparatively analyzed using the nonparametric Mann-Whitney U test via the SPSS program. RESULTS: The AR-TCPT detects image markers with the mobile device camera and displays three-dimensional objects for tooth fragmentation. Users can manipulate the device to view each step or examine the shape of a tooth. The results of the user experience survey revealed that the AR-TCPT experimental group scored significantly higher in tooth carving experience compared with the control group that used the plastic model. CONCLUSION: Compared with the conventional plastic model, the AR-TCPT provided a better user experience for tooth carving. The tool is highly accessible as it is designed to be used on mobile devices by users. Further studies are required to determine the educational impact of the AR-TCTP on quantitative scoring of carved teeth as well as individual user's carving abilities.

Morphological and Molecular Characterization of Diplogasteroides sp., a Cryptic Population of the Haslacheri Group (Diplogastridae), and Parasitorhabditis terebranus (Rhabditidae) from Korea.

Diplogasteroides sp., a cryptic population of D. haslacheri, and Parasitorhabditis terebranus were reported from the frass of Monochamus alternatus galleries in dead Pinus thunbergii for the first time in Korea. Females and males are morphologically characterized and their linked DNA barcodes (18S-rRNA, 28S-rRNA, ITS-rRNA and COI) supplied. Females and males of the two species from Korea conform to the original species descriptions from Europe and the USA, with variations in a few details in morphometrics. Specifically, Diplogasteroides sp. is morphologically very similar to D. haslacheri. However, it cannot be designated as D. haslacheri due to the existence of cryptic species complex within the haslacheri group (D. haslacheri, D. asiaticus, D. nix, D. andrassyi, and D. carinthiacus), a condition requiring hybridization studies to test species identity within the group. Based on analysis of COI sequences, differences among these cryptic species are evident. Thus, in addition to hybridization tests, the COI might be a powerful DNA barcoding marker for the precise identification of these cryptic species within the genus. Additionally, this is the first molecular characterization of P. terebranus, and the species is herein recorded for the first time outside its type locality.

The Potency of Abamectin Formulations against the Pine Wood Nematode, Bursaphelenchus xylophilus.

Abamectin offers great protection against Bursaphelenchus xylophilus, a well-known devastating pathogen of pine tree stands. Trunk injection of nematicides is currently the most preferred method of control. This study aimed to evaluate the potency of the commonly used formulations of abamectin against B. xylophilus. Twenty-one formulations of abamectin were evaluated by comparing their sublethal toxicities and reproduction inhibition potentials against B. xylophilus. Nematodes were treated with diluted formulation concentrations in multi-well culture plates. And, populations pre-exposed to pre-determined concentrations of the formulations were inoculated onto Botrytis cinerea culture, and in pine twig cuttings. Potency was contrastingly different among formulations, with LC95 of 0.00285 and 0.39462 mg/ml for the most, and the least potent formulation, respectively. Paralysis generally occurred at an application dose of 0.06 µg/ml or higher, and formulations with high sublethal toxicities caused significant paralysis levels at the tested doses, albeit the variations. Nematode reproduction was evident at lower doses of 0.00053-0.0006 µg/ml both on Botrytis cinerea and pine twigs, with significant variations among formulations. Thus, the study highlighted the inconsistencies in the potency of similar product formulations with the same active ingredient concentration against the target organism, and the need to analyze the potential antagonistic effects of the additives used in formulations.

Comparative Bioactivity of Emamectin Benzoate Formulations against the Pine Wood Nematode, Bursaphelenchus xylophilus.

The pine wood nematode (PWN), Bursaphelenchus xylophilus is a well-known devastating pathogen of economic importance in the Republic of Korea and other countries. In the Republic of Korea, trunk injection of nematicides is the preferred method of control. In this study, the efficacy of 16 locally produced formulations of emamectin benzoate against the PWN are compared through determining their sublethal toxicities and reproduction inhibition potentials. Nematodes were treated with varying concentrations of the tested chemicals in multi-well culture plates, and rates of paralysis and mortality were determined after 24 h. Reproduction inhibition potential was tested by inoculating pre-treated nematodes onto Botrytis cinerea, and in pine twig cuttings. Despite the uniformity in the concentration of the active ingredient, efficacy was contrastingly different among formulations. The formulations evidently conformed to three distinct groups based on similarities in sublethal activity (group 1: LC95 of 0.00768-0.01443 mg/ml; group 2: LC95 of 0.03202-0.07236 mg/ml, and group 3: LC95 of as high as 0.30643-0.40811 mg/ml). Nematode paralysis generally occurred at the application dose of 0.0134-0.1075 µg/ml, and there were significant differences in nematode paralysis rates among the products. Nematode reproduction was only evident at lower doses both on B. cinerea and pine twigs, albeit the variations among formulations. Group 1 formulations significantly reduced nematode reproduction even at a lower dose of 0.001075 µg/ml. The variations in efficacy might be attributed to differences in inert ingredients. Therefore, there is need to analyze the potential antagonistic effects of the large number of additives used in formulations.

