Injectable Poloxamer Hydrogel Formulations for Intratympanic Delivery of Dexamethasone

Background@#In this study, we prepared and evaluated an injectable poloxamer (P407) hydrogel formulation for intratympanic (IT) delivery of dexamethasone (DEX). @*Methods@#DEX-loaded P407 hydrogels were characterized in terms of thermogelation, drug loading capacities, particle size, and drug release. The in vivo toxicity and drug absorption of the DEX-loaded P407 formulation after IT injection were evaluated using an animal model by performing histopathological analysis and drug concentration measurements. @*Results@#The P407 hydrogel effectively solubilized hydrophobic DEX and demonstrated a sustained release compared to the hydrophilic DEX formulation. The in vivo study showed that the hydrogel formulation delivered considerable drug concentrations to the inner ear and displayed a favorable safety profile without apparent cytotoxicity or inflammation. @*Conclusion@#P407 hydrogel can be useful as an injectable inner ear delivery formulation for hydrophobic drugs due to their biocompatibility, drug-solubilizing capacity, thermogelation, and controlled release.

Pharmacological Management of Germinal Matrix-Intraventricular Hemorrhage

Germinal matrix-intraventricular hemorrhage (GM-IVH) is among the devastating neurological complications with mortality and neurodevelopmental disability rates ranging from 14.7% to 44.7% in preterm infants. The medical techniques have improved throughout the years, as the morbidity-free survival rate of very-low-birth-weight infants has increased; however, the neonatal and long-term morbidity rates have not significantly improved. To this date, there is no strong evidence on pharmacological management on GM-IVH, due to the limitation of well-designed randomized controlled studies. However, recombinant human erythropoietin administration in preterm infants seems to be the only effective pharmacological management in limited situations. Hence, further high-quality collaborative research studies are warranted in the future to ensure better outcomes among preterm infants with GM-IVH.

Importance of Differential Diagnosis of a Possible Brain Tumor in Patients with Cervical Radiculopathy

Lesions occurring simultaneously in the somatosensory or motor cortex of the brain and the cervical spine are rare. Brain tumors can cause similar symptoms to cervical lesions which can lead to confusion in treatment priorities. Moreover, if cervical disease is noticeably observed in radiologic findings of a patient complaining of cervical radiculopathy with non-specific electromyography results, it is common to no longer perform further evaluation. Here we introduce two cases where the cause of cervical radiculopathy was first considered to be the result of a degenerative cervical disease but was later discovered to be a result of a brain tumor.

Pseudomembranous Aspergillus Tracheobronchitis: Case Report of a Rare Manifestation of Airway Invasive Aspergillosis

Aspergillus tracheobronchitis, an uncommon form of invasive pulmonary aspergillosis, is characterized by the development of a pseudomembrane, ulcers, or an obstruction that is predominantly confined to the tracheobronchial tree. Pseudomembranous Aspergillus tracheobronchitis is the most severe form of Aspergillus tracheobronchitis, and only a few cases have been reported in Korea. We report the characteristic chest CT findings in a patient diagnosed with pseudomembranous Aspergillus tracheobronchitis after bronchoscopy and successfully treated by proper antifungal treatment.

High-accuracy quantitative principle of a new compact digital PCR equipment: Lab On An Array

Digital PCR (dPCR) is the third-generation PCR that enables real-time absolute quantification without reference materials. Recently, global diagnosis companies have developed new dPCR equipment. In line with the development, the Lab On An Array (LOAA) dPCR analyzer (Optolane) was launched last year. The LOAA dPCR is a semiconductor chip-based separation PCR type equipment. The LOAA dPCR includes Micro Electro Mechanical System that can be injected by partitioning the target gene into 56 to 20,000 wells. The amount of target gene per wells is digitized to 0 or 1 as the number of well gradually increases to 20,000 wells because its principle follows Poisson distribution, which allows the LOAA dPCR to perform precise absolute quantification. LOAA determined region of interest first prior to dPCR operation. To exclude invalid wells for the quantification, the LOAA dPCR has applied various filtering methods using brightness, slope, baseline, and noise filters. As the coronavirus disease 2019 has now spread around the world, needs for diagnostic equipment of point of care testing (POCT) are increasing. The LOAA dPCR is expected to be suitable for POCT diagnosis due to its compact size and high accuracy. Here, we describe the quantitative principle of the LOAA dPCR and suggest that it can be applied to various fields.

