Association Between Hearing Impairment and Albuminuria With or Without Diabetes Mellitus

Objectives Few studies have evaluated the accurate association between hearing loss (HL) and albuminuria in patients with or without diabetes mellitus (DM). The aim of our study was to identify the clinical effects of albuminuria on HL with or without DM. Methods This study included 9,762 patients from the Korean National Health and Nutrition Examination Survey between 2011 and 2013. Participants were divided into 4 groups based on DM and urine albumin/creatinine ratio levels: group 1 included participants with neither DM nor albuminuria, group 2 included participants without DM and with albuminuria, group 3 included patients with DM and without albuminuria, and group 4 included patients with both DM and albuminuria. The low- or mid-frequency and high-frequency, and average hearing threshold values were obtained. Results There were 7,508, 545, 1,325, and 384 participants in groups 1, 2, 3, and 4, respectively. Univariate and multivariate analyses showed that the 3 hearing thresholds in group 1 were the lowest and those in group 4 were the highest among the 4 groups. No significant differences were observed in those thresholds between groups 2 and 3. Group 4 was associated with HL compared with the other groups, but moderate to severe HL was not associated with DM or albuminuria. Conclusion The presence of albuminuria was associated with a modest effect on hearing thresholds regardless of presence of DM

TRAIL sensitize MDR cells to MDR-related drugs by down-regulation of P-glycoprotein through inhibition of DNA-PKcs/Akt/GSK-3β pathway and activation of caspases

<p>Abstract</p> <p>Background</p> <p>The development of new modulator possessing high efficacy, low toxicity and high selectivity is a pivotal approach to overcome P-glycoprotein (P-gp) mediated multidrug resistance (MDR) in cancer treatment. In this study, we suggest a new molecular mechanism that TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) down-regulates P-glycoprotein (P-gp) through inhibition of DNA-PKcs/Akt/GSK-3β pathway and activation of caspases and thereby sensitize MDR cells to MDR-related drugs.</p> <p>Results</p> <p>MDR variants, CEM/VLB_10-2, CEM/VLB_55-8and CEM/VLB₁₀₀cells, with gradually increased levels of P-gp derived from human lymphoblastic leukemia CEM cells, were gradually more susceptible to TRAIL-induced apoptosis and cytotoxicity than parental CEM cells. The P-gp level of MDR variants was positively correlated with the levels of DNA-PKcs, pAkt, pGSK-3β and c-Myc as well as DR5 and negatively correlated with the level of c-FLIPs. Hypersensitivity of CEM/VLB₁₀₀cells to TRAIL was accompanied by the activation of mitochondrial apoptotic pathway as well as the activation of initiator caspases. In addition, TRAIL-induced down-regulation of DNA-PKcs/Akt/GSK-3β pathway and c-FLIP and up-regulation of cell surface expression of death receptors were associated with the increased susceptibility to TRAIL of MDR cells. Moreover, TRAIL inhibited P-gp efflux function via caspase-3-dependent degradation of P-gp as well as DNA-PKcs and subsequently sensitized MDR cells to MDR-related drugs such as vinblastine and doxorubicin. We also found that suppression of DNA-PKcs by siRNA enhanced the susceptibility of MDR cells to vincristine as well as TRAIL via down-regulation of c-FLIP and P-gp expression and up-regulation of DR5.</p> <p>Conclusion</p> <p>This study showed for the first time that the MDR variant of CEM cells was hypersensitive to TRAIL due to up-regulation of DR5 and concomitant down-regulation of c-FLIP, and degradation of P-gp and DNA-PKcs by activation of caspase-3 might be important determinants of TRAIL-induced sensitization of MDR cells to MDR-related drugs. Therefore, combination of TRAIL and chemotherapeutic drugs may be a good strategy for treatment of cancer with multidrug resistance.</p

Teratogenic Potential of Antiepileptic Drugs in the Zebrafish Model

The zebrafish model is an attractive candidate for screening of developmental toxicity during early drug development. Antiepileptic drugs (AEDs) arouse concern for the risk of teratogenicity, but the data are limited. In this study, we evaluated the teratogenic potential of seven AEDs (carbamazepine (CBZ), ethosuximide (ETX), valproic acid (VPN), lamotrigine (LMT), lacosamide (LCM), levetiracetam (LVT), and topiramate (TPM)) in the zebrafish model. Zebrafish embryos were exposed to AEDs from initiation of gastrula (5.25 hours post-fertilization (hpf)) to termination of hatching (72 hpf) which mimic the mammalian teratogenic experimental design. The lethality and teratogenic index (TI) of AEDs were determined and the TI values of each drug were compared with the US FDA human pregnancy categories. Zebrafish model was useful screening model for teratogenic potential of antiepilepsy drugs and was in concordance with in vivo mammalian data and human clinical data

Protective Effect of Metformin on Gentamicin-Induced Vestibulotoxicity in Rat Primary Cell Culture

