ABSTRACT
Background@#To deliver therapeutics into the brain, it is imperative to overcome the issue of the blood-brain-barrier (BBB). One of the ways to circumvent the BBB is to administer therapeutics directly into the brain parenchyma. To enhance the treatment efficacy for chronic neurodegenerative disorders, repeated administration to the target location is required. However, this increases the number of operations that must be performed. In this study, we developed the IntraBrain Injector (IBI), a new implantable device to repeatedly deliver therapeutics into the brain parenchyma. @*Methods@#We designed and fabricated IBI with medical grade materials, and evaluated the efficacy and safety of IBI in 9 beagles. The trajectory of IBI to the hippocampus was simulated prior to surgery and the device was implanted using 3D-printed adaptor and surgical guides. Ferumoxytol-labeled mesenchymal stem cells (MSCs) were injected into the hippocampus via IBI, and magnetic resonance images were taken before and after the administration to analyze the accuracy of repeated injection. @*Results@#We compared the planned vs. insertion trajectory of IBI to the hippocampus.With a similarity of 0.990 ± 0.001 (mean ± standard deviation), precise targeting of IBI was confirmed by comparing planned vs. insertion trajectories of IBI. Multiple administrations of ferumoxytol-labeled MSCs into the hippocampus using IBI were both feasible and successful (success rate of 76.7%). Safety of initial IBI implantation, repeated administration of therapeutics, and long-term implantation have all been evaluated in this study. @*Conclusion@#Precise and repeated delivery of therapeutics into the brain parenchyma can be done without performing additional surgeries via IBI implantation.
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Background and Objectives@#Ambient particulate matter (PM) in real urban air pollution (RUA) is an environmental health risk factor associated with increased cardiac events. This study investigated the threshold level to induce arrhythmia, as well as arrhythmogenic mechanism of RUA that mainly consisted of PM <2.5 μm in aerodynamic diameter close to ultrafine particles. @*Methods@#RUA was artificially produced by a lately developed pyrolysis based RUA generator.C57BL/6 mice were divided into 4 groups: a control group (control, n=12) and three groups with exposure to RUA with the concentration of 200 µg/㎥ (n=12), 400 µg/㎥ (n=12), and 800 µg/㎥ (n=12). Mice were exposed to RUA at each concentration for 8 hr/day and 5 day/week to mimic ordinary human activity during 3 weeks. @*Results@#The QRS and QTc intervals, as well as intracellular Ca2+ duration, apicobasal action potential duration (APD) gradient, fibrosis, and inflammation of left ventricle of mouse hearts were increased dose-dependently with the increase of RUA concentration, and significantly increased at RUA concentration of 400 µg/㎥ compared to control (all p<0.001). In mice exposed to RUA concentration of 800 µg/㎥ , spontaneous ventricular arrhythmia was observed in 42%, with significant increase of inflammatory markers, phosphorylated Ca2+ /calmodulindependent protein kinase II (CaMKII), and phospholamban (PLB) compared to control. @*Conclusions@#RUA could induce electrophysiological changes such as APD and QT prolongation, fibrosis, and inflammation dose-dependently, with significant increase of ventricular arrhythmia at the concentration of 400 µg/㎥ . RUA concentration of 800 µg/㎥ increased phosphorylation of CaMKII and PLB.
