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2.
Traffic ; 2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31622527

RESUMO

Model organisms are increasingly used to study and understand how neurofilament (NF)-based neurological diseases develop. However, whether a NF homolog exists in C. elegans remains unclear. We characterize TAG-63 as a NF-like protein with sequence homologies to human NEFH carrying various coiled coils as well as clustered phosphorylation sites. TAG-63 also exhibits features of NFL such as a molecular weight of around 70 kD, the lack of KSP repeats and the ability to form 10 nm filamentous structures in transmission electron micrographs. An anti-NEFH antibody detects a band at the predicted molecular weight of TAG-63 in Western blots of whole worm lysates and this band cannot be detected in tag-63 knockout worms. A transcriptional tag-63 reporter expresses in a broad range of neurons, and various anti-NFH antibodies stain worm neurons with an overlapping expression of axonal vesicle transporter UNC-104(KIF1A). Cultured neurons grow shorter axons when incubating with drugs known to disintegrate the NF network and rhodamine-labeled in vitro reconstituted TAG-63 filaments disintegrate upon drug exposure. Speeds of UNC-104 motors are diminished in tag-63 mutant worms with visibly increased accumulations of motors along axons. UNC-104/TAG-63 and SNB-1/TAG-63 not only co-localize in neurons but also revealed positive BiFC (bimolecular fluorescence assay) signals. In summary, we identified and characterized TAG-63 in C. elegans, and demonstrate that lack of this protein limits axonal transport efficiencies. Additionally, this study would aid in developing NF-related disease models in the future. This article is protected by copyright. All rights reserved.

3.
Ann Rheum Dis ; 2019 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-31540936

RESUMO

OBJECTIVES: Fibrosis is a complex pathophysiological process involving interplay between multiple cell types. Experimental modelling of fibrosis is essential for the understanding of its pathogenesis and for testing of putative antifibrotic drugs. However, most current models employ either phylogenetically distant species or rely on human cells cultured in an artificial environment. Here we evaluated the potential of vascularised in vitro human skin equivalents as a novel model of skin fibrosis and a platform for the evaluation of antifibrotic drugs. METHODS: Skin equivalents were assembled on a three-dimensional extracellular matrix by sequential seeding of endothelial cells, fibroblasts and keratinocytes. Fibrotic transformation on exposure to transforming growth factor-ß (TGFß) and response to treatment with nintedanib as an established antifibrotic agent were evaluated by quantitative polymerase chain reaction (qPCR), capillary Western immunoassay, immunostaining and histology. RESULTS: Skin equivalents perfused at a physiological pressure formed a mature, polarised epidermis, a stratified dermis and a functional vessel system. Exposure of these models to TGFß recapitulated key features of SSc skin with activation of TGFß pathways, fibroblast to myofibroblast transition, increased release of collagen and excessive deposition of extracellular matrix. Treatment with the antifibrotic agent nintedanib ameliorated this fibrotic transformation. CONCLUSION: Our data provide evidence that vascularised skin equivalents can replicate key features of fibrotic skin and may serve as a platform for evaluation of antifibrotic drugs in a pathophysiologically relevant human setting.

4.
BMC Musculoskelet Disord ; 20(1): 408, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31484514

RESUMO

BACKGROUND: Mesenchymal chondrosarcoma (MCS) is a rare malignant variant of chondrosarcoma with a high tendency of recurrence and metastasis. Intradural extramedullary spinal MCS is exceedingly rare and usually found in pediatric patients. Herein, we present an elderly patient with primary intradural extramedullary spinal MCS. Relevant literatures are reviewed to disclose characteristics of intradural extramedullary spinal MCS. CASE PRESENTATION: A 64-year-old female presented with urinary difficulty and tightness of upper back preceding progressive weakness of right lower extremity. Magnetic resonance imaging revealed an intradural extramedullary tumor at the level of 3rd thoracic vertebra. This patient underwent total tumor resection and then received adjuvant radiotherapy. Histopathological examination showed that the tumor composed of spindle and round cells with high nucleocytoplasmic ratio accompanied by scattered eosinophilic chondroid matrix. Along with immunohistochemical findings and the existence of HEY1-NCOA2 fusion transcript, the diagnosis of MCS was confirmed. Neurologic deficit recovered nearly completely after surgery. No evidence of local recurrence or distant metastasis was found 5 years after treatments. Including the current case, a total of 18 cases have been reported in the literature with only one case with local recurrence and one case of mortality. The current case was the eldest patient diagnosed with primary intraspinal MCS in the literature. CONCLUSIONS: MCS rarely appears in the intradural space of the spine. In contrast to classic MCS, treatment outcome of primary intradural extramedullary spinal MCS is usually excellent as total tumor resection is commonly achievable. Adjuvant radiotherapy may reduce local recurrence and chemotherapy may be associated with fewer recurrences especially for unresectable tumors.