Prevention of Chemotherapy-Induced Peripheral Neuropathy by Inhibiting C-X-C Motif Chemokine Receptor 2.

Chemotherapy-induced peripheral neuropathy (CIPN) is a major drawback in the use of chemotherapeutic agents for patients with cancer. Although studies have investigated a broad number of molecules that might be related to CIPN, the differences in the chemokine pathways between various chemotherapeutic agents, such as vincristine and oxaliplatin, which are some of the most widely used treatments, have not been fully elucidated. We confirmed that the administration (intraperitoneal injections for seven days) of vincristine (0.1 mg/kg) and oxaliplatin (3 mg/kg) induced pain by using the von Frey behavioral test. Subsequent applications with vincristine and oxaliplatin led to mechanical allodynia that lasted more than one week from the fifth day. After the induction of mechanical allodynia, the mRNA expression of CXCR2, CXCL1, CXCL3, and CXCL5 was examined in the dorsal root ganglia (DRG) and spinal cord of the CIPN models. As a result, the mRNA expression of CXCR2 robustly increased in the lumbar spinal cord in the oxaliplatin-treated mice. Next, to evaluate the involvement of CXCR2 in CIPN, reparixin, a CXCR1/2 inhibitor, was administered intrathecally or intraperitoneally with vincristine or oxaliplatin and was further verified by treatment with ruxolitinib, which inhibits Janus kinase 2 downstream of the CXCR1/2 pathway. Reparixin and ruxolitinib blocked oxaliplatin-induced allodynia but not vincristine-induced allodynia, which suggests that CXCR2-related pathways are associated with the development of oxaliplatin-induced neuropathy. Together with the above results, this suggests that the prevention of oxaliplatin-induced neuropathy by CXCR2 inhibition can lead to successful chemotherapy, and it is important to provide appropriate countermeasures against CIPN development for each specific chemotherapeutic agent.

The eveningness chronotype is associated with nightmare distress and dream recall: a cross-sectional study.

Dreaming may be affected by sleep behavior; however, evidence of the effect of chronotypes on dreaming is limited. We investigated sleep patterns, dream recall, and nightmare distress according to chronotypes. This cross-sectional study retrospectively enrolled adult participants (age > 18 years) who visited a sleep laboratory between 2016 and 2021 and underwent standard polysomnography (PSG) and completed a self-reported questionnaire. Patients with major sleep disorders were excluded. Chronotypes and dreaming components were assessed using the Korean version of the morningness-eveningness questionnaire and a nine-item dreaming questionnaire (nightmare distress and dream recall), respectively. Among healthy participants without major sleep disorders, the eveningness chronotype correlated with better dream recall than the morningness and intermediate chronotypes. Participants with the eveningness chronotype were younger and more likely to be unmarried than those with the other chronotypes. No significant chronotype-based difference was observed in the subjective measurements of sleep quality, insomnia, daytime sleepiness, depression, and anxiety or in respiration and movement events on PSG. In multivariate linear regression analysis, the chronotypes were independently related to nightmare distress (b = - 0.296; p = 0.002) and dream recall (b = - 0.334; p = 0.002). The apnea-hypopnea index was associated with nightmare distress (b = - 0.209; p = 0.029) and dream recall (b = - 0.189; p = 0.044). Depression was positively correlated with nightmare distress (b = 0.450; p = 0.002). Dream recall was best in the eveningness group among healthy adults. Greater eveningness was associated with higher nightmare distress and better dream recall. Further research is needed to understand the role of chronotypes in dreaming.