Nanoscale imaging of rat atrial myocytes by scanning ion conductance microscopy reveals heterogeneity of T-tubule openings and ultrastructure of the cell membrane

In contrast to ventricular myocytes, the structural and functional importance of atrial transverse tubules (T-tubules) is not fully understood. Therefore, we investigated the ultrastructure of T-tubules of living rat atrial myocytes in comparison with ventricular myocytes. Nanoscale cell surface imaging by scanning ion conductance microscopy (SICM) was accompanied by confocal imaging of intracellular T-tubule network, and the effect of removal of T-tubules on atrial excitation-contraction coupling (EC-coupling) was observed. By SICM imaging, we classified atrial cell surface into 4 subtypes. About 38% of atrial myocytes had smooth cell surface with no clear T-tubule openings and intracellular T-tubules (smooth-type). In 33% of cells, we found a novel membrane nanostructure running in the direction of cell length and named it 'longitudinal fissures' (LFs-type). Interestingly, T-tubule openings were often found inside the LFs. About 17% of atrial cells resembled ventricular myocytes, but they had smaller T-tubule openings and a lower Z-groove ratio than the ventricle (ventricular-type). The remaining 12% of cells showed a mixed structure of each subtype (mixed-type). The LFs-, ventricular-, and mixed-type had an appreciable amount of reticular form of intracellular T-tubules. Formamide-induced detubulation effectively removed atrial T-tubules, which was confirmed by both confocal images and decreased cell capacitance. However, the LFs remained intact after detubulation. Detubulation reduced action potential duration and L-type Ca2+ channel (LTCC) density, and prolonged relaxation time of the myocytes. Taken together, we observed heterogeneity of rat atrial T-tubules and membranous ultrastructure, and the alteration of atrial EC-coupling by disruption of T-tubules.

Nanoscale imaging of rat atrial myocytes by scanning ion conductance microscopy reveals heterogeneity of T-tubule openings and ultrastructure of the cell membrane

In contrast to ventricular myocytes, the structural and functional importance of atrial transverse tubules (T-tubules) is not fully understood. Therefore, we investigated the ultrastructure of T-tubules of living rat atrial myocytes in comparison with ventricular myocytes. Nanoscale cell surface imaging by scanning ion conductance microscopy (SICM) was accompanied by confocal imaging of intracellular T-tubule network, and the effect of removal of T-tubules on atrial excitation-contraction coupling (EC-coupling) was observed. By SICM imaging, we classified atrial cell surface into 4 subtypes. About 38% of atrial myocytes had smooth cell surface with no clear T-tubule openings and intracellular T-tubules (smooth-type). In 33% of cells, we found a novel membrane nanostructure running in the direction of cell length and named it 'longitudinal fissures' (LFs-type). Interestingly, T-tubule openings were often found inside the LFs. About 17% of atrial cells resembled ventricular myocytes, but they had smaller T-tubule openings and a lower Z-groove ratio than the ventricle (ventricular-type). The remaining 12% of cells showed a mixed structure of each subtype (mixed-type). The LFs-, ventricular-, and mixed-type had an appreciable amount of reticular form of intracellular T-tubules. Formamide-induced detubulation effectively removed atrial T-tubules, which was confirmed by both confocal images and decreased cell capacitance. However, the LFs remained intact after detubulation. Detubulation reduced action potential duration and L-type Ca2+ channel (LTCC) density, and prolonged relaxation time of the myocytes. Taken together, we observed heterogeneity of rat atrial T-tubules and membranous ultrastructure, and the alteration of atrial EC-coupling by disruption of T-tubules.

Merits of and Technical Tips for Supra-Mesenteric Aortic Cross Clamping

Supra-celiac aortic cross clamping is often utilized during aortic reconstruction for aneurysmal/occlusive disease involving the pararenal aorta. However, this may be accompanied a myriad of complications related to hemodynamic disturbances, cardiopulmonary compromise and hepatic ischemia. Supra-mesenteric aortic cross clamping may be an excellent option in selected patients with suitable anatomy to minimize or avoid these complications. Herein, the merits of and technical tips for supra-mesenteric aortic cross clamping are discussed.

