Genomic insights into inherited bone marrow failure syndromes in a Korean population.

Inherited bone marrow failure syndromes (IBMFS) pose significant diagnostic challenges due to overlapping symptoms and variable expressivity, despite evolving genomic insights. The study aimed to elucidate the genomic landscape among 130 Korean patients with IBMFS. We conducted targeted next-generation sequencing (NGS) and clinical exome sequencing (CES) across the cohort, complemented by whole genome sequencing (WGS) and chromosomal microarray (CMA) in 12 and 47 cases, respectively, with negative initial results. Notably, 50% (n = 65) of our cohort achieved a genomic diagnosis. Among these, 35 patients exhibited mutations associated with classic IBMFSs (n = 33) and the recently defined IBMFS, aplastic anaemia, mental retardation and dwarfism syndrome (AmeDS, n = 2). Classic IBMFSs were predominantly detected via targeted NGS (85%, n = 28) and CES (88%, n = 29), whereas AMeDS was exclusively identified through CES. Both CMA and WGS aided in identifying copy number variations (n = 2) and mutations in previously unexplored regions (n = 2). Additionally, 30 patients were diagnosed with other congenital diseases, encompassing 13 distinct entities including inherited thrombocytopenia (n = 12), myeloid neoplasms with germline predisposition (n = 8), congenital immune disorders (n = 7) and miscellaneous genomic conditions (n = 3). CES was particularly effective in revealing these diverse diagnoses. Our findings underscore the significance of comprehensive genomic analysis in IBMFS, highlighting the need for ongoing exploration in this complex field.

Association of Insulin-like Growth Factor-1 with Bone Mineral Density in Survivors of Childhood Acute Leukemia.

In this study, we investigated bone mineral deficits in children who survived childhood acute leukemia and explored the association between the insulin-like growth factor-1 (IGF-1) level and bone mineral density (BMD). This retrospective analysis enrolled 214 patients treated for acute leukemia, measuring various factors including height, weight, body mass index (BMI), and lumbar spine BMD after the end of treatment. The study found an overall prevalence of low BMD in 15% of participants. Notably, IGF-1 levels were significantly different between patients with low BMD and those with normal BMD, and correlation analyses revealed associations of the IGF-1 level and BMI with lumbar spine BMD. Regression analyses further supported this relationship, suggesting that higher IGF-1 levels were associated with a decreased risk of low BMD. The study findings suggest that IGF-1 may serve as a valuable tool for evaluating and predicting osteoporosis in survivors of childhood acute leukemia.

A Study to Evaluate the Effectiveness and Safety of Prephase Steroid Treatment before Remission Induction Chemotherapy in Patients with Pediatric Acute Lymphoblastic Leukemia Using Common Data Model-Based Real-World Data: A Retrospective Observational Study.

Background: Rapid reduction of leukemic cells in the bone marrow during remission induction chemotherapy (RIC) can lead to significant complications such as tumor lysis syndrome (TLS). We investigated whether prephase steroid treatment before RIC could decrease TLS incidence and improve overall survival in pediatric patients with acute lymphoblastic leukemia (ALL). Methods: Data were extracted from the Common Data Model databases in two tertiary-care hospitals in Seoul, South Korea. Patients were classified into the treated or untreated group if they had received RIC with prephase steroid treatment ≥7 days before RIC in 2012-2021 or not, respectively. Stabilized Inverse Probability of Treatment Weighting (sIPTW) was applied to ensure compatibility between the treated and untreated groups. The incidence of TLS within 14 days of starting RIC, overall survival (OS), and the incidence of adverse events of special interest were the primary endpoints. Multiple sensitivity analyses were performed. Results: Baseline characteristics were effectively balanced between the treated (n=308.4) and untreated (n=246.6) groups after sIPTW. Prephase steroid treatment was associated with a significant 88% reduction in the risk of TLS (OR 0.12, 95% CI: 0.03-0.41). OS was numerically greater in the treated group than in the untreated group although the difference was not statistically significant (HR 0.64, 95% CI 0.25-1.64). The treated group experienced significantly elevated risks for hyperbilirubinemia and hyperglycemia. The reduction in TLS risk by prephase steroid treatment was maintained in all of the sensitivity analyses. Conclusion: Prephase steroid treatment for ≥7 days before RIC in pediatric patients with ALL reduces the risk of TLS, while careful monitoring for toxicities is necessary. If adequately analyzed, real-world data can provide crucial effectiveness and safety information for proper management of pediatric patients with ALL, for whom prospective randomized studies may be difficult to perform for ethical and practical reasons.

