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1.
Crit Care ; 28(1): 297, 2024 Sep 09.
Artículo en Inglés | MEDLINE | ID: mdl-39252133

RESUMEN

BACKGROUND: The potential adverse effects associated with invasive mechanical ventilation (MV) can lead to delayed decisions on starting MV. We aimed to explore the association between the timing of MV and the clinical outcomes in patients with sepsis ventilated in intensive care unit (ICU). METHODS: We analyzed data of adult patients with sepsis between September 2019 and December 2021. Data was collected through the Korean Sepsis Alliance from 20 hospitals in Korea. Patients who were admitted to ICU and received MV were included in the study. Patients were divided into 'early MV' and 'delayed MV' groups based on whether they were on MV on the first day of ICU admission or later. Propensity score matching was applied, and patients in the two groups were compared on a 1:1 ratio to overcome bias between the groups. Outcomes including ICU mortality, hospital mortality, length of hospital and ICU stay, and organ failure at ICU discharge were compared. RESULTS: Out of 2440 patients on MV during ICU stay, 2119 'early MV' and 321 'delayed MV' cases were analyzed. The propensity score matching identified 295 patients in each group with similar baseline characteristics. ICU mortality was lower in 'early MV' group than 'delayed MV' group (36.3% vs. 46.4%; odds ratio, 0.66; 95% confidence interval, 0.47-0.93; p = 0.015). 'Early MV' group had lower in-hospital mortality, shorter ICU stay, and required tracheostomy less frequently than 'delayed MV' group. Multivariable logistic regression model identified 'early MV' as associated with lower ICU mortality (odds ratio, 0.38; 95% confidence interval, 0.29-0.50; p < 0.001). CONCLUSION: In patients with sepsis ventilated in ICU, earlier start (first day of ICU admission) of MV may be associated with lower mortality.


Asunto(s)
Unidades de Cuidados Intensivos , Puntaje de Propensión , Respiración Artificial , Sepsis , Humanos , Masculino , Femenino , Sepsis/terapia , Sepsis/mortalidad , Respiración Artificial/efectos adversos , Respiración Artificial/estadística & datos numéricos , Respiración Artificial/métodos , Persona de Mediana Edad , Anciano , República de Corea/epidemiología , Estudios de Cohortes , Unidades de Cuidados Intensivos/organización & administración , Unidades de Cuidados Intensivos/estadística & datos numéricos , Factores de Tiempo , Mortalidad Hospitalaria , Estudios Retrospectivos
2.
J Korean Med Sci ; 36(43): e306, 2021 Nov 08.
Artículo en Inglés | MEDLINE | ID: mdl-34751013

RESUMEN

Immune thrombocytopenia (ITP) is an autoimmune condition characterized by platelet destruction through antibody-mediated mechanism. ITP is one of the manifestations of a coronavirus disease, as well as an adverse event occurring after vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Several cases of ITP have been described after vaccination with two mRNA-based vaccines-BTN162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna)-against SARS-CoV-2. Herein, we report a case of ITP occurring after vaccination with ChAdOx1 adenovirus vector nCoV-19 (AstraZeneca) vaccine in Korea. A 66-year-old woman presented with multiple ecchymoses on both upper and lower extremities and gingival bleeding, appearing 3 days after receiving the first dose of ChAdOx1 nCoV-19. Her laboratory results showed isolated severe thrombocytopenia without evidence of combined coagulopathy. She was diagnosed with ITP and successfully treated with high-dose dexamethasone and intravenous immunoglobulin. Clinical suspicion to identify vaccine-related ITP is important to promptly initiate appropriate treatment.


