Publications by authors named "Jiwon Ryu"

44 Publications

Machine learning-based prediction of acute kidney injury after nephrectomy in patients with renal cell carcinoma.

Sci Rep 2021 Aug 3;11(1):15704. Epub 2021 Aug 3.

Department of Internal Medicine, Seoul National University College of Medicine, 103 Daehakro, Jongno-gu, Seoul, 03080, South Korea.

The precise prediction of acute kidney injury (AKI) after nephrectomy for renal cell carcinoma (RCC) is an important issue because of its relationship with subsequent kidney dysfunction and high mortality. Herein we addressed whether machine learning (ML) algorithms could predict postoperative AKI risk better than conventional logistic regression (LR) models. A total of 4104 RCC patients who had undergone unilateral nephrectomy from January 2003 to December 2017 were reviewed. ML models such as support vector machine, random forest, extreme gradient boosting, and light gradient boosting machine (LightGBM) were developed, and their performance based on the area under the receiver operating characteristic curve, accuracy, and F1 score was compared with that of the LR-based scoring model. Postoperative AKI developed in 1167 patients (28.4%). All the ML models had higher performance index values than the LR-based scoring model. Among them, the LightGBM model had the highest value of 0.810 (0.783-0.837). The decision curve analysis demonstrated a greater net benefit of the ML models than the LR-based scoring model over all the ranges of threshold probabilities. The application of ML algorithms improves the predictability of AKI after nephrectomy for RCC, and these models perform better than conventional LR-based models.
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http://dx.doi.org/10.1038/s41598-021-95019-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8333365PMC
August 2021

A Smart Diaper System Using Bluetooth and Smartphones to Automatically Detect Urination and Volume of Voiding: Prospective Observational Pilot Study in an Acute Care Hospital.

J Med Internet Res 2021 Jul 30;23(7):e29979. Epub 2021 Jul 30.

Department of Internal Medicine, Seoul National University Bundang Hospital, Gyeonggi-do, Republic of Korea.

Background: Caregivers of patients who wear conventional diapers are required to check for voiding every hour because prolonged wearing of wet diapers causes health problems including diaper dermatitis and urinary tract infections. However, frequent checking is labor intensive and disturbs patients' and caregivers' sleep. Furthermore, assessing patients' urine output with diapers in an acute care setting is difficult. Recently, a smart diaper system with wetness detection technology was developed to solve these issues.

Objective: We aimed to evaluate the applicability of the smart diaper system for urinary detection, its accuracy in measuring voiding volume, and its effect on incontinence-associated dermatitis (IAD) occurrence in an acute care hospital.

Methods: This prospective, observational, single-arm pilot study was conducted at a single tertiary hospital. We recruited 35 participants aged ≥50 years who were wearing diapers due to incontinence between August and November 2020. When the smart diaper becomes wet, the smart diaper system notifies the caregiver to change the diaper and measures voiding volume automatically. Caregivers were instructed to record the weight of wet diapers on frequency volume charts (FVCs). We determined the voiding detection rate of the smart diaper system and compared the urine volume as automatically calculated by the smart diaper system with the volume recorded on FVCs. Agreement between the two measurements was estimated using a Bland-Altman plot. We also checked for the occurrence or aggravation of IAD and bed sores.

Results: A total of 30 participants completed the protocol and 390 episodes of urination were recorded. There were 108 records (27.7%) on both the FVCs and the smart diaper system, 258 (66.2%) on the FVCs alone, 18 (4.6%) on the smart diaper system alone, and 6 (1.5%) on the FVCs with sensing device lost. The detection rate of the smart diaper system was 32.8% (126/384). When analyzing records concurrently listed in both the FVCs and the smart diaper system, linear regression showed a strong correlation between the two measurements (R=0.88, P<.001). The Bland-Altman assessment showed good agreement between the two measurements, with a mean difference of -4.2 mL and 95% limits of agreement of -96.7 mL and 88.3 mL. New occurrence and aggravation of IAD and bed sores were not observed. Bed sores improved in one participant.

Conclusions: The smart diaper system showed acceptable accuracy for measuring urine volume and it could replace conventional FVCs in acute setting hospitals. Furthermore, the smart diaper system has the potential advantage of preventing IAD development and bed sore worsening. However, the detection rate of the smart diaper system was lower than expected. Detection rate polarization among participants was observed, and improvements in the user interface and convenience are needed for older individuals who are unfamiliar with the smart diaper system.
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http://dx.doi.org/10.2196/29979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8367151PMC
July 2021

Human Motor Neurons With SOD1-G93A Mutation Generated From CRISPR/Cas9 Gene-Edited iPSCs Develop Pathological Features of Amyotrophic Lateral Sclerosis.

Front Cell Neurosci 2020 19;14:604171. Epub 2020 Nov 19.

Division of Neuropathology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, United States.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by gradual degeneration and elimination of motor neurons (MNs) in the motor cortex, brainstem, and spinal cord. Some familial forms of ALS are caused by genetic mutations in superoxide dismutase 1 (SOD1) but the mechanisms driving MN disease are unclear. Identifying the naturally occurring pathology and understanding how this mutant SOD1 can affect MNs in translationally meaningful ways in a valid and reliable human cell model remains to be established. Here, using CRISPR/Cas9 genome editing system and human induced pluripotent stem cells (iPSCs), we generated highly pure, iPSC-derived MNs with a SOD1-G93A missense mutation. With the wild-type cell line serving as an isogenic control and MNs from a patient-derived iPSC line with an SOD1-A4V mutation as a comparator, we identified pathological phenotypes relevant to ALS. The mutant MNs accumulated misfolded and aggregated forms of SOD1 in cell bodies and processes, including axons. They also developed distinctive axonal pathologies. Mutants had axonal swellings with shorter axon length and less numbers of branch points. Moreover, structural and molecular abnormalities in presynaptic and postsynaptic size and density were found in the mutants. Finally, functional studies with microelectrode array demonstrated that the individual mutant MNs exhibited decreased number of spikes and diminished network bursting, but increased burst duration. Taken together, we identified spontaneous disease phenotypes relevant to ALS in mutant SOD1 MNs from genome-edited and patient-derived iPSCs. Our findings demonstrate that SOD1 mutations in human MNs cause cell-autonomous proteinopathy, axonopathy, synaptic pathology, and aberrant neurotransmission.
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http://dx.doi.org/10.3389/fncel.2020.604171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710664PMC
November 2020

Cancer development and mortality differences in patients with glomerulonephritis after renal biopsy: a single center retrospective cohort study.

BMC Nephrol 2020 06 10;21(1):221. Epub 2020 Jun 10.

Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.

Background: The association between glomerulonephritis (GN) and cancer has been well known for decades. However, studies evaluating long-term de novo cancer development in patients with GN are limited. This study aimed to evaluate the incidence of cancer development among patients with renal biopsy-proven GN during post-biopsy follow-up and the differences in outcomes according to cancer occurrence.