Investigation of Delirium Occurrence and Intervention Status in Intensive Care Unit at a Hospital and Perception of Delirium by Medical Staff / 중환자간호학회지

Purpose@#: This study aims to investigate the status of delirium intervention in adult intensive care unit (ICU) patients and the perception of this delirium by medical staff. @*Methods@#: This retrospective study involves 185 patients, whereas, a descriptive survey is conducted with 197 medical staff members. @*Results@#: The delirium group includes 100 patients (54.1%). The incidence of delirium is 64.9% in the medical ICU, 65.9% in the surgical ICU, 42.4% in the neuro ICU, and 46.5% in the cardiac ICU. The percentages of delirium prevention intervention differs between the two groups: 65.0% in the delirium group and 95.3% in the non-delirium group. The medical staff recognize that delirium is a common problem in the ICU (100.0%) and requires active medical intervention (98.5%). @*Conclusion@#: The length of stay at the ICU is longer in the delirium group than in the non-delirium group. It is necessary to standardize delirium prevention and treatment protocols to be equally applicable to all ICU patients.

Priming mesenchymal stem cells with α-synuclein enhances neuroprotective properties through induction of autophagy in Parkinsonian models.

BACKGROUND: Mesenchymal stem cells (MSCs) may be one of candidates for disease-modifying therapy in Parkinsonian diseases. As knowledge regarding the therapeutic properties of MSCs accumulates, some obstacles still remain to be overcome, especially, successful clinical translation requires the development of culture systems that mimic the natural MSC niche, while allowing clinical-scale cell expansion without compromising quality and function of the cells. In recent years, priming approaches using bioactive peptide or complement components have been investigated to enhance the therapeutic potential of MSCs. METHODS: We investigated an innovative priming strategy by conditioning the MSCs with α-synuclein (α-syn). To induce priming, MSCs were treated with different concentrations of α-syn and various time course. We evaluated whether α-syn enhances stemness properties of MSCs and priming MSCs with α-syn would modulate autophagy-related gene expression profiles. RESULTS: Treatment of naïve MSCs with α-syn upregulated transcriptional factors responsible for regulation of stemness, which was associated with the elevated expression of genes involved in glycolysis and cell re-programming. Primed MSCs with α-syn enhanced the expression of autophagy-regulating miRNA, and exosomes derived from primed MSCs were packed with autophagy-associated miRNA. In α-syn-overexpressing neuronal cells, primed MSCs with α-syn enhanced neuronal viability relative to naïve MSCs, through the induction of autophagy and lysosome activity. Animal study using an α-syn-overexpressing mice showed that the pro-survival effect of MSCs on dopaminergic neurons was more prominent in primed MSC-treated mice compared with that in naïve MSC-treated mice. CONCLUSIONS: The present data suggest that MSC priming with α-syn exerts neuroprotective effects through augmented stemness and possibly the enhancement of autophagy-mediated α-syn modulation in Parkinsonian models.

Uric Acid Enhances Neurogenesis in a Parkinsonian Model by Remodeling Mitochondria.

Background: Adult neurogenesis is the process of generating new neurons to enter neural circuits and differentiate into functional neurons. However, it is significantly reduced in Parkinson's disease (PD). Uric acid (UA), a natural antioxidant, has neuroprotective properties in patients with PD. This study aimed to investigate whether UA would enhance neurogenesis in PD. Methods: We evaluated whether elevating serum UA levels in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonian mouse model would restore neurogenesis in the subventricular zone (SVZ). For a cellular model, we primary cultured neural precursor cells (NPCs) from post-natal day 1 rat and evaluated whether UA treatment promoted cell proliferation against 1-methyl-4-phenylpyridinium (MPP+). Results: Uric acid enhanced neurogenesis in both in vivo and in vitro parkinsonian model. UA-elevating therapy significantly increased the number of bromodeoxyuridine (BrdU)-positive cells in the SVZ of PD animals as compared to PD mice with normal UA levels. In a cellular model, UA treatment increased the expression of Ki-67. In the process of modulating neurogenesis, UA elevation up-regulated the expression of mitochondrial fusion markers. Conclusion: In MPTP-induced parkinsonian model, UA probably enhanced neurogenesis via regulating mitochondrial dynamics, promoting fusion machinery, and inhibiting fission process.

Implantable cardioverter defibrillator as a treatment for massive left ventricular fibroma-induced ventricular arrhythmia in a child.

Pediatric cardiac tumors are rare. Among these, cardiac fibroma is the second most common. Its clinical manifestations depend on size and location of the tumor and include arrhythmia or obstruction to blood flow. Symptomatic cardiac fibroma is generally treated with surgical resection or cardiac transplantation. We present the case of a 12-year-old boy with a lethal ventricular arrhythmia induced by a remnant tumor that was previously partially resected. An implantable cardioverter defibrillator was inserted as the arrhythmia was resistant to medical treatment. He was discharged in stable condition with an implantable cardioverter defibrillator generator and followed up in the outpatient clinic.