Asunto(s)
Vacunas contra la COVID-19/administración & dosificación , COVID-19/prevención & control , Equimosis/etiología , Púrpura Trombocitopénica Idiopática/inducido químicamente , Vacunación/efectos adversos , Anciano , COVID-19/epidemiología , Vacunas contra la COVID-19/efectos adversos , ChAdOx1 nCoV-19 , Dexametasona/uso terapéutico , Femenino , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Índice Periodontal , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , SARS-CoV-2
3.
Cytotherapy ; 20(8): 1013-1027, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-30072298

RESUMEN

BACKGROUND AND AIMS: Osteoporosis, which is a disease characterized by weakening of the bone, affects a large portion of the senior population. The current therapeutic options for osteoporosis have side effects, and there is no effective treatment for severe osteoporosis. Thus, we urgently need new treatment strategies, such as topical therapies and/or safe and effective stem cell therapies. METHODS: We investigated the therapeutic potential of directly injecting human tonsil-derived mesenchymal stem cells (TMSC) into the right proximal tibias of ovariectomized postmenopausal osteoporosis model mice. Injections were given once (1×) or twice (2×) during the 3-month experimental period. At the end of the experiment, micro-computed tomographic images revealed some improvement in the proximal tibias and more significant improvement in the femoral heads of treated mice. RESULTS: Osteogenic effect was qualitatively and quantitatively more pronounced in TMSC/2×-treated mice. Furthermore, TMSC/2× mice exhibited significant recovery of the serum osteocalcin level, which is pathologically elevated in osteoporosis, and increased serum alkaline phosphatase, which indicates bone formation. TMSC therapy was generally well tolerated and caused no apparent toxicity in the experimental mice. Moreover, TMSC therapy reduced visceral fat. CONCLUSION: Our results demonstrate that double injection of TMSC directly into the proximal tibia triggers recovery of osteoporosis, and thus could be a potential therapeutic approach for severe bone loss.


Asunto(s)
Infusiones Intraóseas , Trasplante de Células Madre Mesenquimatosas/métodos , Células Madre Mesenquimatosas/citología , Osteoporosis/terapia , Tonsila Palatina/citología , Animales , Densidad Ósea/fisiología , Niño , Femenino , Xenoinjertos , Humanos , Infusiones Intraóseas/métodos , Inyecciones , Masculino , Ratones , Ratones Endogámicos ICR , Osteoporosis/diagnóstico , Osteoporosis/patología , Posmenopausia/fisiología , Inducción de Remisión , Tibia/diagnóstico por imagen
4.
Biochem Biophys Res Commun ; 469(2): 263-9, 2016 Jan 08.
Artículo en Inglés | MEDLINE | ID: mdl-26655815

RESUMEN

We previously reported that hypoxia increases angiopoietin-1 (Ang1), but not Ang2, mRNA expression in bovine retinal pericytes (BRP). However, the mechanism underlying Ang1 expression is unknown. Here, we report that Ang1 protein expression increased in hypoxic BRP in a dose- and time-dependent manner. This increase was accompanied by an increase in hypoxia-inducible factor-2α (HIF2α) expression. Transfection with an antisense oligonucleotide for HIF2α partially inhibited the hypoxia-induced increase in Ang1 expression. HIF2α overexpression further potentiated hypoxia-stimulated Ang1 expression, suggesting that HIF2α plays an important role in Ang1 regulation in BRP. When fused the Ang1 promoter (-3040 to +199) with the luciferase reporter gene, we found that hypoxia significantly increased promoter activity by 4.02 ± 1.68 fold. However, progressive 5'-deletions from -3040 to -1799, which deleted two putative hypoxia response elements (HRE), abolished the hypoxia-induced increase in promoter activity. An electrophoretic mobility shift assay revealed that HIF2α was predominantly bound to a HRE site, located specifically at nucleotides -2715 to -2712. Finally, treatment with conditioned medium obtained from hypoxic pericytes stimulated endothelial cell migration and tube formation, which was completely blocked by co-treatment with anti-Ang1 antibody. This study is the first to demonstrate that hypoxia upregulates Ang1 expression via HIF2α-mediated transcriptional activation in pericytes, which plays a key role in angiogenesis.