Methods: We conducted a retrospective cohort study of adult patients who underwent renal biopsy at Seoul National Bundang Hospital between 2003 and 2017. After excluding 778 patients with age < 18 years, cancer diagnosis before or within 6 months after renal biopsy, immunosuppressant therapy before renal biopsy, or pathologic diagnoses other than GN, 822 patients were included in the analysis. Data on baseline clinical characteristics, renal biopsy results, and types and doses of immunosuppressant agents were collected from electronic medical records. The incidence of cancer was censored on the date when the first cancer was diagnosed. We evaluated rates of mortality and end-stage renal disease (ESRD) development during follow-up.

Results: During a mean follow-up period of 58.9 ± 44.5 months, 45 subjects (5.5%) developed de novo cancer. A comparison of clinical characteristics between subjects who did and did not develop cancer revealed that cancer patients were older and had higher comorbidities and immunosuppressant use. Overall, patients with GN had an elevated standardized incidence ratio (SIR) of 7.16 (95% confidence interval (CI): 5.22-9.61) relative to the age- and sex-matched general population. In particular, the SIR was significantly higher in GNs such as membranous nephropathy (MN), IgA nephropathy, lupus nephritis, and focal segmental glomerulosclerosis. Multivariable Cox proportional hazard model revealed that patients with MN had an increased risk of cancer development, with a hazard ratio of 2.30 [95% CI: 1.06-4.98]. Patients with MN who developed cancer had a significantly higher risk of mortality (hazard ratio: 6.59; 95% CI: 1.22-35.56, P = 0.03) than those without cancer, but there was a non-significant difference in ESRD development.

Conclusions: Patients with GN without concurrent cancer, particularly those with MN, have significantly higher risks of cancer development and subsequent mortality and should remain aware of the potential development of malignancy during follow-up.
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http://dx.doi.org/10.1186/s12882-020-01882-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288504PMC
June 2020

Joint Angle Estimation of a Tendon-Driven Soft Wearable Robot through a Tension and Stroke Measurement.

Sensors (Basel) 2020 May 17;20(10). Epub 2020 May 17.

Biorobotics Laboratory, School of Mechanical and Aerospace Engineering, Seoul National University, Gwanak-ro 1, Gwanak-gu, Seoul 08826, Korea.

The size of a device and its adaptability to human properties are important factors in developing a wearable device. In wearable robot research, therefore, soft materials and tendon transmissions have been utilized to make robots compact and adaptable to the human body. However, when used for wearable robots, these methods sometimes cause uncertainties that originate from elongation of the soft material or from undefined human properties. In this research, to consider these uncertainties, we propose a data-driven method that identifies both kinematic and stiffness parameters using tension and wire stroke of the actuators. Through kinematic identification, a method is proposed to find the exact joint position as a function of the joint angle. Through stiffness identification, the relationship between the actuation force and the joint angle is obtained using Gaussian Process Regression (GPR). As a result, by applying the proposed method to a specific robot, the research outlined in this paper verifies how the proposed method can be used in wearable robot applications. This work examines a novel wearable robot named Exo-Index, which assists a human's index finger through the use of three actuators. The proposed identification methods enable control of the wearable robot to result in appropriate postures for grasping objects of different shapes and sizes.
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http://dx.doi.org/10.3390/s20102852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288088PMC
May 2020

Synthesis of Novel Oxazolidines and Study of Its Naked Eye CO₂ Detecting Properties.

J Nanosci Nanotechnol 2020 10;20(10):6428-6434

Department of Advanced Organic Materials Engineering, Chungnam National University, 220 Gung-dong, Yuseong-gu, Daejeon 305-764, Republic of Korea.

Herewith, we synthesized the new oxazolidines (SP-1, SP-2 and SP-3) by without using any withdrawing or donating substitution, and for these molecules we demonstrated CO₂ sensing properties in naked eye condition with different colors (yellow and magenta). All the dyes showed different colors in the presence and absence of CO₂ in ethanol solution with the concept of ring closing and opening. In UV-visible absorption spectrum all the compounds showed visible light absorptions after purging of CO₂. To confirm this mechanism for SP-1 molecule case, we approached the H-NMR and C-NMR techniques deuterated methanol as a solvent and we clearly identified. The stability of the SP-1 molecule in ethanol for CO₂ purging case, we studied repeatability test up to ten cycles and we confirmed that there is no any decrease in sensing ability.
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http://dx.doi.org/10.1166/jnn.2020.18593DOI Listing
October 2020

Robust Photodegradation of Methylene Blue with the Biphenyl-Porphyrin/TiO₂ Photocatalyst Under Visible Light Condition.

J Nanosci Nanotechnol 2020 10;20(10):6266-6273

Department of Advanced Organic Materials Engineering, Chungnam National University, 220 Gung-dong, Yuseong-gu, Daejeon 305-764, South Korea.

Herewith, we approached a synthesis of new biphenyl porphyrin derivative and confirmed its structure with H-NMR and C-NMR studies, FT-IR and mass analytical methods. The porphyrin derivative grafted with TiO₂ and the composite (PORBP-TiO₂) was further confirmed with different analytical techniques like diffuse reflectance spectra, XRD, FT-IR, XPS, SEM analysis. PORBP-TiO₂ was checked for photodegradation of methylene blue in visible light condition and degradation results were compared with bare TiO₂. Our newly synthesized photocatalyst showed a very fast and efficient photocatalytical activity in comparison with bare TiO₂. Fluoresence life time results also supported the strong photocatalytic activity of PORBP-TiO₂. The reusability studies also showed that PORBP-TiO₂ is having very good stability upto 10 cycles also. Finally we proposed a suitable catalytic diagram for PORBP-TiO₂ photocatalysis.
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http://dx.doi.org/10.1166/jnn.2020.18518DOI Listing
October 2020

Targeted disruption of dual leucine zipper kinase and leucine zipper kinase promotes neuronal survival in a model of diffuse traumatic brain injury.

Mol Neurodegener 2019 11 27;14(1):44. Epub 2019 Nov 27.

Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.

Background: Traumatic brain injury (TBI) is a major cause of CNS neurodegeneration and has no disease-altering therapies. It is commonly associated with a specific type of biomechanical disruption of the axon called traumatic axonal injury (TAI), which often leads to axonal and sometimes perikaryal degeneration of CNS neurons. We have previously used genome-scale, arrayed RNA interference-based screens in primary mouse retinal ganglion cells (RGCs) to identify a pair of related kinases, dual leucine zipper kinase (DLK) and leucine zipper kinase (LZK) that are key mediators of cell death in response to simple axotomy. Moreover, we showed that DLK and LZK are the major upstream triggers for JUN N-terminal kinase (JNK) signaling following total axonal transection. However, the degree to which DLK/LZK are involved in TAI/TBI is unknown.

Methods: Here we used the impact acceleration (IA) model of diffuse TBI, which produces TAI in the visual system, and complementary genetic and pharmacologic approaches to disrupt DLK and LZK, and explored whether DLK and LZK play a role in RGC perikaryal and axonal degeneration in response to TAI.