5.
PLoS One ; 14(8): e0220851, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31425528

RESUMO

Recent technical developments have resulted in robotic-assisted pedicle screw placement techniques. However, the use of robotic-assisted navigational techniques is still subject to controversy. This study aims to assess the accuracy and safety of a self-developed navigation system, the point spine navigation system (PSNS), for robotic-assisted pedicle screw placement surgery. Fifty-nine pedicle screws were implanted in three porcine vertebrae at the T6-T10 and L1-L5 levels, with the assistance of the PSNS. The navigation and planning system provides virtual surgical guide images, including sagittal, coronal, axial, oblique planes, and customized three-dimensional reconstructions for each vertebra to establish accurate pedicle screw trajectories and placement tracts. After pedicle screw placement, post-operative spiral computer tomographic scans were performed and screws were evaluated using the Gertzbein-Robbins classification. Differences between the actual pedicle screw position and pre-operative planning paths, including the angle, shortest distance, and entry trajectory were recorded. The 59 pedicle screw placements were all within a safe zone, and there was no spinal canal perforation or any other damage under postoperative computed tomography image data. Fifty-one screws were categorized as group A, seven screws were noted as group B, and one screw was identified as group E under the Gertzbein-Robbins classification. The mean entry point deviation was 2.71 ± 1.72°, mean trajectory distance was 1.56 ± 0.66 mm, and average shortest distance between two paths was 0.96 ± 0.73 mm. Pedicle placement remains a challenging procedure with high reported incidences of nerve and vascular injuries. The implementation of a robotic-assisted navigational system yields an acceptable level of accuracy and safety for the pedicle screw placement surgery.

6.
Arthritis Rheumatol ; 2019 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-31350829

RESUMO

BACKGROUND: Dipeptidyl-peptidase-4 (DPP4) identifies a dermal fibroblast lineage involved in scaring during wound healing. The role of DDP4 in tissue fibrosis, however, is unknown. The aim of the present study was to evaluate DPP4 as a potential target for the treatment of fibrosis in systemic sclerosis (SSc). METHODS: The expression of DPP4 was analyzed by real-time PCR, immunofluorescence and Western blot. The activity of DPP4 was modulated by overexpression, knockdown and pharmacological inhibition using Sitagliptin and Vildagliptin. The effects of DPP4 inhibition were analyzed in human dermal fibroblasts and in different mouse models of SSc (n=6). RESULTS: The expression of DPP4 and the number of DPP4 positive fibroblasts were increased in fibrotic skin of SSc patients in a TGF-ß dependent manner. DPP4 positive fibroblasts expressed higher levels of myofibroblast markers and collagen (p<0.001). Overexpression of DPP4 promoted fibroblast activation, whereas pharmacological or genetic inactivation of DPP4 reduced proliferation, migration, expression of contractile proteins and release of collagen by interfering with TGF-ß-induced ERK signaling (p<0.001). DPP4-knockout mice were less sensitive to bleomycin-induced dermal and pulmonary fibrosis (p<0.0001). Treatment with DPP4 inhibitors promoted regression of fibrosis induced by bleomycin- or chronic graft-versus-host disease and ameliorated fibrosis in TSK1 mice (p<0.001). The antifibrotic effects were associated with reduced inflammation. CONCLUSION: DPP4 characterizes a population of activated fibroblasts and regulates TGF-ß-induced fibroblast activation. Inhibition of DPP4 exerts potent anti-fibrotic effects in well tolerated doses. These results may have direct translational implications as DPP4 inhibitors are already in clinical use for diabetes. This article is protected by copyright. All rights reserved.