Microstructural characterization and inductively coupled plasma-reactive ion etching resistance of Y2O3-Y4Al2O9 composite under CF4/Ar/O2 mixed gas conditions.

In the semiconductor manufacturing process, when conducting inductively coupled plasma-reactive ion etching in challenging environments, both wafers and the ceramic components comprising the chamber's interior can be influenced by plasma attack. When ceramic components are exposed to long-term plasma environments, the eroded components must be replaced. Furthermore, non-volatile reactants can form and settle on semiconductor chips, acting as contaminants and reducing semiconductor production yield. Therefore, for semiconductor processing equipment parts to be utilized, it is necessary that they exhibit minimized generation of contaminant particles and not deviate significantly from the composition of conventionally used Al2O3 and Y2O3; part must also last long in various physicochemical etching environment. Herein, we investigate the plasma etching behavior of Y2O3-Y4Al2O9 (YAM) composites with a variety of mixing ratios under different gas fraction conditions. The investigation revealed that the etching rates and changes in surface roughness for these materials were significantly less than those of Y2O3 materials subjected to both chemical and physical etching. Microstructure analysis was conducted to demonstrate the minimization of crater formation. Mechanical properties of the composite were also analyzed. The results show that the composite can be commercialized as next-generation ceramic component in semiconductor processing equipment applications.

Thiiranes: Intelligent Molecules for S-Persulfidation.

This study presents a global strategy for the transsulfuration of intracellular thiols (RSH) to persulfides (RSSH). Thiiranes comprising fluorenyl/diphenyl and malonate ester moieties directly convert intercellular RSH to low-molecular-weight RSSH in cells. The efficiency of transsulfuration is determined by counting the number of olefins produced as byproducts, providing ratiometric signals for the corresponding persulfide production. Specifically, the direct and rapid protein S-persulfidation by thiirane is validated. Thiiranes are expected to play a crucial role in the study of sulfur signaling.

Effects of Zinc Compounds on the Enzymatic Activities of Lysozyme and Peroxidase and Their Antifungal Activities.

This study aimed to investigate the effects of zinc compounds on the enzymatic activities of lysozyme, peroxidase, and the glucose oxidase-mediated peroxidase (GO-PO) system and their antifungal activities. Four different zinc compounds (zinc chloride, gluconate, lactate, and sulfate) were incubated with hen egg-white lysozyme (HEWL), bovine lactoperoxidase (bLPO), the GO-PO system, and human unstimulated whole saliva in solution and on a hydroxyapatite surface. Enzymatic activities of lysozyme, peroxidase, and the GO-PO system were measured through the hydrolysis of Micrococcus lysodeikticus, oxidation of fluorogenic 2',7'-dichlorofluorescin, and glucose assay, respectively. Interactions between zinc and enzymes were analyzed by surface plasmon resonance (SPR). The minimum inhibitory concentration (MIC) and candidacidal activities of zinc compounds were examined against three Candida albicans strains. Zinc gluconate and sulfate significantly increased the enzymatic activities of salivary lysozyme in the solution assay and of HEWL and salivary lysozyme on the hydroxyapatite surface. However, all examined zinc compounds significantly decreased the enzymatic activities of bLPO and salivary peroxidase in solution and on the surface. SPR analyses revealed binding of zinc to lysozyme and peroxidase, with affinity differing according to the zinc compounds. The MIC of zinc compounds against C. albicans was 1.0-2.4 mM. Candidacidal activities were 17.7-38.8% and 23.7-47.0% at 1.0 and 10 mM concentrations, respectively. In conclusion, zinc compounds enhanced lysozyme activity but inhibited peroxidase activity. Zinc compounds exhibited concentration-dependent candidacidal activity against C. albicans. Zinc compounds are potential therapeutic agents for oral health, especially for geriatric patients.

Accuracy of visual estimation of ejection fraction in patients with heart failure using augmented reality glasses.