Results: Our findings show that the IA model activates DLK/JNK/JUN signaling but, in contrast to axotomy, many RGCs are able to recover from the injury and terminate the activation of the pathway. Moreover, while DLK disruption is sufficient to suppress JUN phosphorylation, combined DLK and LZK inhibition is required to prevent RGC cell death. Finally, we show that the FDA-approved protein kinase inhibitor, sunitinib, which has activity against DLK and LZK, is able to produce similar increases in RGC survival.

Conclusion: The mitogen-activated kinase kinase kinases (MAP3Ks), DLK and LZK, participate in cell death signaling of CNS neurons in response to TBI. Moreover, sustained pharmacologic inhibition of DLK is neuroprotective, an effect creating an opportunity to potentially translate these findings to patients with TBI.
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http://dx.doi.org/10.1186/s13024-019-0345-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6882250PMC
November 2019

Optogenetically transduced human ES cell-derived neural progenitors and their neuronal progenies: Phenotypic characterization and responses to optical stimulation.

PLoS One 2019 11;14(11):e0224846. Epub 2019 Nov 11.

Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.

Optogenetically engineered human neural progenitors (hNPs) are viewed as promising tools in regenerative neuroscience because they allow the testing of the ability of hNPs to integrate within nervous system of an appropriate host not only structurally, but also functionally based on the responses of their differentiated progenies to light. Here, we transduced H9 embryonic stem cell-derived hNPs with a lentivirus harboring human channelrhodopsin (hChR2) and differentiated them into a forebrain lineage. We extensively characterized the fate and optogenetic functionality of hChR2-hNPs in vitro with electrophysiology and immunocytochemistry. We also explored whether the in vivo phenotype of ChR2-hNPs conforms to in vitro observations by grafting them into the frontal neocortex of rodents and analyzing their survival and neuronal differentiation. Human ChR2-hNPs acquired neuronal phenotypes (TUJ1, MAP2, SMI-312, and synapsin 1 immunoreactivity) in vitro after an average of 70 days of coculturing with CD1 astrocytes and progressively displayed both inhibitory and excitatory neurotransmitter signatures by immunocytochemistry and whole-cell patch clamp recording. Three months after transplantation into motor cortex of naïve or injured mice, 60-70% of hChR2-hNPs at the transplantation site expressed TUJ1 and had neuronal cytologies, whereas 60% of cells also expressed ChR2. Transplant-derived neurons extended axons through major commissural and descending tracts and issued synaptophysin+ terminals in the claustrum, endopiriform area, and corresponding insular and piriform cortices. There was no apparent difference in engraftment, differentiation, or connectivity patterns between injured and sham subjects. Same trends were observed in a second rodent host, i.e. rat, where we employed longer survival times and found that the majority of grafted hChR2-hNPs differentiated into GABAergic neurons that established dense terminal fields and innervated mostly dendritic profiles in host cortical neurons. In physiological experiments, human ChR2+ neurons in culture generated spontaneous action potentials (APs) 100-170 days into differentiation and their firing activity was consistently driven by optical stimulation. Stimulation generated glutamatergic and GABAergic postsynaptic activity in neighboring ChR2- cells, evidence that hChR2-hNP-derived neurons had established functional synaptic connections with other neurons in culture. Light stimulation of hChR2-hNP transplants in vivo generated complicated results, in part because of the variable response of the transplants themselves. Our findings show that we can successfully derive hNPs with optogenetic properties that are fully transferrable to their differentiated neuronal progenies. We also show that these progenies have substantial neurotransmitter plasticity in vitro, whereas in vivo they mostly differentiate into inhibitory GABAergic neurons. Furthermore, neurons derived from hNPs have the capacity of establishing functional synapses with postsynaptic neurons in vitro, but this outcome is technically challenging to explore in vivo. We propose that optogenetically endowed hNPs hold great promise as tools to explore de novo circuit formation in the brain and, in the future, perhaps launch a new generation of neuromodulatory therapies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0224846PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6844486PMC
March 2020

Comparison of cancer prevalence between patients with glomerulonephritis and the general population at the time of kidney biopsy.

PLoS One 2019 18;14(10):e0224024. Epub 2019 Oct 18.

Department of Biomedical Engineering, Seoul National University College of Medicine, Seoul, Republic of Korea.

Glomerulonephritis (GN) has been associated with many solid and hematologic malignancies. However, cancer prevalence at the time of GN diagnosis has been rarely examined. We aimed to evaluate the cancer prevalence in patients with GN at the time of kidney biopsy and to compare the results to those of the general population. A total of 1,155 patients who underwent kidney biopsy between 2003 and 2017 were included. We investigated patients diagnosed with cancer within one month of kidney biopsy. The occurrence of cancer was compared with that of the Korean general population using the observed-to-expected rates (O/E ratio). Twenty-nine patients with GN had cancer. The mean age of patients with and without cancer was 49 and 66 years old, respectively. The proportion of male patients with and without cancer was 49.4% and 58.6%, respectively. The glomerular filtration rate was different between the groups (78.1 ± 37.0, 58.0 ± 43.6 ml/min/1.73 m2, p = 0.006), but the urine protein/creatinine ratio was not (3.21 ± 4.01, 5.38 ± 7.47 g/gCr, p = 0.172). Immunoglobulin A nephropathy (IgAN) was the most common GN (37.9%), followed by membranous GN (13.5%), focal segmental glomerulosclerosis (9.7%), minimal change disease (9.2%), amyloidosis (1.2%). Amyloidosis was the most common GN associated with malignancy (20.7%). In patients with amyloidosis, cancer was observed almost 28 times more than expected and these patients showed higher cancer occurrence than patients with other GN (Relative Risk [RR]: 15.73; 95% confidence interval [CI]: 4.82-51.30; p < 0.01). Cancer occurrence was three times greater in GN patients aged > 50 years compared to the general population (O/E ratio: 3.42; 95% CI: 1.37-5.46; p = 0.027). Patients with GN, especially amyloidosis, have higher risk of cancer than the general population at the time of GN diagnosis. Older age (> 50 years) was one of the major determinants of the presence of cancer in GN patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0224024PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6799918PMC
March 2020

Extraction of Green Tea Phenolics Using Water Bubbled with Gases.

J Food Sci 2019 Jun 1;84(6):1308-1314. Epub 2019 May 1.

Dept. of Food Science and Biotechnology and Food Flavor Sensory Research Center, Sungkyunkwan Univ., Suwon, Republic of Korea.