ABSTRACT
Background@#Recently, mesenchymal stem cells therapy has been performed in dogs, although the outcome is not always favorable. @*Objectives@#To investigate the therapeutic efficacy of mesenchymal stem cells (MSCs) using dog leukocyte antigen (DLA) matching between the donor and recipient in vitro. @*Methods@#Canine adipose-derived MSCs (cA-MSCs) isolated from the subcutaneous tissue of Dog 1 underwent characterization. For major DLA genotyping (DQA1, DQB1, and DRB1), peripheral blood mononuclear cells (PBMCs) from two dogs (Dogs 1 and 2) were analyzed by direct sequencing of polymerase chain reaction (PCR) products. The cA-MSCs were co-cultured at a 1:10 ratio with activated PBMCs (DLA matching or mismatching) for 3 days and analyzed for immunosuppressive ( IDO, PTGS2, and PTGES ), inflammatory (IL6 and IL10 ), and apoptotic genes (CASP8, BAX, TP53, and BCL2) by quantitative real-time reverse transcriptase-PCR. @*Results@#cA-MSCs were expressed cell surface markers such as CD90+/44+/29+/45- and differentiated into osteocytes, chondrocytes, and adipocytes in vitro. According to the Immuno Polymorphism Database, DLA genotyping comparisons of Dogs 1 and 2 revealed complete differences in genes DQA1, DQB1, and DRB1. In the co-culturing of cA-MSCs and PBMCs, DLA mismatch between the two cell types induced a significant increase in the expression of immunosuppressive (IDO/PTGS2) and apoptotic (CASP8/BAX) genes. @*Conclusions@#The administration of cA-MSCs matching the recipient DLA type can alleviate the need to regulate excessive immunosuppressive responses associated with genes, such as IDO and PTGES. Furthermore, easy and reliable DLA genotyping technology is required because of the high degree of genetic polymorphisms of DQA1, DQB1, and DRB1 and the low readability of DLA 88.
ABSTRACT
Background and Objectives@#Ambient particulate matter (PM) in real urban air pollution (RUA) is an environmental health risk factor associated with increased cardiac events. This study investigated the threshold level to induce arrhythmia, as well as arrhythmogenic mechanism of RUA that mainly consisted of PM <2.5 μm in aerodynamic diameter close to ultrafine particles. @*Methods@#RUA was artificially produced by a lately developed pyrolysis based RUA generator.C57BL/6 mice were divided into 4 groups: a control group (control, n=12) and three groups with exposure to RUA with the concentration of 200 µg/㎥ (n=12), 400 µg/㎥ (n=12), and 800 µg/㎥ (n=12). Mice were exposed to RUA at each concentration for 8 hr/day and 5 day/week to mimic ordinary human activity during 3 weeks. @*Results@#The QRS and QTc intervals, as well as intracellular Ca2+ duration, apicobasal action potential duration (APD) gradient, fibrosis, and inflammation of left ventricle of mouse hearts were increased dose-dependently with the increase of RUA concentration, and significantly increased at RUA concentration of 400 µg/㎥ compared to control (all p<0.001). In mice exposed to RUA concentration of 800 µg/㎥ , spontaneous ventricular arrhythmia was observed in 42%, with significant increase of inflammatory markers, phosphorylated Ca2+ /calmodulindependent protein kinase II (CaMKII), and phospholamban (PLB) compared to control. @*Conclusions@#RUA could induce electrophysiological changes such as APD and QT prolongation, fibrosis, and inflammation dose-dependently, with significant increase of ventricular arrhythmia at the concentration of 400 µg/㎥ . RUA concentration of 800 µg/㎥ increased phosphorylation of CaMKII and PLB.
ABSTRACT
Background@#Recently, mesenchymal stem cells therapy has been performed in dogs, although the outcome is not always favorable. @*Objectives@#To investigate the therapeutic efficacy of mesenchymal stem cells (MSCs) using dog leukocyte antigen (DLA) matching between the donor and recipient in vitro. @*Methods@#Canine adipose-derived MSCs (cA-MSCs) isolated from the subcutaneous tissue of Dog 1 underwent characterization. For major DLA genotyping (DQA1, DQB1, and DRB1), peripheral blood mononuclear cells (PBMCs) from two dogs (Dogs 1 and 2) were analyzed by direct sequencing of polymerase chain reaction (PCR) products. The cA-MSCs were co-cultured at a 1:10 ratio with activated PBMCs (DLA matching or mismatching) for 3 days and analyzed for immunosuppressive ( IDO, PTGS2, and PTGES ), inflammatory (IL6 and IL10 ), and apoptotic genes (CASP8, BAX, TP53, and BCL2) by quantitative real-time reverse transcriptase-PCR. @*Results@#cA-MSCs were expressed cell surface markers such as CD90+/44+/29+/45- and differentiated into osteocytes, chondrocytes, and adipocytes in vitro. According to the Immuno Polymorphism Database, DLA genotyping comparisons of Dogs 1 and 2 revealed complete differences in genes DQA1, DQB1, and DRB1. In the co-culturing of cA-MSCs and PBMCs, DLA mismatch between the two cell types induced a significant increase in the expression of immunosuppressive (IDO/PTGS2) and apoptotic (CASP8/BAX) genes. @*Conclusions@#The administration of cA-MSCs matching the recipient DLA type can alleviate the need to regulate excessive immunosuppressive responses associated with genes, such as IDO and PTGES. Furthermore, easy and reliable DLA genotyping technology is required because of the high degree of genetic polymorphisms of DQA1, DQB1, and DRB1 and the low readability of DLA 88.