Pentamidine Inhibits Titanium Particle-Induced Osteolysis In Vivo and Receptor Activator of Nuclear Factor-κB Ligand-Mediated Osteoclast Differentiation In Vitro

BACKGROUND: Wear debris-induced osteolysis leads to periprosthetic loosening and subsequent prosthetic failure. Since excessive osteoclast formation is closely implicated in periprosthetic osteolysis, identification of agents to suppress osteoclast formation and/or function is crucial for the treatment and prevention of wear particle-induced bone destruction. In this study, we examined the potential effect of pentamidine treatment on titanium (Ti) particle-induced osteolysis, and receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis. METHODS: The effect of pentamidine treatment on bone destruction was examined in Ti particle-induced osteolysis mouse model. Ti particles were implanted onto mouse calvaria, and vehicle or pentamidine was administered for 10 days. Then, calvarial bone tissue was analyzed using micro-computed tomography and histology. We performed in vitro osteoclastogenesis assay using bone marrow-derived macrophages (BMMs) to determine the effect of pentamidine on osteoclast formation. BMMs were treated with 20 ng/mL RANKL and 10 ng/mL macrophage colony-stimulating factor in the presence or absence of pentamidine. Osteoclast differentiation was determined by tartrate-resistant acid phosphatase staining, real-time polymerase chain reaction, and immunofluorescence staining. RESULTS: Pentamidine administration decreased Ti particle-induced osteoclast formation significantly and prevented bone destruction compared to the Ti particle group in vivo. Pentamidine also suppressed RANKL-induced osteoclast differentiation and actin ring formation markedly, and inhibited the expression of nuclear factor of activated T cell c1 and osteoclast-specific genes in vitro. Additionally, pentamidine also attenuated RANKL-mediated phosphorylation of IκBα in BMMs. CONCLUSION: These results indicate that pentamidine is effective in inhibiting osteoclast formation and significantly attenuates wear debris-induced bone loss in mice.

Mobile Text Messaging Interventions for Smoking Cessation: A Systematic Review

BACKGROUND: Smoking is one of the most serious health problems worldwide. The aim of this systematic review was to demonstrate the effect of text messaging-based interventions on smoking cessation.METHODS: Electronic databases were searched using specific key terms. The inclusion criteria were (1) articles that employed a randomized controlled trial and (2) articles that examined the effect of text messaging interventions on smoking cessation. However, studies employing multimedia messaging service and smartphone apps were excluded.RESULTS: In total, six randomized controlled trial studies with seven interventions were included in this systematic review. Of these six studies, almost all concluded that text-messaging interventions had no significant effect on smoking cessation. However, one study conducted in England revealed that text messaging intervention groups had a higher rate of six-month prolonged abstinence from smoking than did the control group.CONCLUSION: Text messaging interventions could be effective for those who want to quit smoking. We aimed to determine the effectiveness of using text messaging interventions for smoking cessation. However, there were only six studies that employed randomized controlled trials to determine such effectiveness. More studies on the effect of text messaging interventions for smoking cessation using subjects from various age groups and socioeconomic backgrounds are needed in the future.

Effect of Placenta-Derived Mesenchymal Stem Cells in a Dementia Rat Model via Microglial Mediation: a Comparison between Stem Cell Transplant Methods

PURPOSE: Loss of cholinergic neurons in the hippocampus is a hallmark of many dementias. Administration of stem cells as a therapeutic intervention for patients is under active investigation, but the optimal stem cell type and transplantation modality has not yet been established. In this study, we studied the therapeutic effects of human placenta-derived mesenchymal stem cells (pMSCs) in dementia rat model using either intracerebroventricular (ICV) or intravenous (IV) injections and analyzed their mechanisms of therapeutic action. MATERIALS AND METHODS: Dementia modeling was established by intraventricular injection of 192 IgG-saporin, which causes lesion of cholinergic neurons. Sixty-five male Sprague-Dawley rats were divided into five groups: control, lesion, lesion+ICV injection of pMSCs, lesion+IV injection of pMSCs, and lesion+donepezil. Rats were subjected to the Morris water maze and subsequent immunostaining analyses. RESULTS: Both ICV and IV pMSC administrations allowed significant cognitive recovery compared to the lesioned rats. Acetylcholinesterase activity was significantly rescued in the hippocampus of rats injected with pMSCs post-lesion. Choline acetyltransferase did not co-localize with pMSCs, showing that pMSCs did not directly differentiate into cholinergic cells. Number of microglial cells increased in lesioned rats and significantly decreased back to normal levels with pMSC injection. CONCLUSION: Our results suggest that ICV and IV injections of pMSCs facilitate the recovery of cholinergic neuronal populations and cognitive behavior. This recovery likely occurs through paracrine effects that resemble microglia function rather than direct differentiation of injected pMSCs into cholinergic neurons.