Water was bubbled with gases including nitrogen (N ), oxygen (O ), hydrogen (H ), carbon dioxide (CO ), and air for 10 min and phenolics from green tea leaves were extracted using the prepared gas-bubbled water. To retain the gases in water, the extraction conditions were maintained in an air-tight container at room temperature under magnetic stirring. Radical scavenging ability, total phenolic content, and phenolic profiles of the extracts were analyzed, and gas-bubbled water was examined to explain the differences in phenolic contents. Overall, green tea infusion prepared from H -bubbled water contained significantly high levels of total phenolic compounds and antioxidant activity compared to other gas-bubbled waters including N , O , CO , and air (P < 0.05).Control samples and those bubbled with CO showed the lowest antioxidant activities in green tea infusion. However, green tea extracts with O bubbling showed the lowest catechin content. Green tea leaves treated with hydrogen gas-bubbled water had much greater damage to their surface morphological properties compared to the other groups, which may explain the higher yield of phenolic compounds. Overall, hydrogen gas-bubbled water showed better extraction yield of phenolics from green tea leaves than other gas-bubbled water. PRACTICAL APPLICATION: Green tea or green tea infusion has diverse health beneficial functionality due to the presence of phenolic compounds. In this study, different gases including nitrogen, oxygen, hydrogen, and carbon dioxide were treated in water and these gas-bubbled water were used to extract phenolics from green tea leaves. Among them, hydrogen-bubbled water extracted the highest phenolic contents from tea leaves and showed the highest in vitro antioxidant ability in green tea infusion compared to other gas-bubbled water. This new knowledge could help to produce green teas with higher antioxidant activity in beverage industry.
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http://dx.doi.org/10.1111/1750-3841.14606DOI Listing
June 2019

Surface expression of TTYH2 is attenuated by direct interaction with β-COP.

BMB Rep 2019 Jul;52(7):445-450

School of Biosystems and Biomedical Sciences, College of Health Sciences, Korea University, Seoul 02841, Korea.

TTYH2 is a calcium-activated, inwardly rectifying anion channel that has been shown to be related to renal cancer and colon cancer. Based on the topological prediction, TTYH2 protein has five transmembrane domains with the extracellular N-terminus and the cytoplasmic C-terminus. In the present study, we identified a vesicle transport protein, β-COP, as a novel specific binding partner of TTYH2 by yeast two-hybrid screening using a human brain cDNA library with the C-terminal region of TTYH2 (TTYH2-C) as a bait. Using in vitro and in vivo binding assays, we confirmed the protein-protein interactions between TTYH2 and β-COP. We also found that the surface expression and activity of TTYH2 were decreased by co-expression with β-COP in the heterologous expression system. In addition, β-COP associated with TTYH2 in a native condition at a human colon cancer cell line, LoVo cells. The over-expression of β-COP in the LoVo cells led to a dramatic decrease in the surface expression and activity of endogenous TTYH2. Collectively, these data suggested that β-COP plays a critical role in the trafficking of the TTYH2 channel to the plasma membrane. [BMB Reports 2019; 52(7): 445-450].
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6675250PMC
July 2019

A Kalman-Filter-Based Common Algorithm Approach for Object Detection in Surgery Scene to Assist Surgeon's Situation Awareness in Robot-Assisted Laparoscopic Surgery.

J Healthc Eng 2018 2;2018:8079713. Epub 2018 May 2.

Department of Biomedical Engineering, College of Medicine, Institute of Medical and Biological Engineering, Medical Research Center, Seoul National University, Seoul, Republic of Korea.

Although the use of the surgical robot is rapidly expanding for various medical treatments, there still exist safety issues and concerns about robot-assisted surgeries due to limited vision through a laparoscope, which may cause compromised situation awareness and surgical errors requiring rapid emergency conversion to open surgery. To assist surgeon's situation awareness and preventive emergency response, this study proposes situation information guidance through a vision-based common algorithm architecture for automatic detection and tracking of intraoperative hemorrhage and surgical instruments. The proposed common architecture comprises the location of the object of interest using feature texture, morphological information, and the tracking of the object based on Kalman filter for robustness with reduced error. The average recall and precision of the instrument detection in four prostate surgery videos were 96% and 86%, and the accuracy of the hemorrhage detection in two prostate surgery videos was 98%. Results demonstrate the robustness of the automatic intraoperative object detection and tracking which can be used to enhance the surgeon's preventive state recognition during robot-assisted surgery.
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http://dx.doi.org/10.1155/2018/8079713DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5954863PMC
November 2019

Seropositive rate of the anti-hepatitis A immunoglobulin G antibody in maintenance hemodialysis subjects from two hospitals in Korea.

Korean J Intern Med 2019 Nov 23;34(6):1297-1303. Epub 2018 Feb 23.

Division of Nephrology, Department of Internal Medicine, Hallym University Kangnam Sacred Heart Hospital, Seoul, Korea.

Background/aims: Hepatitis A virus (HAV) is a self-limiting infectious disease, but 1% of subjects develop fulminant hepatitis. The prevalence of the anti-HAV immunoglobulin G (IgG) antibody in hemodialysis subjects in Korea remains unknown. The purpose of this study was to describe and compare the seropositive rate of anti-HAV antibody among hemodialysis subjects in two hospitals according to age group.

Methods: A total of 170 hemodialysis subjects were evaluated for the seropositive rate of the anti-HAV IgG antibody and its titer.

Results: Of the 170 maintenance hemodialysis subjects in two hospitals (Kangnam 92 vs. Chuncheon 78), 79 (46.5%) were male. The mean age was 53.2 years old, and 94.1% of the subjects were over 40 years old. The median vintage of hemodialysis was 29.0 months. Anti-HAV antibody was found in 163 subjects (95.9%), with no significant difference between the two areas (Kangnam 97.8% [n = 90] vs. Chuncheon 93.6% [n = 73]). Subjects younger than 40 years old showed a seropositive rate of 50%, while the seropositive rate increased with age for subjects aged 40 or older (p for trend < 0.001). Seropositive subjects from Kangnam showed a higher anti-HAV antibody titer than those from Chuncheon (median: Kangnam 14.2 vs. Chuncheon 11.7). Only age influenced seropositivity. The only factor that influenced the antibody level was the location of hospital (p < 0.001).

Conclusion: The seropositive rate of the anti-HAV antibody in hemodialysis subjects was 95%, which is similar to findings in the general population. Active immunization against hepatitis A is strongly recommended for hemodialysis subjects under 40 years of age after anti-HAV testing.
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http://dx.doi.org/10.3904/kjim.2017.293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823562PMC
November 2019

Vascular calcification and cardiac function according to residual renal function in patients on hemodialysis with urination.

PLoS One 2017 27;12(9):e0185296. Epub 2017 Sep 27.

Department of Internal Medicine, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea.

Background: Vascular calcification is common and may affect cardiac function in patients with end-stage renal disease (ESRD). However, little is known about the effect of residual renal function on vascular calcification and cardiac function in patients on hemodialysis.

Methods: This study was conducted between January 2014 and January 2017. One hundred six patients with residual renal function on maintenance hemodialysis for 3 months were recruited. We used residual renal urea clearance (KRU) to measure residual renal function. First, abdominal aortic calcification score (AACS) and brachial-ankle pulse wave velocity (baPWV) were measured in patients on hemodialysis. Second, we performed echocardiography and investigated new cardiovascular events after study enrollment.