OBJECTIVE: Left ventricular ejection fraction (LVEF) is measured to assess haemodynamic status and cardiac function. It may be difficult to accurately measure in patients with heart failure (HF) as they are often poorly echogenic. The augmented reality (AR) technology is expected to provide real-time guidance that will enable more accurate measurements. METHODS: A prospective, randomised, case-crossover simulation study was conducted to confirm the effect of AR glasses on echocardiographic interpretation in patients with HF. 22 emergency physicians participated. The participants were randomly assigned to two groups. Group A estimated the visual ejection fraction of echocardiographic video clips without the AR glasses, while group B estimated them with glasses. After a washout period, the two groups crossed over. The estimates were then compared with the ejection fraction measurements obtained by echocardiologists; intraclass correlation coefficient (ICC) was calculated. RESULTS: The ICC with glasses (0.969, 95% CI 0.966 to 0.971) was higher than without glasses (0.705, 95% CI 0.681 to 0.727) among all participants. In the subgroup analysis, the first-year and second-year residents showed the most significant difference, with an ICC of 0.568 (95% CI 0.508 to 0.621) without glasses compared with 0.963 (95% CI 0.958 to 0.968) with glasses. For the third-year and fourth-year residents group, the ICC was 0.754 (95% CI 0.720 to 0.784) without glasses and 0.972 (95% CI 0.958 to 0.968) with glasses. Among the group of attending physicians, the ICC was 0.807 (95% CI 0.775 to 0.834) without glasses and 0.973 (95% CI 0.969 to 0.977) with glasses. CONCLUSIONS: AR glasses could be helpful in measuring LVEF and could be more helpful to those with little visual estimation experience.

AptaTrans: a deep neural network for predicting aptamer-protein interaction using pretrained encoders.

BACKGROUND: Aptamers, which are biomaterials comprised of single-stranded DNA/RNA that form tertiary structures, have significant potential as next-generation materials, particularly for drug discovery. The systematic evolution of ligands by exponential enrichment (SELEX) method is a critical in vitro technique employed to identify aptamers that bind specifically to target proteins. While advanced SELEX-based methods such as Cell- and HT-SELEX are available, they often encounter issues such as extended time consumption and suboptimal accuracy. Several In silico aptamer discovery methods have been proposed to address these challenges. These methods are specifically designed to predict aptamer-protein interaction (API) using benchmark datasets. However, these methods often fail to consider the physicochemical interactions between aptamers and proteins within tertiary structures. RESULTS: In this study, we propose AptaTrans, a pipeline for predicting API using deep learning techniques. AptaTrans uses transformer-based encoders to handle aptamer and protein sequences at the monomer level. Furthermore, pretrained encoders are utilized for the structural representation. After validation with a benchmark dataset, AptaTrans has been integrated into a comprehensive toolset. This pipeline synergistically combines with Apta-MCTS, a generative algorithm for recommending aptamer candidates. CONCLUSION: The results show that AptaTrans outperforms existing models for predicting API, and the efficacy of the AptaTrans pipeline has been confirmed through various experimental tools. We expect AptaTrans will enhance the cost-effectiveness and efficiency of SELEX in drug discovery. The source code and benchmark dataset for AptaTrans are available at https://github.com/pnumlb/AptaTrans .

Iterative machine learning-based chemical similarity search to identify novel chemical inhibitors.

Machine learning-based chemical screening has made substantial progress in recent years. However, these predictions often have low accuracy and high uncertainty when identifying new active chemical scaffolds. Hence, a high proportion of retrieved compounds are not structurally novel. In this study, we proposed a strategy to address this issue by iteratively optimizing an evolutionary chemical binding similarity (ECBS) model using experimental validation data. Various data update and model retraining schemes were tested to efficiently incorporate new experimental data into ECBS models, resulting in a fine-tuned ECBS model with improved accuracy and coverage. To demonstrate the effectiveness of our approach, we identified the novel hit molecules for the mitogen-activated protein kinase kinase 1 (MEK1). These molecules showed sub-micromolar affinity (Kd 0.1-5.3 µM) to MEKs and were distinct from previously-known MEK1 inhibitors. We also determined the binding specificity of different MEK isoforms and proposed potential docking models. Furthermore, using de novo drug design tools, we utilized one of the new MEK inhibitors to generate additional drug-like molecules with improved binding scores. This resulted in the identification of several potential MEK1 inhibitors with better binding affinity scores. Our results demonstrated the potential of this approach for identifying novel hit molecules and optimizing their binding affinities.