Asunto(s)
Angiopoyetina 1/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Vasos Sanguíneos/crecimiento & desarrollo , Neovascularización Fisiológica/fisiología , Pericitos/citología , Pericitos/fisiología , Animales , Vasos Sanguíneos/citología , Bovinos , Hipoxia de la Célula/fisiología , Movimiento Celular/fisiología , Células Cultivadas , Células Endoteliales/citología , Células Endoteliales/fisiología , Oxígeno/metabolismo
5.
Tissue Eng Regen Med ; 16(6): 631-643, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31824825

RESUMEN

Background: Stem cell engineering is appealing consideration for regenerating damaged endothelial cells (ECs) because stem cells can differentiate into EC-like cells. In this study, we demonstrate that tonsil-derived mesenchymal stem cells (TMSCs) can differentiate into EC-like cells under optimal physiochemical microenvironments. Methods: TMSCs were preconditioned with Dulbecco's Modified Eagle Medium (DMEM) or EC growth medium (EGM) for 4 days and then replating them on Matrigel to observe the formation of a capillary-like network under light microscope. Microarray, quantitative real time polymerase chain reaction, Western blotting and immunofluorescence analyses were used to evaluate the expression of gene and protein of EC-related markers. Results: Preconditioning TMSCs in EGM for 4 days and then replating them on Matrigel induced the formation of a capillary-like network in 3 h, but TMSCs preconditioned with DMEM did not form such a network. Genome analyses confirmed that EGM preconditioning significantly affected the expression of genes related to angiogenesis, blood vessel morphogenesis and development, and vascular development. Western blot analyses revealed that EGM preconditioning with gelatin coating induced the expression of endothelial nitric oxide synthase (eNOS), a mature EC-specific marker, as well as phosphorylated Akt at serine 473, a signaling molecule related to eNOS activation. Gelatin-coating during EGM preconditioning further enhanced the stability of the capillary-like network, and also resulted in the network more closely resembled to those observed in human umbilical vein endothelial cells. Conclusion: This study suggests that under specific conditions, i.e., EGM preconditioning with gelatin coating for 4 days followed by Matrigel, TMSCs could be a source of generating endothelial cells for treating vascular dysfunction.


Asunto(s)
Diferenciación Celular , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Colágeno/química , Medios de Cultivo Condicionados/farmacología , Combinación de Medicamentos , Gelatina/química , Regulación de la Expresión Génica/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana , Humanos , Laminina/química , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Óxido Nítrico Sintasa de Tipo III/genética , Óxido Nítrico Sintasa de Tipo III/metabolismo , Tonsila Palatina/citología , Fosforilación , Proteoglicanos/química , Proteínas Proto-Oncogénicas c-akt/metabolismo , Factor A de Crecimiento Endotelial Vascular/farmacología
6.
PLoS One ; 13(7): e0200111, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29975738

RESUMEN

We investigated therapeutic potential of human tonsil-derived mesenchymal stem cells (TMSC) subcutaneously delivered to ovariectomized (OVX) mice for developing more safe and effective therapy for osteoporosis. TMSC were isolated from tonsil tissues of children undergoing tonsillectomy, and TMSC-embedded in situ crosslinkable gelatin-hydroxyphenyl propionic acid hydrogel (TMSC-GHH) or TMSC alone were delivered subcutaneously to the dorsa of OVX mice. After 3 months, three-dimensionally reconstructed micro-computed tomographic images revealed better recovery of the femoral heads in OVX mice treated with TMSC-GHH. Serum osteocalcin and alkaline phosphatase were also recovered, indicating bone formation only in TMSC-GHH-treated mice, and absence in hypercalcemia or other severe macroscopic deformities showed biocompatibility of TMSC-GHH. Additionally, visceral fat reduction effects by TMSC-GHH further supported their therapeutic potential. TMSC provided therapeutic benefits toward osteoporosis only when embedded in GHH, and showed potential as a supplement or alternative to current therapies.


Asunto(s)
Células Madre Adultas/fisiología , Osteoporosis Posmenopáusica/terapia , Fosfatasa Alcalina/sangre , Animales , Regeneración Ósea/fisiología , Niño , Femenino , Gelatina/uso terapéutico , Humanos , Hidrogeles/uso terapéutico , Células Madre Mesenquimatosas/fisiología , Ratones , Ratones Endogámicos ICR , Modelos Animales , Osteocalcina/sangre , Osteoporosis/terapia , Ovariectomía , Tonsila Palatina/metabolismo
7.
J Tissue Eng Regen Med ; 12(3): e1747-e1756, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-28244684