Results: The median KRU was 0.9 (0.3-2.5) mL/min/1.73m2. AACS (4.0 [1.0-10.0] vs. 3.0 [0.0-8.0], p = 0.05) and baPWV (1836.1 ± 250.4 vs. 1676.8 ± 311.0 cm/s, p = 0.01) were significantly higher in patients with a KRU < 0.9 mL/min/1.73m2 than a KRU ≥ 0.9 mL/min/1.73m2. Log-KRU significantly negatively correlated with log-AACS (ß = -0.29, p = 0.002) and baPWV (ß = -0.19, P = 0.05) after factor adjustment. The proportion of left ventricular diastolic dysfunction was significantly higher in patients with a KRU < 0.9 mL/min/1.73m2 than with a KRU ≥ 0.9 mL/min/1.73m2 (67.9% vs. 49.1%, p = 0.05). Patients with a KRU < 0.9 mL/min/1.73m2 showed a higher tendency of cumulative cardiovascular events compared to those with a KRU ≥ 0.9 ml/min/1.73m2 (P = 0.08).

Conclusions: Residual renal function was significantly associated with vascular calcification and left ventricular diastolic dysfunction in patients on hemodialysis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0185296PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5617191PMC
October 2017

Impact of Electronic Acute Kidney Injury (AKI) Alerts With Automated Nephrologist Consultation on Detection and Severity of AKI: A Quality Improvement Study.

Am J Kidney Dis 2018 01 25;71(1):9-19. Epub 2017 Jul 25.

Department of Internal Medicine, Seoul National University Bundang Hospital, Gyeonggi-do, Korea; Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea. Electronic address:

Background: Several electronic alert systems for acute kidney injury (AKI) have been introduced. However, their clinical benefits require further investigation.

Study Design: Before-and-after quality improvement study.

Setting & Participants: A tertiary teaching hospital in Korea, which adopted an AKI alert system on June 1, 2014. Before and after launch of the alert system, 1,884 and 1,309 patients with AKI were included in the usual-care and alert groups, respectively.

Quality Improvement Plan: Implementation of an AKI alert system through which clinicians could generate automated consultations to the nephrology division for all hospitalized patients.

Outcomes: Primary outcomes included overlooked AKI events, defined as not measuring the follow-up creatinine value, and the consultation pattern of clinicians. Secondary outcomes were severe AKI events; AKI recovery, defined based on the creatinine-based criterion; and patient mortality.

Measurements: ORs for events of overlooked AKI, early consultation, and severe AKI were calculated with logistic regression. AKI recovery rate and patient mortality were assessed using Cox regression.

Results: After introduction of the alert system, the odds of overlooked AKI events were significantly lower (adjusted OR, 0.40; 95% CI, 0.30-0.52), and the odds of an early consultation with a nephrologist were greater (adjusted OR, 6.13; 95% CI, 4.80-7.82). The odds of a severe AKI event was reduced after implementation of the alerts (adjusted OR, 0.75; 95% CI, 0.64-0.89). Furthermore, the likelihood of AKI recovery was improved in the alert group (adjusted HR, 1.70; 95% CI, 1.53-1.88). Mortality was not affected by the AKI alert system (adjusted HR, 1.07; 95% CI, 0.68-1.68).

Limitations: Possible unreported differences between the alert and usual-care groups.

Conclusions: Implementation of the AKI alert system was associated with beneficial effects in terms of an improved rate of recovery from AKI. Therefore, widespread adoption of such systems could be considered in general hospitals.
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http://dx.doi.org/10.1053/j.ajkd.2017.06.008DOI Listing
January 2018

Image Fusion of Real-Time Ultrasonography with Computed Tomography: Factors Affecting the Registration Error and Motion of Focal Hepatic Lesions.

Ultrasound Med Biol 2017 09 19;43(9):2024-2032. Epub 2017 Jun 19.

Department of Radiology, Chung-Ang University Hospital, Chung-Ang University College of Medicine, Seoul, Korea.

Factors affecting the registration error (RE) and motion of focal hepatic lesions (FHLs) in image fusion of real-time ultrasonography (US) with computed tomography (CT) images were prospectively assessed by focusing on respiratory movement and FHL location. Real-time US and pre-acquired CT images at end-inspiration were fused with FHLs for 103 patients. Three-dimensional US data containing FHLs were obtained during end-inspiratory/expiratory phases. Multivariate analysis revealed that diaphragm motion (p < 0.001), chronic liver disease (p = 0.02) and the absolute difference in distance between the FHL and the central portal vein (CPV) during respiration (p = 0.03) were the independent factors that revealed the maximum effect on RE. In contrast, diaphragm motion (p < 0.001) and distance between the FHL and CPV at inspiration (p = 0.036) revealed the maximum effect on FHL motion. In conclusion, RE and FHL motion are affected by the degree of respiratory movement and the location of the FHL. Therefore, image fusion with CT images should be used with caution if the degree of respiratory motion is significant or if the FHL is located at the periphery of the liver.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2017.01.027DOI Listing
September 2017

Comparison Between CT and MR Images as More Favorable Reference Data Sets for Fusion Imaging-Guided Radiofrequency Ablation or Biopsy of Hepatic Lesions: A Prospective Study with Focus on Patient's Respiration.

Cardiovasc Intervent Radiol 2017 Oct 1;40(10):1567-1575. Epub 2017 May 1.

Biostatistics and Clinical Epidemiology Center, Samsung Medical Center, Seoul, Republic of Korea.

Purpose: To identify the more accurate reference data sets for fusion imaging-guided radiofrequency ablation or biopsy of hepatic lesions between computed tomography (CT) and magnetic resonance (MR) images.

Materials And Methods: This study was approved by the institutional review board, and written informed consent was received from all patients. Twelve consecutive patients who were referred to assess the feasibility of radiofrequency ablation or biopsy were enrolled. Automatic registration using CT and MR images was performed in each patient. Registration errors during optimal and opposite respiratory phases, time required for image fusion and number of point locks used were compared using the Wilcoxon signed-rank test.

Results: The registration errors during optimal respiratory phase were not significantly different between image fusion using CT and MR images as reference data sets (p = 0.969). During opposite respiratory phase, the registration error was smaller with MR images than CT (p = 0.028). The time and the number of points locks needed for complete image fusion were not significantly different between CT and MR images (p = 0.328 and p = 0.317, respectively).

Conclusion: MR images would be more suitable as the reference data set for fusion imaging-guided procedures of focal hepatic lesions than CT images.
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http://dx.doi.org/10.1007/s00270-017-1666-5DOI Listing
October 2017

Automatic image fusion of real-time ultrasound with computed tomography images: a prospective comparison between two auto-registration methods.

Acta Radiol 2017 Nov 20;58(11):1349-1357. Epub 2017 Feb 20.