Evaluation of Validity and Reliability of Inertial Measurement Unit-Based Gait Analysis Systems

OBJECTIVE: To replace camera-based three-dimensional motion analyzers which are widely used to analyze body movements and gait but are also costly and require a large dedicated space, this study evaluates the validity and reliability of inertial measurement unit (IMU)-based systems by analyzing their spatio-temporal and kinematic measurement parameters. METHODS: The investigation was conducted in three separate hospitals with three healthy participants. IMUs were attached to the abdomen as well as the thigh, shank, and foot of both legs of each participant. Each participant then completed a 10-m gait course 10 times. During each gait cycle, the hips, knees, and ankle joints were observed from the sagittal, frontal, and transverse planes. The experiments were conducted with both a camerabased system and an IMU-based system. The measured gait analysis data were evaluated for validity and reliability using root mean square error (RMSE) and intraclass correlation coefficient (ICC) analyses. RESULTS: The differences between the RMSE values of the two systems determined through kinematic parameters ranged from a minimum of 1.83 to a maximum of 3.98 with a tolerance close to 1%. The results of this study also confirmed the reliability of the IMU-based system, and all of the variables showed a statistically high ICC. CONCLUSION: These results confirmed that IMU-based systems can reliably replace camera-based systems for clinical body motion and gait analyses.

International Classification of Diseases 10th edition-based disability adjusted life years for measuring of burden of specific injury

OBJECTIVE: We aimed to develop an International Classification of Diseases (ICD) 10th edition injury code-based disability-adjusted life year (DALY) to measure the burden of specific injuries. METHODS: Three independent panels used novel methods to score disability weights (DWs) of 130 indicator codes sampled from 1,284 ICD injury codes. The DWs were interpolated into the remaining injury codes (n=1,154) to estimate DWs for all ICD injury codes. The reliability of the estimated DWs was evaluated using the test-retest method. We calculated ICD-DALYs for individual injury episodes using the DWs from the Korean National Hospital Discharge Injury Survey (HDIS, n=23,160 of 2004) database and compared them with DALY based on a global burden of disease study (GBD-DALY) regarding validation, correlation, and agreement for 32 injury categories. RESULTS: Using 130 ICD 10th edition injury indicator codes, three panels determined the DWs using the highest reliability (person trade-off 1, Spearman r=0.724, 0.788, and 0.875 for the three panel groups). The test-retest results for the reliability were excellent (Spearman r=0.932) (P<0.001). The HDIS database revealed injury burden (years) as follows: GBD-DALY (138,548), GBD-years of life disabled (130,481), and GBD-years of life lost (8,117) versus ICD-DALY (262,246), ICD-years of life disabled (255,710), and ICD-years of life lost (6,537), respectively. Spearman’s correlation coefficient of the DALYs between the two methods was 0.759 (P<0.001), and the Bland-Altman test displayed an acceptable agreement, with exception of two categories among 32 injury groups. CONCLUSION: The ICD-DALY was developed to calculate the burden of injury for all injury codes and was validated with the GBD-DALY. The ICD-DALY was higher than the GBD-DALY but showed acceptable agreement.