RESUMEN

Biomimetic parathyroid regeneration with sustained release of parathyroid hormone (PTH) into the blood stream is a considerable challenge in hypoparathyroidism treatment. We recently reported that tonsil-derived mesenchymal stem cells (TMSCs), if these cells were both differentiated in vitro before implantation and incorporated into a scaffold Matrigel, are a good cell source for parathyroid regeneration in a parathyroidectomized (PTX) animal model. Here, we present a new strategy for improved clinical application that enhances the sustained release of PTH by controlling mechanical stiffness using in situ-forming gelatin-hydroxyphenyl propionic acid (GH) hydrogels (GHH). Differentiated TMSCs (dTMSCs) embedded in a GHH with a strength of 4.4 kPa exhibited the best sustained release of PTH and were the most effective in hypoparathyroidism treatment, showing improved blood calcium homeostasis compared with Matrigel-embedded dTMSCs. Interestingly, undifferentiated control TMSCs (cTMSCs) also released PTH in a sustained manner if incorporated into GHH. Collectively, these findings may establish a new paradigm for parathyroid regeneration that could ultimately evolve into an improved clinical application. Copyright © 2017 John Wiley & Sons, Ltd.


Asunto(s)
Reactivos de Enlaces Cruzados/química , Gelatina/química , Hidrogeles/química , Hipoparatiroidismo/terapia , Trasplante de Células Madre Mesenquimatosas , Tonsila Palatina/citología , Hormona Paratiroidea/administración & dosificación , Hormona Paratiroidea/farmacología , Animales , Calcio/sangre , Supervivencia Celular , Preparaciones de Acción Retardada , Hipoparatiroidismo/sangre , Implantes Experimentales , Cinética , Masculino , Células Madre Mesenquimatosas/citología , Neovascularización Fisiológica , Hormona Paratiroidea/sangre , Propionatos/química , Ratas Sprague-Dawley , Porcinos
8.
Tissue Eng Regen Med ; 14(4): 411-420, 2017 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-30603497

RESUMEN

Differentiation of mesenchymal stem cells (MSC) into a variety of cell lineages such as adipocytes, osteocytes, and chondrocytes is often accompanied up-regulation of autophagy. In our study, we demonstrated that the expression of autophagy-associated proteins (p-Beclin 1, LC3A, LC3B, p-AMPK, p-mTOR and ATG3, ATG7, and ATG12-5) over a period of time was hardly distinguishable from control tonsil-derived MSC (TMSC). Despite the unnoticeable difference in autophagy activation between differentiated TMSC (dTMSC) and the control (cTMSC), we reported significant changes in intracellular compositions in differentiated TMSC into functional parathyroid-like cells secreting parathyroid hormone (PTH). By using transmission electron microscopy (TEM), we observed accumulation of multivesicular bodies (MVB) comprising small, degraded compartments densely accumulated as dark granular or amorphous clumps, multilamellar bodies and lipid droplets in dTMSC. However, no such structures were found in cTMSC. These results suggest that differentiation of TMSC into parathyroid-like cells producing PTH hormone is hardly dependent on autophagy activation in the beginning of our conditions. Furthermore, our results of intracellular remodeling and accumulated endo-lysosomal storage bodies in the later stages of TMSC differentiation present a possible role of the structures in PTH secretion.

9.
Acta Biomater ; 35: 215-27, 2016 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-26945633

RESUMEN

To restore damaged parathyroid function, parathyroid tissue engineering is the best option. Previously, we reported that differentiated tonsil-derived mesenchymal stem cells (dTMSC) restore in vivo parathyroid function, but only if they are embedded in a scaffold. Because of the limited biocompatibility of Matrigel, however, here we developed a more clinically applicable, scaffold-free parathyroid regeneration system. Scaffold-free dTMSC spheroids were engineered in concave microwell plates made of polydimethylsiloxane in control culture medium for the first 7days and differentiation medium (containing activin A and sonic hedgehog) for next 7days. The size of dTMSC spheroids showed a gradual and significant decrease up to day 5, whereafter it decreased much less. Cells in dTMSC spheroids were highly viable (>80%). They expressed high levels of intact parathyroid hormone (iPTH), the parathyroid secretory protein 1, and cell adhesion molecule, N-cadherin. Furthermore, dTMSC spheroids-implanted parathyroidectomized (PTX) rats revealed higher survival rates (50%) over a 3-month period with physiological levels of both serum iPTH (57.7-128.2pg/mL) and ionized calcium (0.70-1.15mmol/L), compared with PTX rats treated with either vehicle or undifferentiated TMSC spheroids. This is the first report of a scaffold-free, human stem cell-based parathyroid tissue engineering and represents a more clinically feasible strategy for hypoparathyroidism treatment than those requiring scaffolds. STATEMENT OF SIGNIFICANCE: Herein, we have for the first time developed a scaffold-free parathyroid tissue spheroids using differentiated tonsil-derived mesenchymal stem cells (dTMSC) to restore in vivo parathyroid cell functions. This new strategy is effective, even for long periods (3months), and is thus likely to be more feasible in clinic for hypoparathyroidism treatment. Development of TMSC spheroids may also provide a convenient and efficient scaffold-free platform for researchers investigating conditions involving abnormal calcium homeostasis, such as osteoporosis.