4 Biostatistics and Clinical Epidemiology Center, Samsung Medical Center, Seoul, Republic of Korea.

Background A major drawback of conventional manual image fusion is that the process may be complex, especially for less-experienced operators. Recently, two automatic image fusion techniques called Positioning and Sweeping auto-registration have been developed. Purpose To compare the accuracy and required time for image fusion of real-time ultrasonography (US) and computed tomography (CT) images between Positioning and Sweeping auto-registration. Material and Methods Eighteen consecutive patients referred for planning US for radiofrequency ablation or biopsy for focal hepatic lesions were enrolled. Image fusion using both auto-registration methods was performed for each patient. Registration error, time required for image fusion, and number of point locks used were compared using the Wilcoxon signed rank test. Results Image fusion was successful in all patients. Positioning auto-registration was significantly faster than Sweeping auto-registration for both initial (median, 11 s [range, 3-16 s] vs. 32 s [range, 21-38 s]; P < 0.001] and complete (median, 34.0 s [range, 26-66 s] vs. 47.5 s [range, 32-90]; P = 0.001] image fusion. Registration error of Positioning auto-registration was significantly higher for initial image fusion (median, 38.8 mm [range, 16.0-84.6 mm] vs. 18.2 mm [6.7-73.4 mm]; P = 0.029), but not for complete image fusion (median, 4.75 mm [range, 1.7-9.9 mm] vs. 5.8 mm [range, 2.0-13.0 mm]; P = 0.338]. Number of point locks required to refine the initially fused images was significantly higher with Positioning auto-registration (median, 2 [range, 2-3] vs. 1 [range, 1-2]; P = 0.012]. Conclusion Positioning auto-registration offers faster image fusion between real-time US and pre-procedural CT images than Sweeping auto-registration. The final registration error is similar between the two methods.
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http://dx.doi.org/10.1177/0284185117693459DOI Listing
November 2017

A prospective comparison between auto-registration and manual registration of real-time ultrasound with MR images for percutaneous ablation or biopsy of hepatic lesions.

Abdom Radiol (NY) 2017 06;42(6):1799-1808

Biostatistics and Clinical Epidemiology Center, Samsung Medical Center, Seoul, South Korea.

Purpose: To compare the accuracy and required time for image fusion of real-time ultrasound (US) with pre-procedural magnetic resonance (MR) images between positioning auto-registration and manual registration for percutaneous radiofrequency ablation or biopsy of hepatic lesions.

Methods: This prospective study was approved by the institutional review board, and all patients gave written informed consent. Twenty-two patients (male/female, n = 18/n = 4; age, 61.0 ± 7.7 years) who were referred for planning US to assess the feasibility of radiofrequency ablation (n = 21) or biopsy (n = 1) for focal hepatic lesions were included. One experienced radiologist performed the two types of image fusion methods in each patient. The performance of auto-registration and manual registration was evaluated. The accuracy of the two methods, based on measuring registration error, and the time required for image fusion for both methods were recorded using in-house software and respectively compared using the Wilcoxon signed rank test.

Results: Image fusion was successful in all patients. The registration error was not significantly different between the two methods (auto-registration: median, 3.75 mm; range, 1.0-15.8 mm vs. manual registration: median, 2.95 mm; range, 1.2-12.5 mm, p = 0.242). The time required for image fusion was significantly shorter with auto-registration than with manual registration (median, 28.5 s; range, 18-47 s, vs. median, 36.5 s; range, 14-105 s, p = 0.026).

Conclusion: Positioning auto-registration showed promising results compared with manual registration, with similar accuracy and even shorter registration time.
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http://dx.doi.org/10.1007/s00261-017-1075-xDOI Listing
June 2017

Automatic Registration between Real-Time Ultrasonography and Pre-Procedural Magnetic Resonance Images: A Prospective Comparison between Two Registration Methods by Liver Surface and Vessel and by Liver Surface Only.

Ultrasound Med Biol 2016 07 13;42(7):1627-36. Epub 2016 Apr 13.

Biostatistics and Clinical Epidemiology Center, Samsung Medical Center, Seoul, Korea.

The aim of this study was to compare the accuracy of and the time required for image fusion between real-time ultrasonography (US) and pre-procedural magnetic resonance (MR) images using automatic registration by a liver surface only method and automatic registration by a liver surface and vessel method. This study consisted of 20 patients referred for planning US to assess the feasibility of percutaneous radiofrequency ablation or biopsy for focal hepatic lesions. The first 10 consecutive patients were evaluated by an experienced radiologist using the automatic registration by liver surface and vessel method, whereas the remaining 10 patients were evaluated using the automatic registration by liver surface only method. For all 20 patients, image fusion was automatically executed after following the protocols and fused real-time US and MR images moved synchronously. The accuracy of each method was evaluated by measuring the registration error, and the time required for image fusion was assessed by evaluating the recorded data using in-house software. The results obtained using the two automatic registration methods were compared using the Mann-Whitney U-test. Image fusion was successful in all 20 patients, and the time required for image fusion was significantly shorter with the automatic registration by liver surface only method than with the automatic registration by liver surface and vessel method (median: 43.0 s, range: 29-74 s vs. median: 83.0 s, range: 46-101 s; p = 0.002). The registration error did not significantly differ between the two methods (median: 4.0 mm, range: 2.1-9.9 mm vs. median: 3.7 mm, range: 1.8-5.2 mm; p = 0.496). The automatic registration by liver surface only method offers faster image fusion between real-time US and pre-procedural MR images than does the automatic registration by liver surface and vessel method. However, the degree of accuracy was similar for the two methods.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2016.02.008DOI Listing
July 2016

Ubiquitination-dependent degradation of p73 by the mitochondrial E3 ubiquitin ligase Hades.

Biochem Biophys Res Commun 2015 Nov 3;467(2):316-21. Epub 2015 Oct 3.

Department of Bio and Brain Engineering, KAIST, Daejeon 305-701, Republic of Korea. Electronic address:

p73 is a member of the p53 family of transcription factors which plays an essential role in tumor suppression. p73 is associated with the sensitivity of cancer cells to chemotherapy and the prognosis of many cancers. In this study, we showed the ubiquitination-dependent degradation of p73 by the mitochondrial E3 ubiquitin ligase Hades. First, the binding between p73 and Hades was identified by co-immunoprecipitation experiments, and it was found that the Hades RING-finger domain mediates the interaction with p73. Immunofluorescence analysis showed that p73 moves to the mitochondria and colocalizes with Hades during etoposide-induced apoptosis. By performing in vivo and in vitro ubiquitination assays, we observed that the Hades RING-finger domain promotes ubiquitination of p73. Finally, it was shown that SiRNA-mediated depletion of Hades stabilizes p73. Taken together, our results showed that Hades mediates the ubiquitination-dependent degradation of mitochondrial p73 under apoptotic conditions. These findings suggest that Hades-mediated p73 ubiquitination is a novel regulatory mechanism for the exonuclear function of p73.
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http://dx.doi.org/10.1016/j.bbrc.2015.09.163DOI Listing
November 2015

Time points for obtaining representative values of 24-hour blood pressure in chronic kidney disease.

Korean J Intern Med 2015 Sep 27;30(5):665-74. Epub 2015 Aug 27.

Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.

Background/aims: Ambulatory blood pressure (BP) monitoring has been widely recommended for evaluating the status of BP, but is lacking in practicality. Determination of the specific time points for BP measurement that are representative of 24-hour mean BP could be useful and convenient in hypertensive patients with chronic kidney disease (CKD).

Methods: A total of 1,317 patients for whom 24-hour ambulatory BP monitoring was performed were enrolled in a multicenter study on hypertensive CKD. We analyzed the time points at which systolic blood pressure (SBP) values exhibited the smallest differences from 24-hour mean SBP (mSBP). We included office mSBP and analyzed the relationships between SBPs at the office and the time points with the smallest differences from 24-hour mSBP using several methods.