7.
Artif Cells Nanomed Biotechnol ; 47(1): 3021-3028, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31334674

RESUMO

Identification of specific cell markers is crucial for recognizing functionally healthy nucleus pulposus (NP) cells. The objective of this study was to investigate the role of CD24 expression in adult human NP cells. Cells were retrieved from NP tissues of 20 patients (aged 17-44) operated on for lumbar disc herniation. Based on CD24 expression, NP cells were separated by sorting and then used to examine phenotypic behavior, the effects of culture conditions and cellular senescence pathway related proteins. CD24 expression was positive in 35.5 ± 3.7% (range 9.1-65.2%) of NP cells. Consistently, normoxic expansion and serial passages in monolayers decreased percentage positivity for CD24 in NP cells. CD24- NP cells showed a markedly decreased GSK-3ß activity and increased mitogen-activated protein kinase phosphorylation accompanying by an increased ß-catenin expression. Higher levels of matrix metalloproteinases, as well as lower levels of ACAN and COL2 in CD24- cells, indicated the breakdown and reduced the formation of key extracellular matrix components. CD24+ NP cells presented a more favorable phenotype while CD24- cells showed a more prominent cellular senescence fate. CD24 in NP cells may be a surrogate marker of healthy cells, in the cell-based therapeutic treatment of degenerative disc disorders.

9.
Asian Spine J ; 2019 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-31079432

RESUMO

Study Design: In vitro cell culture study. Purpose: This study aims to investigate the impact of transforming growth factor-beta1 (TGF-ß1) and lovastatin on differentiating human mesenchymal stem cells (MSCs) toward nucleus pulposus (NP)-like phenotype. Overview of Literature: MSCs offer a cell source to the cell-based therapy for intervertebral disc degeneration. TGF-ß1 is used to induce MSCs to differentiate into NP-like cells; however, an undesired expression of collagen type I has been reported. Statins reportedly stimulate expression of bone morphogenetic protein-2 (BMP-2) and promote the chondrogenic phenotype to NP cells. However, the effects of statins with or without TGF-ß1 on the differentiation of MSCs into NP-like cells remain unclear. Methods: Human MSCs were treated with TGF-ß1 alone, lovastatin alone, and simultaneous or sequential treatment with TGF-ß1 and lovastatin. After the proposed stimulation, the total RNA was extracted to assess the expression profile of NP cells-specific genes. Hematoxylin-eosin staining was used for examining the microscopic morphology. Furthermore, we detected the syntheses of S-100 protein, aggrecan , and collagen type II in the extracellular matrix using immunohistochemical staining. Results: Simultaneous or sequential treatment of TGF-ß1 and lovastatin could further augment the BMP-2 overexpression compared with lovastatin-alone treatment. However, the mRNA expression of aggrecan and collagen type II was not compatible with the expression level of BMP-2 . Immunohistochemical studies revealed compatible production of aggrecan, collagen type II , and S-100 protein in all three groups treated with lovastatin. Cells in groups treated with lovastatin were less populated than that in the group treated with TGF-ß1 alone. Conclusions: This study demonstrates a promising role of lovastatin in inducing human MSCs into NP-like cells. However, further optimization of cell density before lovastatin treatment, treatment duration, and combination with TGF-ß1 are warranted to attain better stimulatory effects.

10.
BMC Urol ; 19(1): 27, 2019 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-31035980

RESUMO

BACKGROUND: Vasitis or inflammation of the vas deferens is a rare condition, and few case reports with computed tomography images have been published since 1980. CASE PRESENTATION: A 50-year-old man presented with severe right inguinal and lower abdominal pain. Initial diagnosis at the emergency department was incarcerated or strangulated inguinal hernia. The computed tomography scan revealed diffuse edematous changes of right spermatic cord and vas deferens with peripheral fat stranding. Correlating with his clinical symptoms, signs, and imaging findings, the diagnosis of vasitis was made. We report a case of acute vasitis about the cause, symptom, pathogen, differential diagnoses, image findings, and treatment. CONCLUSION: Although very rare, vasitis should be listed as one of the differential diagnosis for inguinal mass lesions. Cross-sectional imaging may be necessary to confirm the diagnosis and exclude differentials such as an inguinal hernia. Recognition of the characteristic image findings can help to make the correct diagnosis and avoid unnecessary surgery.