Front-Line Tyrosine Kinase Inhibitors in Pediatric Chronic Myeloid Leukemia: A Study on Efficacy and Safety.

We conducted a retrospective study on 51 pediatric patients with newly diagnosed chronic myeloid leukemia chronic phase or accelerated phase. The patients were classified into the IMA group (N = 33), treated with imatinib, and the DSA group (N = 18), treated with dasatinib, as front-line tyrosine kinase inhibitors (TKIs). At 12 months, the rates of complete cytogenetic response were similar between the IMA group (92.3%) and DSA group (100%) (p = 0.305). However, the rate of early molecular response was higher in the DSA group than in the IMA group (100.0% vs. 80.0%, p = 0.043). By 12 and 24 months, the DSA group showed faster and higher cumulative rates of both major (DSA group: 72.2% and 100%, respectively; IMA group: 41.2% and 68.7%, respectively; p = 0.002) and deep molecular responses (DSA group: 26.0% and 43.6%, respectively; IMA group: 13.8% and 17.5%, respectively; p = 0.004). Both TKIs were well tolerated. Although the height standard deviation scores decreased in both groups, the height decline was greater in the DSA group between one and two years from the start of TKI therapy. In this study, dasatinib achieved faster and higher molecular responses with an acceptable safety profile. Further follow-up is necessary to assess the long-term outcomes of TKI treatment in children.

Clinical factors distinguishing renal infarction from acute pyelonephritis: A randomly matched retrospective case-control study.

INTRODUCTION: Renal infarction (RI) is rare but clinically important because the appropriate treatment depends on the time of diagnosis. RI is often misdiagnosed as acute pyelonephritis (APN) because both diseases have nonspecific symptoms such as flank pain and abdominal pain. We identified predictors for distinguishing RI from APN. METHODS: The data of patients visited the emergency department and diagnosed with RI or APN from March 2016 to May 2020 were prospectively collected and retrospectively analyzed. Patients aged under 18 years, with a history of trauma, or incomplete medical records were excluded. Using a matching ratio of 1:5, RI patients were randomly matched to APN patients. Multivariable logistic regression analysis was performed to identify factors that could distinguish RI from APN. In addition, we constructed a decision tree to identify patterns of risk factors and develop prediction algorithms. RESULTS: The RI and APN groups included 55 and 275 patients, respectively. Multivariable logistic regression analysis showed that male sex (OR, 6.161; p = 0.009), atrial fibrillation (AF) (OR, 14.303; p = 0.021), costovertebral angle tenderness (CVAT) (OR, 0.106; p < 0.001), aspartate transaminase (AST) level > 21.50 U/L (OR, 19.820; p < 0.001), C-reactive protein (CRP) level < 19.75 mg/L (OR, 10.167; p < 0.001), and pyuria (OR, 0.037; p < 0.001) were significantly associated with RI distinguishing from APN. CONCLUSION: Male sex, AF, no CVAT, AST level > 21.50 U/L, CRP level < 19.75 mg/L, and no pyuria were significant factors that could distinguish RI from APN.

Generative Adversarial Network-Based Image Conversion Among Different Computed Tomography Protocols and Vendors: Effects on Accuracy and Variability in Quantifying Regional Disease Patterns of Interstitial Lung Disease.