The "Intermediate" CD14 + CD16 + monocyte subpopulation plays a role in IVIG responsiveness of children with Kawasaki disease.

BACKGROUND: Kawasaki disease (KD) is an acute, self-limited febrile illness of unknown cause. Intravenous immunoglobulin (IVIG)-resistance are related to greater risk for permanent cardiac complications. We aimed to determine the correlation between monocytes and the phenotype of KD in relation to IVIG responsiveness in children. MATERIALS AND METHODS: The study cohort included 62 patients who were diagnosed with KD, 20 non febrile healthy controls (NFC), and 15 other febrile controls (OFC). In all enrolled patients, blood was taken at least 4 times and laboratory tests were performed. In addition, subtypes of monocytes were characterized via flow cytometry. RESULTS: The numbers of intermediate monocytes were significantly lower in IVIG-resistant group compared to IVIG-responsive group before IVIG infusion (p < 0.0001). After infusion, intermediate monocytes decreased in the responsive group, while a trend of increase was observed in the resistant group. Only intermediate monocytes were significant in logistic regression with adjusted OR of 0.001 and p value of 0.03. CONCLUSIONS: CD14 + CD16 + intermediate monocyte may play an important role in IVIG responsiveness among KD children. Low starting levels of intermediate monocytes, followed by a dramatic increase post-IVIG infusion during acute phase of KD are associated with IVIG-resistance. Functional studies on intermediate monocyte may help to reveal the pathophysiology.

Ablation of CRBN induces loss of type I collagen and SCH in mouse skin by fibroblast senescence via the p38 MAPK pathway.

Cereblon (CRBN) is a substrate receptor of the cullin-RING E3 ubiquitin ligase (CRL) complex that mediates the ubiquitination of several substrates. In this study, CRBN knockout (KO) mice exhibited decreased levels of stratum corneum hydration (SCH) and collagen I expression with an elevated protein level of matrix metalloprotease 1 (MMP1). The absence of cereblon in the skin of CRBN KO mice mimics the damage caused by narrowband ultraviolet B (NB-UVB). The primary CRBN deficient mouse embryonic fibroblasts (MEFs) undergo G2/M-arrested premature senescence via protein signaling of p38 MAPK and its dependent p53/p21pathway. The absence of CRBN induced the markers of cellular senescence, such as the senescence-associated heterochromatin foci (SAHF), SA-ß-Gal staining, and p21 upregulation while the ectopic expression of CRBN reversed the phenotypes of SA-ß-Gal staining and p21 upregulation. Reversion of the decreased protein level of collagen I was demonstrated after the reintroduction of the CRBN gene back into CRBN KO MEFs, validating the promising role of CRBN as a potential regulator for the function of the skin barrier and its cellular homeostasis.

PF-3845, a Fatty Acid Amide Hydrolase Inhibitor, Directly Suppresses Osteoclastogenesis through ERK and NF-κB Pathways In Vitro and Alveolar Bone Loss In Vivo.

Alveolar bone loss, the major feature of periodontitis, results from the activation of osteoclasts, which can consequently cause teeth to become loose and fall out; the development of drugs capable of suppressing excessive osteoclast differentiation and function is beneficial for periodontal disease patients. Given the difficulties associated with drug discovery, drug repurposing is an efficient approach for identifying alternative uses of commercially available compounds. Here, we examined the effects of PF-3845, a selective fatty acid amide hydrolase (FAAH) inhibitor, on receptor activator of nuclear factor kappa B ligand (RANKL)-mediated osteoclastogenesis, its function, and the therapeutic potential for the treatment of alveolar bone destruction in experimental periodontitis. PF-3845 significantly suppressed osteoclast differentiation and decreased the induction of nuclear factor of activated T-cells cytoplasmic 1 (NFATc1) and the expression of osteoclast-specific markers. Actin ring formation and osteoclastic bone resorption were also reduced by PF-3845, and the anti-osteoclastogenic and anti-resorptive activities were mediated by the suppression of phosphorylation of rapidly accelerated fibrosarcoma (RAF), mitogen-activated protein kinase (MEK), extracellular signal-regulated kinase, (ERK) and nuclear factor κB (NF-κB) inhibitor (IκBα). Furthermore, the administration of PF-3845 decreased the number of osteoclasts and the amount of alveolar bone destruction caused by ligature placement in experimental periodontitis in vivo. The present study provides evidence that PF-3845 is able to suppress osteoclastogenesis and prevent alveolar bone loss, and may give new insights into its role as a treatment for osteoclast-related diseases.