Structural Variation of Alu Element and Human Disease

Transposable elements are one of major sources to cause genomic instability through various mechanisms including de novo insertion, insertion-mediated genomic deletion, and recombination-associated genomic deletion. Among them is Alu element which is the most abundant element, composing ~10% of the human genome. The element emerged in the primate genome 65 million years ago and has since propagated successfully in the human and non-human primate genomes. Alu element is a non-autonomous retrotransposon and therefore retrotransposed using L1-enzyme machinery. The 'master gene' model has been generally accepted to explain Alu element amplification in primate genomes. According to the model, different subfamilies of Alu elements are created by mutations on the master gene and most Alu elements are amplified from the hyperactive master genes. Alu element is frequently involved in genomic rearrangements in the human genome due to its abundance and sequence identity between them. The genomic rearrangements caused by Alu elements could lead to genetic disorders such as hereditary disease, blood disorder, and neurological disorder. In fact, Alu elements are associated with approximately 0.1% of human genetic disorders. The first part of this review discusses mechanisms of Alu amplification and diversity among different Alu subfamilies. The second part discusses the particular role of Alu elements in generating genomic rearrangements as well as human genetic disorders.

Mutational Analysis of Extranodal NK/T-Cell Lymphoma Using Targeted Sequencing with a Comprehensive Cancer Panel

Extranodal natural killer (NK)/T-cell lymphoma, nasal type (NKTCL), is a malignant disorder of cytotoxic lymphocytes of NK or T cells. It is an aggressive neoplasm with a very poor prognosis. Although extranodal NKTCL reportedly has a strong association with Epstein-Barr virus, the molecular pathogenesis of NKTCL has been unexplored. The recent technological advancements in next-generation sequencing (NGS) have made DNA sequencing cost- and time-effective, with more reliable results. Using the Ion Proton Comprehensive Cancer Panel, we sequenced 409 cancer-related genes to identify somatic mutations in five NKTCL tissue samples. The sequencing analysis detected 25 mutations in 21 genes. Among them, KMT2D, a histone modification-related gene, was the most frequently mutated gene (four of the five cases). This result was consistent with recent NGS studies that have suggested KMT2D as a novel driver gene in NKTCL. Mutations were also found in ARID1A, a chromatin remodeling gene, and TP53, which also recurred in recent NGS studies. We also found mutations in 18 novel candidate genes, with molecular functions that were potentially implicated in cancer development. We suggest that these genes may result in multiple oncogenic events and may be used as potential bio-markers of NKTCL in the future.

Increased osteoinductivity and mineralization by minimal concentration of bone morphogenetic protein-2 loaded onto biphasic calcium phosphate in a rabbit sinus

PURPOSE: The purpose of the present study was to evaluate the effectiveness of a minimal concentration of bone morphogenetic protein-2 (BMP-2) in terms of quantitative and qualitative analyses of newly formed bone in a rabbit maxillary sinus model. METHODS: In 7 rabbits, sinus windows were prepared bilaterally. Biphasic calcium phosphate (BCP) loaded with 0.05 mg/mL BMP-2 was grafted into one sinus (the BMP group) and saline-soaked BCP was placed into the other (the control group) in each animal. The animals were allowed an 8-week healing period before being sacrificed. Specimens including the augmented area and surrounding tissues were then removed and evaluated both radiographically and histologically. RESULTS: There was a difference in the mineralization of new bone between the groups. In the BMP group, the greater part of the new bone consisted of mature lamellar bone with an evident trabecular pattern, whereas the control group showed mostly woven bone, consisting only partially of lamellar bone. Histometrically, the area of new bone was significantly greater (4.55±1.35 mm2 vs. 2.99±0.86 mm2) in the BMP group than in the control group (P<0.05); however, the total augmentation volumes were not significantly different between the groups. CONCLUSIONS: Within the limitations of this study, it can be suggested that a minimal concentration of BMP-2 (0.05 mg/mL) had an osteoinductive effect with accelerated mineralization in a rabbit sinus model using a BCP carrier.