ABSTRACT
Acute fatty liver of pregnancy (AFLP) is unusual but can potentially progress to overwhelming liver failure, resulting in maternal and fetal death. AFLP is characterized by the accumulation of microvesicular fat within hepatocytes. We report the case of a 37-year-old woman at 36 weeks' gestation with a twin pregnancy who was admitted with the diagnosis of intrauterine fetal death of one baby. The patient showed profile of AFLP on her laboratory findings and underwent emergency cesarean section. Then she progressed to cryptogenic fulminant hepatic failure and underwent successful orthotopic liver transplantation on 9th day of admission. This case demonstrates that liver transplantation is a feasible therapeutic option for the treatment of patients with this condition.
Subject(s)
Adult , Female , Humans , Pregnancy , Anesthesia, General , Cesarean Section , Diagnosis , Emergencies , Fatty Liver , Fetal Death , Hepatocytes , Liver Failure , Liver Failure, Acute , Liver Transplantation , Liver , Pregnancy, TwinABSTRACT
PURPOSE: The present study developed formulas for estimation of standard liver volume (SLV) with high accuracy for the Korean population. MATERIALS AND METHODS: SLV estimation formulas were established using gender-balanced and gender-unbalanced measurements of anthropometric variables, body composition variables, and abdominal geometry of healthy Koreans (n=790). Total liver volume excluding blood volume, was measured based on CT volumetry. RESULTS: SLV estimation formulas as preferred in various conditions of data availability were suggested in the present study. The suggested SLV estimation formulas in the present study were found superior to existing formulas, with an increased accuracy of 4.0–217.5 mL for absolute error and 0.2–18.7% for percentage of absolute error. CONCLUSION: SLV estimation formulas using gender-balanced measurements showed better performance than those using gender-unbalanced measurements. Inclusion of body composition and abdominal geometry variables contributed to improved performance of SLV estimation.
Subject(s)
Blood Volume , Body Composition , LiverABSTRACT
PURPOSE: The purpose of this study was to verify the new hip protector design with respect to the comfort and mobility. The new hip protector was developed based on a pattern of draping and body shape of Korean elderly individuals. MATERIALS AND METHODS: An wearing characteristics evaluation was conducted on 101 elderly women wearing hip protector using a questionnaire of preference and ease of wearing. Hip protectors, with existing and newly developed belt and underwear types, which were previously preferred by the Korean elderly, were evaluated. RESULTS: The newly developed belt type (65.0%) and newly developed underwear type (30.1%) hip protectors were preferred to the existing type (3.9%) and existing underwear type (1.0%) ones. The convenience of the newly developed belt type was greater than 4 out of 5 points (1 for strongly disagree and 5 for strongly agree) for all nine measures, including fit, allowance, mobility, pad placement, pad thickness, pad size, material, design, ease of dressing, and ease of undressing. The newly developed hip protectors showed less discomfort than the existing ones. In particular, the newly developed belt type and developed underwear type improved sitting convenience by 31.1% and 26.1%, respectively, compared with the existing ones. CONCLUSION: The hip protectors developed in the present study is expected to provide better fit for the body shape of Korean elderly individuals and prevent hip fracture due to fall.