OBJECTIVE: To assess whether computed tomography (CT) conversion across different scan parameters and manufacturers using a routable generative adversarial network (RouteGAN) can improve the accuracy and variability in quantifying interstitial lung disease (ILD) using a deep learning-based automated software. MATERIALS AND METHODS: This study included patients with ILD who underwent thin-section CT. Unmatched CT images obtained using scanners from four manufacturers (vendors A-D), standard- or low-radiation doses, and sharp or medium kernels were classified into groups 1-7 according to acquisition conditions. CT images in groups 2-7 were converted into the target CT style (Group 1: vendor A, standard dose, and sharp kernel) using a RouteGAN. ILD was quantified on original and converted CT images using a deep learning-based software (Aview, Coreline Soft). The accuracy of quantification was analyzed using the dice similarity coefficient (DSC) and pixel-wise overlap accuracy metrics against manual quantification by a radiologist. Five radiologists evaluated quantification accuracy using a 10-point visual scoring system. RESULTS: Three hundred and fifty CT slices from 150 patients (mean age: 67.6 ± 10.7 years; 56 females) were included. The overlap accuracies for quantifying total abnormalities in groups 2-7 improved after CT conversion (original vs. converted: 0.63 vs. 0.68 for DSC, 0.66 vs. 0.70 for pixel-wise recall, and 0.68 vs. 0.73 for pixel-wise precision; P < 0.002 for all). The DSCs of fibrosis score, honeycombing, and reticulation significantly increased after CT conversion (0.32 vs. 0.64, 0.19 vs. 0.47, and 0.23 vs. 0.54, P < 0.002 for all), whereas those of ground-glass opacity, consolidation, and emphysema did not change significantly or decreased slightly. The radiologists' scores were significantly higher (P < 0.001) and less variable on converted CT. CONCLUSION: CT conversion using a RouteGAN can improve the accuracy and variability of CT images obtained using different scan parameters and manufacturers in deep learning-based quantification of ILD.

Synthesis and Biological Properties of Pyranocoumarin Derivatives as Potent Anti-Inflammatory Agents.

This study aimed to synthesize 23 coumarin derivatives and analyze their anti-inflammatory effects on lipopolysaccharide (LPS)-induced inflammation in RAW264.7 macrophages. A cytotoxicity test performed on LPS-induced RAW264.7 macrophages revealed that none of the 23 coumarin derivatives were cytotoxic. Among the 23 coumarin derivatives, coumarin derivative 2 showed the highest anti-inflammatory activity by significantly reducing nitric oxide production in a concentration-dependent manner. Coumarin derivative 2 inhibited the production of proinflammatory cytokines, including tumor necrosis factor alpha and interleukin-6, and decreased the expression level of each mRNA. In addition, it inhibited the phosphorylation of extracellular signal-regulated kinase, p38, c-Jun NH2-terminal kinase, nuclear factor kappa-B p65 (NF-κB p65), and inducible nitric oxide synthase. These results indicated that coumarin derivative 2 inhibited LPS-induced mitogen-activated protein kinase and NF-κB p65 signal transduction pathways in RAW264.7 cells, as well as proinflammatory cytokines and enzymes related to inflammatory responses, to exert anti-inflammatory effects. Coumarin derivative 2 showed potential for further development as an anti-inflammatory drug for the treatment of acute and chronic inflammatory diseases.

Case report: First report of isolated central nervous system lymphoblastic crisis in a child with chronic myeloid leukemia on dasatinib therapy.

Most children with chronic myeloid leukemia (CML) present with the chronic phase (CML-CP) at diagnosis, exhibiting an excellent treatment response to contemporary tyrosine kinase inhibitors (TKIs). However, despite TKI therapy, patients with CML-CP may progress to blastic crisis (BC). CML-BC rarely occurs in extramedullary sites, and isolated central nervous system (CNS) BC is an extremely rare condition. It may with present various neurologic symptoms that necessitates differential diagnosis from other causes such as TKI toxicity. Information on the diagnosis and treatment of this condition is lacking, as are well-established diagnostic criteria. Here, we report a case of isolated CNS lymphoblastic crisis in a child with CML-CP who was treated with dasatinib. The patient, an 8-year-old girl, was admitted owing to visual disturbance and severe headache. We highlight the importance of a CSF study for the differential diagnosis of CNS BC in patients with CML-CP who present with common neurologic symptoms during TKI therapy.

Response to chemotherapy in juvenile myelomonocytic leukemia and its clinical implications for survival: A retrospective registry-based study of the Korean Pediatric Hematology-Oncology Group.