Results: The time points with the smallest differences from 24-hour mSBP were 7:00 AM, 2:00 PM, and 9:30 PM. In regression analysis, SBPs at 7:00 AM and 9:30 PM were better correlated with 24-hour mSBP than SBPs at 2:00 PM and the office. The proportions of patients with SBPs within 30% of 24-hour mSBP were higher at 7:00 AM and 9:30 PM. The best consistency between the uncontrolled hypertensive groups, defined as ≥ 135 mmHg of 24-hour mSBP and higher values of SBPs corresponding to 135 mmHg of 24-hour mSBP, were observed at the 7:00 AM and 9:30 PM time points.

Conclusions: The specific time points for SBPs that correlated well with 24-hour mSBP in hypertensive CKD patients were 7:00 AM and 9:30 PM.
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http://dx.doi.org/10.3904/kjim.2015.30.5.665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4578022PMC
September 2015

Evidence for accelerated tauopathy in the retina of transgenic P301S tau mice exposed to repetitive mild traumatic brain injury.

Exp Neurol 2015 Nov 24;273:168-76. Epub 2015 Aug 24.

Division of Neuropathology, Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address:

Chronic traumatic encephalopathy (CTE) is associated with repetitive mild traumatic brain injury (mTBI) in the context of contact and collision sports, but not all exposed individuals develop this condition. In addition, experiments in animal models in several laboratories have shown that non-transgenic mice do not develop tauopathy after exposure to repetitive mTBI schedules. It is thus reasonable to assume that genetic factors may play an etiological role in the development of CTE. More than 40 mutations in the tau gene are known to confer proneness to aggregation and are thought to cause neurodegenerative diseases including frontotemporal degeneration (FTD). Transgenic mice harboring these mutations can be used to ask the question whether repetitive mTBI can accelerate onset and course of tauopathy or worsen the outcomes of transgenic disease. In this study, we exposed mice harboring the tau P301S transgene associated with FTD to repetitive mTBI schedules by impact acceleration (IA) that we have previously characterized. We explored the progression of tauopathy in the retina and neocortex based on density of neuronal profiles loaded with tau pS422, a marker of advanced tau hyperphosphorylation. We found that the density of tau pS422 (+) retinal ganglion cells (RGCs) increased twenty fold with one mTBI hit, a little over fifty fold with four mTBI hits and sixty fold with 12 mTBI hits. The severity of mTBI burden (number of hits) was a significant factor in tauopathy outcome. On the other hand, we found no association between repetitive mTBI and density of pS422 (+) neuronal profiles in neocortex, a region that is not featured by significant TAI in our repetitive mTBI model. We observed similar, but less prominent, trends in tauopathy-prone transgenic mice harboring all 6 isoforms of wild-type human tau without mouse tau. Our findings indicate that repetitive mTBI accelerates tauopathy under diverse genetic conditions predisposing to tau aggregation and suggest a vulnerability-stress model in understanding some cases of acquired neurodegenerative disease after repetitive mTBI.
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http://dx.doi.org/10.1016/j.expneurol.2015.08.014DOI Listing
November 2015

Pretransplant malnutrition, inflammation, and atherosclerosis affect cardiovascular outcomes after kidney transplantation.

BMC Nephrol 2015 Jul 21;16:109. Epub 2015 Jul 21.

Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, South Korea.

Background: Malnutrition, inflammation, and atherosclerosis (MIA) syndrome is associated with a high mortality rate in patients with end-stage renal disease. However, the clinical relevance of MIA syndrome in kidney transplantation (KT) recipients remains unknown.

Methods: We enrolled 1348 adult KT recipients. Recipients were assessed based on serum albumin, cholesterol, or body mass index for the malnutrition factor and C-reactive protein level for the inflammation factor. Any history of cardiovascular (CV), cerebrovascular, or peripheral vascular disease satisfied the atherosclerosis factor. Each MIA factors were assessed by univariate analysis and we calculated an overall risk score by summing up scores for each independent variable. The enrolled patients were divided into 4 groups depending on the MIA score (0, 2-4, 6, 8-10).

Results: The patients with higher MIA score showed worse outcome of fatal/non-fatal acute coronary syndrome (ACS) (p < 0.001) and composite outcomes of ACS and all-cause mortality (p < 0.001) than with the lower MIA score. In multivariate analysis, ACS showed significantly higher incidence in the MIA score 8-10 group than in the MIA score 0 group (Hazard ratio 6.12 95 % Confidence interval 1.84-20.32 p = 0.003).

Conclusions: The presence of MIA factors before KT is an independent predictor of post-transplant CV outcomes.
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http://dx.doi.org/10.1186/s12882-015-0108-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4508766PMC
July 2015

Transplantation of human oligodendrocyte progenitor cells in an animal model of diffuse traumatic axonal injury: survival and differentiation.

Stem Cell Res Ther 2015 May 14;6:93. Epub 2015 May 14.

Division of Neuropathology, Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.

Introduction: Diffuse axonal injury is an extremely common type of traumatic brain injury encountered in motor vehicle crashes, sports injuries, and in combat. Although many cases of diffuse axonal injury result in chronic disability, there are no current treatments for this condition. Its basic lesion, traumatic axonal injury, has been aggressively modeled in primate and rodent animal models. The inexorable axonal and perikaryal degeneration and dysmyelination often encountered in traumatic axonal injury calls for regenerative therapies, including therapies based on stem cells and precursors. Here we explore the proof of concept that treatments based on transplants of human oligodendrocyte progenitor cells can replace or remodel myelin and, eventually, contribute to axonal regeneration in traumatic axonal injury.

Methods: We derived human oligodendrocyte progenitor cells from the human embryonic stem cell line H9, purified and characterized them. We then transplanted these human oligodendrocyte progenitor cells into the deep sensorimotor cortex next to the corpus callosum of nude rats subjected to traumatic axonal injury based on the impact acceleration model of Marmarou. We explored the time course and spatial distribution of differentiation and structural integration of these cells in rat forebrain.

Results: At the time of transplantation, over 90 % of human oligodendrocyte progenitor cells expressed A2B5, PDGFR, NG2, O4, Olig2 and Sox10, a profile consistent with their progenitor or early oligodendrocyte status. After transplantation, these cells survived well and migrated massively via the corpus callosum in both injured and uninjured brains. Human oligodendrocyte progenitor cells displayed a striking preference for white matter tracts and were contained almost exclusively in the corpus callosum and external capsule, the striatopallidal striae, and cortical layer 6. Over 3 months, human oligodendrocyte progenitor cells progressively matured into myelin basic protein(+) and adenomatous polyposis coli protein(+) oligodendrocytes. The injured environment in the corpus callosum of impact acceleration subjects tended to favor maturation of human oligodendrocyte progenitor cells. Electron microscopy revealed that mature transplant-derived oligodendrocytes ensheathed host axons with spiral wraps intimately associated with myelin sheaths.