Subject(s)
Aged , Female , Humans , Bandages , HipABSTRACT
BACKGROUND: Idiopathic pulmonary fibrosis is a common interstitial lung disease; it is a chronic, progressive, and fatal lung disease of unknown etiology. Over the last two decades, knowledge about the underlying mechanisms of pulmonary fibrosis has improved markedly and facilitated the identification of potential targets for novel therapies. However, despite the large number of antifibrotic drugs being described in experimental pre-clinical studies, the translation of these findings into clinical practices has not been accomplished yet. NADH:quinone oxidoreductase 1 (NQO1) is a homodimeric enzyme that catalyzes the oxidation of NADH to NAD+ by various quinones and thereby elevates the intracellular NAD⁺ levels. In this study, we examined the effect of increase in cellular NAD⁺ levels on bleomycin-induced lung fibrosis in mice. METHODS: C57BL/6 mice were treated with intratracheal instillation of bleomycin. The mice were orally administered with β-lapachone from 3 days before exposure to bleomycin to 1-3 weeks after exposure to bleomycin. Bronchoalveolar lavage fluid (BALF) was collected for analyzing the infiltration of immune cells. In vitro, A549 cells were treated with transforming growth factor β1 (TGF-β1) and β-lapachone to analyze the extracellular matrix (ECM) and epithelial-mesenchymal transition (EMT). RESULTS: β-Lapachone strongly attenuated bleomycin-induced lung inflammation and fibrosis, characterized by histological staining, infiltrated immune cells in BALF, inflammatory cytokines, fibrotic score, and TGF-β1, α-smooth muscle actin accumulation. In addition, β-lapachone showed a protective role in TGF-β1–induced ECM expression and EMT in A549 cells. CONCLUSION: Our results suggest that β-lapachone can protect against bleomycin-induced lung inflammation and fibrosis in mice and TGF-β1–induced EMT in vitro, by elevating the NAD+/NADH ratio through NQO1 activation.
Subject(s)
Animals , Mice , Actins , Bleomycin , Bronchoalveolar Lavage Fluid , Cytokines , Epithelial-Mesenchymal Transition , Extracellular Matrix , Fibrosis , Idiopathic Pulmonary Fibrosis , In Vitro Techniques , Inflammation , Lung Diseases , Lung Diseases, Interstitial , Lung , NAD , Pneumonia , Pulmonary Fibrosis , Quinones , Transforming Growth Factor beta1 , Transforming Growth FactorsABSTRACT
Transplantation of spermatogonial stem cells (SSCs) in experimental animal models has been used to study germ line stem cell biology and to produce transgenic animals. The species-specific recipient model preparation is important for the characterization of SSCs and the production of offspring. Here, we investigated the effects of surgically induced cryptorchidism in dog as a new recipient model for spermatogonial stem cell transplantation. Artificially unilateral or bilateral cryptorchidism was induced in ten mature male dogs by surgically returning the testis and epididymis to the abdominal cavity. The testes and epididymides were collected every week after the induction of artificial cryptorchidism (surgery) for one month. To determine the effect of surgical cryptorchidism, the seminiferous tubule diameter was measured and immunohistochemistry using PGP9.5 and GATA4 antibodies was analyzed. The diameters of the seminiferous tubules of abdominal testes were significantly reduced compared to those of the scrotal testes. Immunohistochemistry results showed that PGP9.5 positive undifferentiated spermatogonia were significantly reduced after surgical cryptorchidism induction, but there were no significant changes in GATA-4 positive sertoli cells. To evaluate the testis function recovery rate, orchiopexy was performed on two dogs after 30 days of bilateral cryptorchidism. In the orchiopexy group, SCP3 positive spermatocytes were detected, and spermatogenesis was recovered 8 weeks after orchiopexy. In this study, we provided optimum experimental conditions and time for surgical preparation of a recipient canine model for SSC transplantation. Additionally, our data will contribute to recipient preparation by using surgically induced cryptorchidism in non-rodent species.