12.
Nature ; 566(7744): 344-349, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30700907

RESUMO

Fibroblasts are polymorphic cells with pleiotropic roles in organ morphogenesis, tissue homeostasis and immune responses. In fibrotic diseases, fibroblasts synthesize abundant amounts of extracellular matrix, which induces scarring and organ failure. By contrast, a hallmark feature of fibroblasts in arthritis is degradation of the extracellular matrix because of the release of metalloproteinases and degrading enzymes, and subsequent tissue destruction. The mechanisms that drive these functionally opposing pro-fibrotic and pro-inflammatory phenotypes of fibroblasts remain unknown. Here we identify the transcription factor PU.1 as an essential regulator of the pro-fibrotic gene expression program. The interplay between transcriptional and post-transcriptional mechanisms that normally control the expression of PU.1 expression is perturbed in various fibrotic diseases, resulting in the upregulation of PU.1, induction of fibrosis-associated gene sets and a phenotypic switch in extracellular matrix-producing pro-fibrotic fibroblasts. By contrast, pharmacological and genetic inactivation of PU.1 disrupts the fibrotic network and enables reprogramming of fibrotic fibroblasts into resting fibroblasts, leading to regression of fibrosis in several organs.


Assuntos
Diferenciação Celular/genética , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose/genética , Fibrose/patologia , Proteínas Proto-Oncogênicas/metabolismo , Transativadores/metabolismo , Animais , Sequência de Bases , Epigênese Genética , Feminino , Humanos , Inflamação/genética , Inflamação/patologia , Masculino , Camundongos , Regiões Promotoras Genéticas/genética , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Transativadores/antagonistas & inibidores
13.
RNA ; 25(5): 600-606, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30733327

RESUMO

The 70S ribosome is a major target for antibacterial drugs. Two of the classical antibiotics, chloramphenicol (CHL) and erythromycin (ERY), competitively bind to adjacent but separate sites on the bacterial ribosome: the catalytic peptidyl transferase center (PTC) and the nascent polypeptide exit tunnel (NPET), respectively. The previously reported competitive binding of CHL and ERY might be due either to a direct collision of the two drugs on the ribosome or due to a drug-induced allosteric effect. Because of the resolution limitations, the available structures of these antibiotics in complex with bacterial ribosomes do not allow us to discriminate between these two possible mechanisms. In this work, we have obtained two crystal structures of CHL and ERY in complex with the Thermus thermophilus 70S ribosome at a higher resolution (2.65 and 2.89 Å, respectively) allowing unambiguous placement of the drugs in the electron density maps. Our structures provide evidence of the direct collision of CHL and ERY on the ribosome, which rationalizes the observed competition between the two drugs.


Assuntos
Antibacterianos/química , Cloranfenicol/química , Eritromicina/química , Subunidades Ribossômicas/efeitos dos fármacos , Thermus thermophilus/efeitos dos fármacos , Antibacterianos/farmacologia , Sítios de Ligação , Ligação Competitiva , Cloranfenicol/farmacologia , Cristalografia por Raios X , Eritromicina/farmacologia , Escherichia coli/química , Escherichia coli/efeitos dos fármacos , Escherichia coli/genética , Escherichia coli/metabolismo , Modelos Moleculares , Peptidil Transferases/antagonistas & inibidores , Peptidil Transferases/química , Peptidil Transferases/genética , Peptidil Transferases/metabolismo , Ligação Proteica , Biossíntese de Proteínas , Conformação Proteica , Subunidades Ribossômicas/genética , Subunidades Ribossômicas/metabolismo , Subunidades Ribossômicas/ultraestrutura , Thermus thermophilus/química , Thermus thermophilus/genética , Thermus thermophilus/metabolismo
14.
Proc Natl Acad Sci U S A ; 116(2): 566-574, 2019 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-30587587