Juvenile myelomonocytic leukemia (JMML) is a life-threatening myeloproliferative neoplasm. The chemotherapeutic effect on survival remains unclear, and feasible standardized response criteria are yet to be established. We aimed to evaluate the chemotherapeutic response and its effect on survival in patients with JMML. A retrospective registry was reviewed for children diagnosed with JMML between 2000 and 2019. Response was assessed according to the criteria proposed by the International JMML Symposium in 2007 (criteria I) and the updated version in 2013 with its modifications (criteria II). A total of 73 patients were included in this study. Complete response (CR) rates were 46.6% and 28.8% using the criteria I and criteria II, respectively. A platelet count ≥ 40 × 109/L at diagnosis was associated with higher CR rates using the criteria II. Patients with criteria I-based CR had a better overall survival (OS) than those without CR (81.1% vs. 49.1% at 5 years). Patients with criteria II-based CR showed better OS (85.7% vs. 55.5% at 5 years) and event-free survival (EFS) (71.1% vs. 44.7% at 5 years) than those without CR. Additionally, a trend toward better EFS was observed in patients with criteria II-based CR than in those with criteria I-based CR but without criteria II-based CR (71.1% vs. 53.8% at 5 years). Chemotherapeutic response is associated with better survival outcomes. Along with splenomegaly, the addition of platelet count recovery, existence of extramedullary leukemic infiltration, and more stringent leukocyte counts to the response criteria allows for a more sensitive prediction of survival outcomes.

Facet Connectivity-Based Estimation Algorithm for Manufacturability of Supportless Parts Fabricated via LPBF.

Recent advances in additive manufacturing have provided more freedom in the design of metal parts; hence, the prototyping of fluid machines featuring extremely complex geometries has been investigated extensively. The fabrication of fluid machines via additive manufacturing requires significant attention to part stability; however, studies that predict regions with a high risk of collapse are few. Therefore, a novel algorithm that can detect collapse regions precisely is proposed herein. The algorithm reflects the support span over the faceted surface via propagation and invalidates overestimated collapse regions based on the overhang angle. A heat exchanger model with an extremely complex internal space is adopted to validate the algorithm. Three samples from the model are extracted and their prototypes are fabricated via laser powder bed fusion. The results yielded by the fabricated samples and algorithm with respect to the sample domain are compared. Regions of visible collapse identified on the surface of the fabricated samples are predicted precisely by the algorithm. Thus, the supporting span reflected by the algorithm provides an extremely precise prediction of collapse.

Malachite Green Assay for the Discovery of Heat-Shock Protein 90 Inhibitors.

Heat shock protein 90 (Hsp90) is a promising anticancer target because of its chaperoning effect on multiple oncogenic proteins. The activity of Hsp90 is dependent on its ability to hydrolyze adenosine triphosphate (ATP) to adenosine diphosphate (ADP) and free phosphate. The ATPase activity of Hsp90 is linked to its chaperoning function; ATP binds to the N-terminal domain of the Hsp90, and disrupting its binding was found to be the most successful strategy in suppressing Hsp90 function. The ATPase activity can be measured by a colorimetric malachite green assay, which determines the amount of free phosphate formed by ATP hydrolysis. Here, a procedure for determining the ATPase activity of yeast Hsp90 by using the malachite green phosphate assay kit is described. Further, detailed instructions for the discovery of Hsp90 inhibitors by taking geldanamycin as an authentic inhibitor is provided. Finally, the application of this assay protocol through the high-throughput screening (HTS) of inhibitor molecules against yeast Hsp90 is discussed.

Design, Synthesis, and Biological Evaluation of 3-Substituted-Indolin-2-One Derivatives as Potent Anti-Inflammatory Agents.

This study aimed to synthesize and evaluate the anti-inflammatory activity of 3-substituted-indolin-2-one derivatives. Cell viability of 3-substituted-indolin-2-one derivatives was measured with the EZ-Cytox reagent; interleukin (IL)-6, tumor necrosis factor (TNF)-α, and inducible NOS mRNA levels were measured using Taqman qRT-PCR; pro-inflammatory cytokine IL-6 and TNF-α levels were determined using ELISA kits; the phosphorylation of Akt, JNK, ERK, p38, p65, and IκB protein levels were measured by immunoblotting. Among the nineteen 3-substituted-indolin-2-one derivatives synthesized, 3-(3-hydroxyphenyl)-indolin-2-one showed the highest anti-inflammatory activity, inhibiting the nitric oxide production related to inflammation, suppressing the production of TNF-α and IL-6 in a concentration-dependent manner and mRNA expression. Moreover, 3-(3-hydroxyphenyl)-indolin-2-one significantly inhibited lipopolysaccharide (LPS)-induced signal pathways such as the Akt, MAPK, and NF-κB signaling pathways. Our findings revealed that a 3-substituted-indolin-2-one derivative, 3-(3-hydroxyphenyl)-indolin-2-one, possesses excellent anti-inflammatory activity and can be considered for future research.