Asunto(s)
Células Madre Mesenquimatosas/citología , Tonsila Palatina/citología , Glándulas Paratiroides/fisiología , Ingeniería de Tejidos/métodos , Andamios del Tejido/química , Animales , Biomarcadores/metabolismo , Peso Corporal , Cadherinas/metabolismo , Calcio/sangre , Forma de la Célula , Tamaño de la Célula , Supervivencia Celular , Niño , Femenino , Técnica del Anticuerpo Fluorescente , Humanos , Masculino , Glándulas Paratiroides/cirugía , Hormona Paratiroidea/metabolismo , Paratiroidectomía , Ratas Sprague-Dawley , Esferoides Celulares/citología , Análisis de Supervivencia
10.
Free Radic Biol Med ; 89: 229-40, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26393424

RESUMEN

Although CCN1 (also known as cysteine-rich, angiogenic inducer 61, CYR61) has been reported to promote angiogenesis and neovascularization in endothelial cells (ECs), its effects on endothelial nitric oxide (NO) production have never been studied. Using human umbilical vein ECs, we investigated whether and how CCN1 regulates NO production. CCN1 acutely increased NO production in a time- and dose-dependent manner, which was accompanied by increased phosphorylation of endothelial NO synthase (eNOS) at serine 1177 (eNOS-Ser(1177)), but not that of eNOS-Thr(495) or eNOS-Ser(114). The level of total eNOS expression was unaltered. Treatment with either LY294002, a selective inhibitor of phosphoinositide 3-kinase known as an upstream kinase of Akt, or H-89, an inhibitor of protein kinase A, mitogen- and stress-activated protein kinase 1, Rho-associated protein kinase 2, and ribosomal protein S6 kinase (S6K), inhibited CCN1-stimulated eNOS-Ser(1177) phosphorylation and subsequent NO production. Ectopic expression of small interfering RNA against Akt and S6K significantly inhibited the effects of CCN1. Consistently, CCN1 increased the phosphorylation of Akt-Ser(473) and S6K-Thr(389). However, CCN1 did not alter the expression or secretion of VEGF, a known downstream factor of CCN1 and a potential upstream factor of Akt-mediated eNOS-Ser(1177) phosphorylation. Furthermore, neutralization of integrin αvß3 with corresponding antibody completely reversed all of the observed effects of CCN1. Moreover, CCN1 increased acetylcholine-induced relaxation in the rat aortas. Finally, we also found that CCN1-stimulated eNOS-Ser(1177) phosphorylation and NO production are true for other types of EC tested. In conclusion, CCN1 acutely increases NO production via activation of a signaling axis in integrin αvß3-Akt-S6K-eNOS-Ser(1177) phosphorylation, suggesting an important role for CCN1 in vasodilation.


Asunto(s)
Proteína 61 Rica en Cisteína/farmacología , Integrina alfaVbeta3/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Óxido Nítrico/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Quinasas S6 Ribosómicas/metabolismo , Serina/metabolismo , Vasodilatadores/farmacología , Animales , Aorta/citología , Aorta/efectos de los fármacos , Aorta/metabolismo , Western Blotting , Bovinos , Células Cultivadas , Endotelio Vascular/citología , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Células Endoteliales de la Vena Umbilical Humana/citología , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Masculino , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Retina/citología , Retina/efectos de los fármacos , Retina/metabolismo , Serina/química
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