RESUMO

We report a patient who presented with congenital hypotonia, hypoventilation, and cerebellar histopathological alterations. Exome analysis revealed a homozygous mutation in the initiation codon of the NME3 gene, which encodes an NDP kinase. The initiation-codon mutation leads to deficiency in NME3 protein expression. NME3 is a mitochondrial outer-membrane protein capable of interacting with MFN1/2, and its depletion causes dysfunction in mitochondrial dynamics. Consistently, the patient's fibroblasts were characterized by a slow rate of mitochondrial dynamics, which was reversed by expression of wild-type or catalytic-dead NME3. Moreover, glucose starvation caused mitochondrial fragmentation and cell death in the patient's cells. The expression of wild-type and catalytic-dead but not oligomerization-attenuated NME3 restored mitochondrial elongation. However, only wild-type NME3 sustained ATP production and viability. Thus, the separate functions of NME3 in mitochondrial fusion and NDP kinase cooperate in metabolic adaptation for cell survival in response to glucose starvation. Given the critical role of mitochondrial dynamics and energy requirements in neuronal development, the homozygous mutation in NME3 is linked to a fatal mitochondrial neurodegenerative disorder.


Assuntos
Trifosfato de Adenosina , Metabolismo Energético/genética , Homozigoto , Dinâmica Mitocondrial/genética , Nucleosídeo NM23 Difosfato Quinases , Doenças Neurodegenerativas , Trifosfato de Adenosina/genética , Trifosfato de Adenosina/metabolismo , Linhagem Celular , Sobrevivência Celular , Feminino , Humanos , Masculino , Mitocôndrias/enzimologia , Mitocôndrias/genética , Mitocôndrias/patologia , Nucleosídeo NM23 Difosfato Quinases/genética , Nucleosídeo NM23 Difosfato Quinases/metabolismo , Doenças Neurodegenerativas/enzimologia , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia
15.
J Neurosci Res ; 2018 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-30311677

RESUMO

Bidirectional cargo transport in neurons can be explained by two models: the "tug-of-war model" for short-range transport, in which several kinesin and dynein motors are bound to the same cargo but travel in opposing directions, and by the "motor coordination model" for long-range transport, in which small adaptors or the cargo itself activates or deactivates opposing motors. Direct interactions between the major axonal transporter kinesin-3 UNC-104(KIF1A) and the dynein/dynactin complex remains unknown. In this study, we dissected and evaluated the interaction sites between UNC-104 and dynein as well as between UNC-104 and dynactin using yeast two-hybrid assays. We found that the DYLT-1(Tctex) subunit of dynein binds near the coiled coil 3 (CC3) of UNC-104, and that the DYRB-1(Roadblock) subunit binds near the CC2 region of UNC-104. Regarding dynactin, we specifically revealed strong interactions between DNC-6(p27) and the FHA-CC3 stretch of UNC-104, as well as between the DNC-5(p25) and the CC2-CC3 region of UNC-104. Motility analysis of motors and cargo in the nervous system of Caenorhabditis elegans revealed impaired transport of UNC-104 and synaptic vesicles in dynein and dynactin mutants (or in RNAi knockdown animals). Further, in these mutants UNC-104 clustering along axons was diminished. Interestingly, when dynamic UNC-104 motors enter a stationary UNC-104 cluster their dwelling times are increased in dynein mutants (suggesting that dynein may act as an UNC-104 activator). In summary, we provide novel insights on how UNC-104 interacts with the dynein/dynactin complex and how UNC-104 driven axonal transport depends on dynein/dynactin in C. elegans neurons.

16.
Acta Cardiol Sin ; 34(5): 417-423, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30271092

RESUMO

Background: Type D, otherwise known as distressed personality type, has been associated with an increased risk of cardiovascular morbidity and mortality. Blood pressure reactivity and recovery to stress could be a possible underlying pathway linking type D personality and cardiovascular events. Methods: A total of 41 patients with hypertension were recruited from a regional hospital in southern Taiwan. Demographic and clinical characteristics were obtained from all participants. Type D personality was assessed using the 14-item Type D Scale-Taiwanese version. Systolic blood pressure, diastolic blood pressure, and heart rate were measured at the end of baseline, anger recall, verbal, and recovery phases of an anger recall task. Analysis of covariance was used to examine differences in blood pressure and heart rate at the anger recall, verbal, and recovery phase between patients with or without type D personality. Results: After adjusting for baseline measurements, sex, and age, systolic blood pressure (p = 0.002) and diastolic blood pressure (p = 0.011) at the recovery phase were significantly higher in the patients with type D personality. No significant differences in blood pressure or heart rate were observed in the anger recall or verbal phase between the two groups of patients. Conclusions: The findings of this study support the notion that prolonged blood pressure recovery rather than high reactivity could be an underlying pathway linking type D personality and the risk of future cardiovascular events among patients with hypertension.