ObjectivesOne of the antidiabetic drugs, metformin, have shown that it prevented oxidative stress-induced death in several cell types through a mechanism involving the opening of the permeability transition pore and cytochrome c release. Thus, it is possible that the antioxidative effect of metformin can also serve as protection against gentamicin-induced cytotoxicity related to reactive oxygen species (ROS). The aim of this study was to examine the protective effect of metformin on gentamicin-induced vestibulotoxicity in primary cell culture derived from rat utricle.MethodsFor vestibular primary cell culture, rat utricles were dissected and incubated. Gentamicin-induced cytotoxicity was measured in both the auditory and vestibular cells. To examine the effects of metformin on gentamicin-induced cytotoxicity in the primary cell culture, the cells were pretreated with metformin at a concentration of 1 mM for 24 hours, and then exposed to 2.5 mM gentamicin for 48 hours. The intracellular ROS level was measured using a fluorescent dye, and also measured using a FACScan flow cytometer. Intracellular calcium levels in the vestibular cells were measured with calcium imaging using Fura-2 AM.ResultsVestibular cells were more sensitive to gentamicin-induced cytotoxicity than auditory hair cells. Metformin protects against gentamicin-induced cytotoxicity in vestibular cells. Metformin significantly reduced a gentamicin-induced increase in ROS, and also reduced an increase in intracellular calcium concentrations in gentamicin-induced cytotoxicity.ConclusionMetformin significantly reduced a gentamicin-induced increase in ROS, stabilized the intracellular calcium concentration, and inhibited gentamicin-induced apoptosis. Thus, Metformin showed protective effect on gentamicin-induced cytotoxicity in vestibular primary cell culture

Mechanical Stability of Pixel-Isolated Liquid Crystal Mode with Plastic Substrates

We have fabricated a plastic liquid crystal display using the pixel-isolated liquid crystal (PILC) mode and characterized the mechanical stability of the sample against mechanical pressure and bending. Since the liquid crystal molecules are fully isolated in the pixels by the phase-separated polymer walls in the PILC mode, the electrooptic properties of the sample show good mechanical stability. In addition, a polymer layer formed on the upper substrate enhances the adhesion between two plastic substrates

Comparison of treatment plans between IMRT with MR-linac and VMAT for lung SABR

Background The aim of this study was to compare the plan quality of magnetic-resonance image-based intensity modulated radiation therapy (MRI-based-IMRT) with the MRIdian Linac system to that of volumetric modulated arc therapy (VMAT) with the TrueBeam STx system for lung stereotactic ablative radiotherapy (SABR). Methods A total of 22 patients with tumors located in the lower lobe were retrospectively selected for the study. For each patient, both the MRI-based-IMRT and VMAT plans were generated using an identical CT image set and identical structures with the exception of the planning target volume (PTV). The PTVs of the MRI-based-IMRT were generated by adding an isotropic margin of 3 mm from the gross tumor volume, whereas those of VMAT were generated by adding an isotropic margin of 5 mm from the internal target volume. For both the MRI-based-IMRT and VMAT, the prescription doses to the PTVs were 60 Gy in four fractions. Results The average PTV volume of the MRI-based-IMRT was approximately 4-times smaller than that of VMAT (p <  0.001). The maximum dose to the bronchi for the MRI-based-IMRT was smaller than that for the VMAT (20.4 Gy versus 24.2 Gy, p <  0.001). In addition, V40Gy of the rib for the MRI-based-IMRT was smaller than that for the VMAT (1.8 cm3 versus 7.7 cm3, p = 0.008). However, the maximum doses to the skin and spinal cord for the MRI-based-IMRT (33.0 Gy and 14.5 Gy, respectively) were larger than those for the VMAT (27.8 Gy and 11.0 Gy, respectively) showing p values of less than 0.02. For the ipsilateral lung, the mean dose, V20Gy, V10Gy, and V5Gy for the MRI-based-IMRT were smaller than those for the VMAT (all with p <  0.05). For the contralateral lung, V5Gy, V10Gy, D1500cc, and D1000cc for the MRI-based-IMRT were larger than those for the VMAT (all with p <  0.05). The mean dose and V50% of the whole body for the MRI-based-IMRT were smaller than those for the VMAT (0.9 Gy versus 1.2 Gy, and 78.7 cm3 versus 103.5 cm3, respectively, all at p <  0.001). Conclusions The MRI-based-IMRT using the MRIdian Linac system could reduce doses to bronchi, rib, ipsilateral lung, and whole body compared to VMAT for lung SABR when the tumor was located in the lower lobe.This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIP) (No. 2017M2A2A7A02020640, 2017M2A2A7A02020641, and 2017M2A2A7A02020643)

Decision-tree-based ion-specific dosing algorithm for enhancing closed hydroponic efficiency and reducing carbon emissions