Subject(s)
Animals , Dogs , Humans , Male , Abdominal Cavity , Animals, Genetically Modified , Antibodies , Biology , Cryptorchidism , Epididymis , Germ Cells , Immunohistochemistry , Models, Animal , Orchiopexy , Recovery of Function , Seminiferous Tubules , Sertoli Cells , Spermatocytes , Spermatogenesis , Spermatogonia , Stem Cell Transplantation , Stem Cells , TestisABSTRACT
The triggering receptor expressed on myeloid cells (TREM) family, which is abundantly expressed in myeloid lineage cells, plays a pivotal role in innate and adaptive immune response. In this study, we aimed to identify a novel receptor expressed on hematopoietic stem cells (HSCs) by using in silico bioinformatics and to characterize the identified receptor. We thus found the TREM-like transcript (TLT)-6, a new member of TREM family. TLT-6 has a single immunoglobulin domain in the extracellular region and a long cytoplasmic region containing 2 immunoreceptor tyrosine-based inhibitory motif-like domains. TLT-6 transcript was expressed in HSCs, monocytes and macrophages. TLT-6 protein was up-regulated on the surface of bone marrow-derived and peritoneal macrophages by lipopolysaccharide stimulation. TLT-6 exerted anti-proliferative effects in macrophages. Our results demonstrate that TLT-6 may regulate the activation and proliferation of macrophages.
Subject(s)
Humans , Adaptive Immunity , Computational Biology , Computer Simulation , Cytoplasm , Hematopoietic Stem Cells , Immunoglobulins , Macrophages , Macrophages, Peritoneal , Monocytes , Myeloid CellsABSTRACT
Malignant melanoma of the temporal bone is a very rare disease. We report here a case of malignant melanoma of the temporal bone initially presenting as dizziness. The patient was a 48-year-old man presenting with dizziness. Physical examination showed horizontal nystagmus toward the left on the left lateral gaze and an intact tympanic membrane. Caloric tests demonstrated right-sided unilateral weakness. Vestibular neuritis was suspected, and conservative treatment was thus carried out. On follow-up, other symptoms were noted and the tumor of the temporal bone was diagnosed by computed tomography and magnetic resonance imaging of the temporal bone. This case shows that if the dizziness symptom is not improved after conservative management in patients who present with vestibular neuritis, an imaging evaluation could be necessary, taking into consideration the possibility of a tumor in the temporal bone.
Subject(s)
Humans , Middle Aged , Caloric Tests , Dizziness , Follow-Up Studies , Magnetic Resonance Imaging , Melanoma , Nystagmus, Pathologic , Physical Examination , Rare Diseases , Temporal Bone , Tympanic Membrane , Vestibular NeuronitisABSTRACT
Muscle atrophy is the result of two opposing conditions that can be found in pathological or diseased muscles: an imbalance in protein synthesis and degradation mechanisms. Thus, we investigated whether exogenous melatonin could regulate muscle components in stroke-induced muscle atrophy in rats. Comparing muscle phenotypes, we found that long-term melatonin administration could influence muscle mass. Muscle atrophy-related genes, including muscle atrophy F-box (MAFbx) and muscle ring finger 1 (MuRF1) were significantly down-regulated in melatonin-administered rats in the gastrocnemius. However, only MAFbx at the mRNA level was attenuated in the soleus of melatonin-administered rats. Insulin-like growth factor-1 receptor (IGF-1R) was significantly over-expressed in melatonin-administered rats in both the gastrocnemius and soleus muscles. Comparing myosin heavy chain (MHC) components, in the gastrocnemius, expression of both slow- and fast-type isoforms were significantly enhanced in melatonin-administered rats. These results suggest that long-term exogenous melatonin-administration may have a prophylactic effect on muscle atrophy through the MuRF1/MAFbx signaling pathway, as well as a potential therapeutic effect on muscle atrophy through the IGF-1-mediated hypertrophic signaling pathway in a stroke animal model.