Neuroprotective Effects of Ethanol Extract of Polyscias fruticosa (EEPF) against Glutamate-Mediated Neuronal Toxicity in HT22 Cells.

In traditional herbal medicine, the Polyscias fruticosa has been frequently used for the treatment of ischemia and inflammation. Oxidative stress mediated by elevated glutamate levels cause neuronal cell death in ischemia and various neurodegenerative diseases. However, so far, the neuroprotective effects of this plant extract against glutamate-mediated cell death have not been investigated in cell models. The current study investigates the neuroprotective effects of ethanol extracts of Polyscias fruticosa (EEPF) and elucidates the underlying molecular mechanisms of EEPFs relevant to neuroprotection against glutamate-mediated cell death. The oxidative stress-mediated cell death was induced by 5 mM glutamate treatment in HT22 cells. The cell viability was measured by a tetrazolium-based EZ-Cytox reagent and Calcein-AM fluorescent dye. Intracellular Ca2+ and ROS levels were measured by fluorescent dyes, fluo-3 AM and 2',7'-dichlorodihydrofluorescein diacetate (DCF-DA), respectively. Protein expressions of p-AKT, BDNF, p-CREB, Bax, Bcl-2, and apoptosis-inducing factor (AIF) were determined by western blot analysis. The apoptotic cell death was measured by flow cytometry. The in vivo efficacy of EEPF was evaluated using the Mongolian gerbil mouse by surgery-induced brain ischemia. EEPF treatment showed a neuroprotective effect against glutamate-induced cell death. The EEPF co-treatment reduced the intracellular Ca2+ and ROS and apoptotic cell death. Furthermore, it recovered the p-AKT, p-CREB, BDNF, and Bcl-2 levels decreased by glutamate. The EEPF co-treatment suppressed the activation of apoptotic Bax, the nuclear translocation of AIF, and mitogen-activated protein kinase (MAPK) pathway proteins (ERK1/2, p38, JNK). Further, EEPF treatment significantly rescued the degenerative neurons in the ischemia-induced Mongolian gerbil in vivo model. EEPF exhibited neuroprotective properties that suppress glutamate-mediated neurotoxicity. The underlying mechanism of EEPF is increasing the level of p-AKT, p-CREB, BDNF, and Bcl-2 associated with cell survival. It has therapeutic potential for the treatment of glutamate-mediated neuropathology.

Predictors for Distinguishing Renal Infarction From Urolithiasis in the Emergency Department: A Randomly Matched Retrospective Case-Control Study.

BACKGROUND: Emergency department (ED) clinicians may misdiagnose renal infarction (RI) as urolithiasis because RI is a rare disease with presenting symptoms similar to the symptoms of urolithiasis. However, earlier diagnosis of RI can improve patient prognosis. OBJECTIVES: We investigated potential predictors for distinguishing RI from urolithiasis based on clinical findings and laboratory results. METHODS: This randomly matched retrospective case-control study included patients who had been diagnosed with acute RI or acute urolithiasis between January 2016 and March 2020. Patients were excluded if they were aged under 18 years, had a history of trauma, or had incomplete medical records. Using a matching ratio of 1:4, RI patients were randomly matched to urolithiasis patients. Multivariable logistic regression was performed to identify factors that could distinguish RI from urolithiasis. RESULTS: In total, 48 patients were included in the RI group and 192 patients were included in the urolithiasis group. Multivariable logistic regression showed that age ≥ 65 years (odds ratio [OR] 6.155; p = 0.022), atrial fibrillation (OR 18.472; p = 0.045), current smoking (OR 17.070; p = 0.001), costovertebral angle tenderness (OR 0.179; p = 0.037), aspartate aminotransferase level ≥ 27.5 U/L (OR 6.932; p = 0.009), sodium level ≥ 138.5 mEq/L (OR 0.079; p = 0.004), and hematuria (OR 0.042; p = 0.001) were significant predictors that could distinguish RI from urolithiasis. Based on these results, a nomogram was constructed. CONCLUSION: Age ≥ 65 years, atrial fibrillation, current smoking, absence of costovertebral angle tenderness, aspartate aminotransferase level ≥ 27.5 U/L, sodium level < 138.5 mEq/L, and absence of hematuria were predictors that can distinguish between RI and urolithiasis.