Emergency Department Crowding Disparity: a Nationwide Cross-Sectional Study

In this study, we evaluated national differences in emergency department (ED) crowding to identify factors significantly associated with crowding in institutes and communities across Korea. This was a cross-sectional nationwide observational study using data abstracted from the National Emergency Department Information System (NEDIS). We calculated mean occupancy rates to quantify ED crowding status and divided EDs into three groups according to their occupancy rates (cutoffs: 0.5 and 1.0). Factors potentially related to ED crowding were collected from the NEDIS. We performed a multivariate regression analysis to identify variables significantly associated with ED crowding. A total of 120 EDs were included in the final analysis. Of these, 73 were categorized as 'low crowded' (LC, occupancy rate < 0.50), 37 as 'middle crowded' (MC, 0.50 ≤ occupancy rate < 1.00), 10 EDs as 'high crowded' (HC, 1.00 ≤ occupancy rate). The mean ED occupancy rate varied widely, from 0.06 to 2.33. The median value was 0.39 with interquartile ranges (IQRs) from 0.20 to 0.71. Multivariate analysis revealed that after adjustment, ED crowding was significantly associated with the number of visits, percentage of patients referred, number of nurses, and ED disposition. This nationwide study observed significant variety in ED crowding. Several input, throughput, and output factors were associated with crowding.

Emergency Department Crowding Disparity: a Nationwide Cross-Sectional Study

In this study, we evaluated national differences in emergency department (ED) crowding to identify factors significantly associated with crowding in institutes and communities across Korea. This was a cross-sectional nationwide observational study using data abstracted from the National Emergency Department Information System (NEDIS). We calculated mean occupancy rates to quantify ED crowding status and divided EDs into three groups according to their occupancy rates (cutoffs: 0.5 and 1.0). Factors potentially related to ED crowding were collected from the NEDIS. We performed a multivariate regression analysis to identify variables significantly associated with ED crowding. A total of 120 EDs were included in the final analysis. Of these, 73 were categorized as 'low crowded' (LC, occupancy rate < 0.50), 37 as 'middle crowded' (MC, 0.50 ≤ occupancy rate < 1.00), 10 EDs as 'high crowded' (HC, 1.00 ≤ occupancy rate). The mean ED occupancy rate varied widely, from 0.06 to 2.33. The median value was 0.39 with interquartile ranges (IQRs) from 0.20 to 0.71. Multivariate analysis revealed that after adjustment, ED crowding was significantly associated with the number of visits, percentage of patients referred, number of nurses, and ED disposition. This nationwide study observed significant variety in ED crowding. Several input, throughput, and output factors were associated with crowding.

Stanford type A aortic dissection in a patient with Marfan syndrome during pregnancy: a case report / 대한마취과학회지

Aortic dissection during pregnancy is a devastating event for both the pregnant woman and the baby. We report a case of acute aortic dissection (Stanford type A) in a pregnant woman with Marfan syndrome at the 29th week of gestation. She underwent a cesarean section followed by an ascending aorta and total arch replacement with cardiopulmonary bypass, without a prior sternotomy. The hemodynamic parameters were kept stable during the cesarean section by using inotropes and vasopressors under transesophageal echocardiography monitoring. The newborn survived after endotracheal intubation and management in a neonatal intensive care unit.

Useful MRI Features for Distinguishing Benign Peripheral Nerve Sheath Tumors and Myxoid Tumors in the Musculoskeletal System

PURPOSE: To identify the differential MRI findings between myxoid tumors and benign peripheral nerve sheath tumors (BPNSTs) in the musculoskeletal system. MATERIALS AND METHODS: The study participants included a total of 35 consecutive patients who underwent MRI between September 2011 and December 2013. The patients were pathologically diagnosed with myxoid tumors (22 patients) or BPNSTs (13 patients). Evaluation was done by two radiologists, based on the following characteristics: size, margin, degree of signal intensity (SI) on T2-weighted images (T2WI), homogeneity of SI on T2WI, enhancement pattern, enhancement homogeneity, presence of cystic portion, internal fat component, presence of fat split sign, presence of target sign, presence of continuation with adjacent neurovascular bundle, and presence of surrounding halo. RESULTS: Large size, high SI on T2WI, heterogeneous enhancement, and internal fat component were commonly observed in myxoid tumors, while homogenous enhancement, fat split sign, target sign were common in BPNSTs. The differences were statistically significant (P 0.05). CONCLUSION: In the differential diagnosis of myxoid tumors and BPNSTs involving the musculoskeletal system, several MRI findings such as degree of SI on T2WI, enhancement homogeneity, internal fat component, fat split sign, and target sign, may be helpful in establishing the diagnosis.