Conclusions: Our findings suggest that, instead of differentiating locally, human oligodendrocyte progenitor cells migrate massively along white matter tracts and differentiate extensively into ensheathing oligodendrocytes. These features make them appealing candidates for cellular therapies of diffuse axonal injury aiming at myelin remodeling and axonal protection or regeneration.
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http://dx.doi.org/10.1186/s13287-015-0087-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4453242PMC
May 2015

Repetitive mild traumatic brain injury with impact acceleration in the mouse: Multifocal axonopathy, neuroinflammation, and neurodegeneration in the visual system.

Exp Neurol 2016 Jan 20;275 Pt 3:436-449. Epub 2014 Nov 20.

Division of Neuropathology, Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address:

Repetitive mild traumatic brain injury (mTBI) is implicated in chronic neurological illness. The development of animal models of repetitive mTBI in mice is essential for exploring mechanisms of these chronic diseases, including genetic vulnerability by using transgenic backgrounds. In this study, the rat model of impact acceleration (IA) was redesigned for the mouse cranium and used in two clinically relevant repetitive mTBI paradigms. We first determined, by using increments of weight dropped from 1m that the 40g weight was most representative of mTBI and was not associated with fractures, brain contusions, anoxic-ischemic injury, mortality, or significant neurological impairments. Quantitative evaluation of traumatic axonal injury (TAI) in the optic nerve/tract, cerebellum and corpus callosum confirmed that weight increase produced a graded injury. We next evaluated two novel repetitive mTBI paradigms (1 time per day or 3 times per day at days 0, 1, 3, and 7) and compared the resulting TAI, neuronal cell death, and neuroinflammation to single hit mTBI at sub-acute (7days) and chronic time points (10weeks) post-injury. Both single and repetitive mTBI caused TAI in the optic nerve/tract, cerebellum, corticospinal tract, lateral lemniscus and corpus callosum. Reactive microglia with phagocytic phenotypes were present at injury sites. Severity of axonal injury corresponded to impact load and frequency in the optic nerve/tract and cerebellum. Both single and repeat injury protocols were associated with retinal ganglion cell loss and optic nerve degeneration; these outcomes correlated with impact load and number/frequency. No phosphorylated tau immunoreactivity was detected in the brains of animals subjected to repetitive mTBI. Our findings establish a new model of repetitive mTBI model featured by TAI in discrete CNS tracts, especially the visual system and cerebellum. Injury in retina and optic nerve provides a sensitive measure of severity of mTBI, thus enabling further studies on mechanisms and experimental therapeutics. Our model can also be useful in exploring mechanisms of chronic neurological disease caused by repetitive mTBI in wild-type and transgenic mice.
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http://dx.doi.org/10.1016/j.expneurol.2014.11.004DOI Listing
January 2016

The problem of axonal injury in the brains of veterans with histories of blast exposure.

Acta Neuropathol Commun 2014 Nov 25;2:153. Epub 2014 Nov 25.

Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.

Introduction: Blast injury to brain, a hundred-year old problem with poorly characterized neuropathology, has resurfaced as health concern in recent deployments in Iraq and Afghanistan. To characterize the neuropathology of blast injury, we examined the brains of veterans for the presence of amyloid precursor protein (APP)-positive axonal swellings typical of diffuse axonal injury (DAI) and compared them to healthy controls as well as controls with opiate overdose, anoxic-ischemic encephalopathy, and non-blast TBI (falls and motor vehicle crashes).

Results: In cases with blast history, we found APP (+) axonal abnormalities in several brain sites, especially the medial dorsal frontal white matter. In white matter, these abnormalities were featured primarily by clusters of axonal spheroids or varicosities in a honeycomb pattern with perivascular distribution. Axonal abnormalities colocalized with IBA1 (+) reactive microglia and had an appearance that was distinct from classical DAI encountered in TBI due to motor vehicle crashes. Opiate overdose cases also showed APP (+) axonal abnormalities, but the intensity of these lesions was lower compared to cases with blast histories and there was no clear association of such lesions with microglial activation.

Conclusions: Our findings demonstrate that many cases with history of blast exposure are featured by APP (+) axonopathy that may be related to blast exposure, but an important role for opiate overdose, antemortem anoxia, and concurrent blunt TBI events in war theater or elsewhere cannot be discounted.
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http://dx.doi.org/10.1186/s40478-014-0153-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4260204PMC
November 2014

The clinical association of the blood pressure variability with the target organ damage in hypertensive patients with chronic kidney disease.

J Korean Med Sci 2014 Jul 11;29(7):957-64. Epub 2014 Jul 11.

Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.

It is known that blood pressure variability (BPV) can independently affect target organ damage (TOD), even with normal blood pressure. There have been few studieson chronic kidney disease (CKD) patients. We evaluated the relationship between BPV and TOD in a cross-sectional, multicenter study on hypertensive CKD patients. We evaluated 1,173 patients using 24-hr ambulatory blood pressure monitoring. BPV was defined as the average real variability, with a mean value of the absolute differences between consecutive readings of systolic blood pressure. TOD was defined as left ventricular hypertrophy (LVH) (by the Romhilt-Estes score ≥4 in electrocardiography) and kidney injury (as determined from an estimated glomerular filtration rate [eGFR]<30 mL/min/1.73 m(2) and proteinuria).The mean BPV of the subjects was 15.9±4.63 mmHg. BPV displayed a positive relationship with LVH in a univariate analysis and after adjustment for multi-variables (odds ratio per 1 mmHg increase in BPV: 1.053, P=0.006). In contrast, BPV had no relationship with kidney injury. These data suggest that BPV may be positively associated with LVH in hypertensive CKD patients.
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http://dx.doi.org/10.3346/jkms.2014.29.7.957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4101784PMC
July 2014

Induced pluripotent stem cells from familial Alzheimer's disease patients differentiate into mature neurons with amyloidogenic properties.

Stem Cells Dev 2014 Dec;23(24):2996-3010

1 Division of Neuropathology, Department of Pathology, Johns Hopkins University School of Medicine , Baltimore, Maryland.

Although the majority of Alzheimer's disease (AD) cases are sporadic, about 5% of cases are inherited in an autosomal dominant pattern as familial AD (FAD) and manifest at an early age. Mutations in the presenilin 1 (PSEN1) gene account for the majority of early-onset FAD. Here, we describe the generation of virus-free human induced pluripotent stem cells (hiPSCs) derived from fibroblasts of patients harboring the FAD PSEN1 mutation A246E and fibroblasts from healthy age-matched controls using nonintegrating episomal vectors. We have differentiated these hiPSC lines to the neuronal lineage and demonstrated that hiPSC-derived neurons have mature phenotypic and physiological properties. Neurons from mutant hiPSC lines express PSEN1-A246E mutations themselves and show AD-like biochemical features, that is, amyloidogenic processing of amyloid precursor protein (APP) indicated by an increase in β-amyloid (Aβ)42/Aβ40 ratio. FAD hiPSCs harboring disease properties can be used as humanized models to test novel diagnostic methods and therapies and explore novel hypotheses for AD pathogenesis.
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http://dx.doi.org/10.1089/scd.2013.0511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4267410PMC
December 2014
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