The maintenance of ion balance in closed hydroponic solutions is essential to improve the crop quality and recycling efficiency of nutrient solutions. However, the absence of robust ion sensors for key ions such as P and Mg and the coupling of ions in fertilizer salts render it difficult to effectively manage ion-specific nutrient solutions. Although ion-specific dosing algorithms have been established, their effectiveness has been inadequately explored. In this study, a decision-tree-based dosing algorithm was developed to calculate the optimal volumes of individual nutrient stock solutions to be supplied for five major nutrient ions, i.e., NO3, K, Ca, P, and Mg, based on the concentrations of NO3, K, and Ca and remaining volume of the recycled nutrient solution. In the performance assessment based on five nutrient solution samples encompassing the typical concentration ranges for leafy vegetable cultivation, the ion-selective electrode array demonstrated feasible accuracies, with root mean square errors of 29.5, 10.1, and 6.1 mg·L-1 for NO3, K, and Ca, respectively. In a five-step replenishment test involving varying target concentrations and nutrient solution volumes, the system formulated nutrient solutions according to the specified targets, exhibiting average relative errors of 10.6 ± 8.0%, 7.9 ± 2.1%, 8.0 ± 11.0%, and 4.2 ± 3.7% for the Ca, K, and NO3 concentrations and volume of the nutrient solution, respectively. Furthermore, the decision tree method helped reduce the total fertilizer injections and carbon emissions by 12.8% and 20.6% in the stepwise test, respectively. The findings demonstrate that the decision-tree-based dosing algorithm not only enables more efficient reuse of nutrient solution compared to the existing simplex method but also confirms the potential for reducing carbon emissions, indicating the possibility of sustainable agricultural development

Multiparametric Monitoring of Early Response to Antiangiogenic Therapy: A Sequential Perfusion CT and PET/CT Study in a Rabbit VX2 Tumor Model

Objectives. To perform dual analysis of tumor perfusion and glucose metabolism using perfusion CT and FDG-PET/CT for the purpose of monitoring the early response to bevacizumab therapy in rabbit VX2 tumor models and to assess added value of FDG-PET to perfusion CT. Methods. Twenty-four VX2 carcinoma tumors implanted in bilateral back muscles of 12 rabbits were evaluated. Serial concurrent perfusion CT and FDG-PET/CT were performed before and 3, 7, and 14 days after bevacizumab therapy (treatment group) or saline infusion (control group). Perfusion CT was analyzed to calculate blood flow (BF), blood volume (BV), and permeability surface area product (PS); FDG-PET was analyzed to calculate SUVmax, SUVmean, total lesion glycolysis (TLG), entropy, and homogeneity. The flow-metabolic ratio (FMR) was also calculated and immunohistochemical analysis of microvessel density (MVD) was performed. Results. On day 14, BF and BV in the treatment group were significantly lower than in the control group. There were no significant differences in all FDG-PET-derived parameters between both groups. In the treatment group, FMR prominently decreased after therapy and was positively correlated with MVD. Conclusions. In VX2 tumors, FMR could provide further insight into the early antiangiogenic effect reflecting a mismatch in intratumor blood flow and metabolism

Serum Neopterin Concentration and Impaired Glucose Metabolism: Relationship With β-Cell Function and Insulin Resistance

Aim: The purpose of this study was to measure the serum neopterin according to glucose metabolism and to evaluate neopterin as a predictor of type 2 diabetes (T2D) in a hospital-based cohort.Methods: A 75-g oral glucose tolerance test (OGTT) was performed by people who visited the outpatient clinic in Seoul National University Bundang Hospital for suspected abnormal glucose tolerance or a strong family history of T2D. Neopterin was measured using an enzyme-link immunosorbent assay with baseline samples from the OGTT.Results: Neopterin was measured in 184 participants. Indices related to glucose metabolism, such as the HOMA-IR, disposition index, etc. were calculated based on the results of the OGTT. The classifications for the 184 participants were: 24 (13%) had NGT, 89 (48.4%) prediabetes, and 60 (38.6%) T2D. Neopterin increased with deterioration of glucose metabolism (0.55 ± 0.25 vs. 0.58 ± 0.27 vs. 0.67 ± 0.27 ng/ml, p = 0.041; NGT, prediabetes, and T2D, respectively). Neopterin also correlated with fasting plasma glucose, 30-min and 120-min glucose of OGTT and HbA1c (r = 0.251, 0.259, 0.184, and 0.270, all p &lt; 0.05). The HOMA-IR and disposition index correlated with neopterin (r = 0.291 and −0.170, respectively, both p &lt; 0.05). When combined with C-peptide level, neopterin was as powerful as HOMA-IR in predicting future T2D.Conclusion: Serum neopterin appears to be related to impaired insulin secretion and insulin resistance in the development of T2D. Further investigation of the relationship between neopterin and glucose metabolism would be helpful to understand the pathophysiology for the development of T2D