17.
Acad Radiol ; 2018 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-30195416

RESUMO

RATIONALE AND OBJECTIVES: To evaluate image quality and radiation exposure when using the adaptive statistical iterative reconstruction-V (ASIR-V) algorithm for reconstructing craniocervical computed tomographic angiography images acquired at 100 kVp. MATERIALS AND METHODS: We randomly divided 121 patients into three groups: group A (conventional protocol), 120 kVp with filtered back projection; group B, 120 kVp with 50% ASIR-V; and group C, 100 kVp with 50% ASIR-V. All patients underwent scans in a 256-slice computed tomography (CT) scanner. Radiation dose (volume CT dose index), dose-length product, and effective dose, objective parameters such as arterial attenuation value, signal-to-noise ratio, contrast-to-noise ratio, and noise obtained at head, neck, and shoulder levels were compared among the groups. Subjective image quality was independently assessed by two radiologists, and interobserver reliability was assessed using kappa analysis. RESULTS: The radiation dose in group C was the lowest (p < 0.01) with a 40% reduction in volume CT dose index, dose-length product, and effective dose values compared to group A, and group C showed higher arterial attenuation than either group A or B (p < 0.01). Additionally, signal-to-noise ratio and contrast-to-noise ratio were higher and noise was lower in groups B and C than group A. Group C had better subjective image quality than groups A and B (p < 0.05), and the interobserver reliability between the two radiologists was high (k = 0.783). CONCLUSION: Compared to the conventional protocol, using 50% ASIR-V and the 100 kVp protocol during craniocervical computed tomographic angiography yields better objective and subjective image quality at lower radiation doses.

18.
Nat Commun ; 9(1): 3259, 2018 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-30108215

RESUMO

Uncontrolled activation of TGFß signaling is a common denominator of fibrotic tissue remodeling. Here we characterize the tyrosine phosphatase SHP2 as a molecular checkpoint for TGFß-induced JAK2/STAT3 signaling and as a potential target for the treatment of fibrosis. TGFß stimulates the phosphatase activity of SHP2, although this effect is in part counterbalanced by inhibitory effects on SHP2 expression. Stimulation with TGFß promotes recruitment of SHP2 to JAK2 in fibroblasts with subsequent dephosphorylation of JAK2 at Y570 and activation of STAT3. The effects of SHP2 on STAT3 activation translate into major regulatory effects of SHP2 on fibroblast activation and tissue fibrosis. Genetic or pharmacologic inactivation of SHP2 promotes accumulation of JAK2 phosphorylated at Y570, reduces JAK2/STAT3 signaling, inhibits TGFß-induced fibroblast activation and ameliorates dermal and pulmonary fibrosis. Given the availability of potent SHP2 inhibitors, SHP2 might thus be a potential target for the treatment of fibrosis.

20.
J Am Coll Cardiol ; 72(5): 477-485, 2018 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-30049307

RESUMO

BACKGROUND: Low-dose rivaroxaban (10 mg/day) has been widely used in Asia for patients with atrial fibrillation (AF), although there is a lack of evidence regarding its effectiveness. In Asians, it is unclear whether low-dose rivaroxaban is equally effective as that of the standard dose or is associated with less bleeding risk. OBJECTIVES: The aim of this study was to evaluate the effectiveness and safety of standard-dose (15 or 20 mg/day) and low-dose (10 mg/day) rivaroxaban in Asians with AF. METHODS: Using data files from the National Health Insurance Research Database between May 1, 2014, and September 30, 2015, a retrospective population-based cohort study was conducted in patients diagnosed with AF or atrial flutter and treated with low- or standard-dose rivaroxaban. Patients were followed up until the first occurrence of the study outcome or the end of the observation period (December 31, 2015). RESULTS: Among 6,558 eligible patients, a total of 2,373 and 4,185 patients took low- and standard-dose rivaroxaban, respectively. Compared to standard-dose rivaroxaban, low-dose rivaroxaban was associated with a significantly higher risk of myocardial infarction (subdistribution hazard ratio: 2.26; 95% confidence interval: 1.13 to 4.52), with similar risk of ischemic stroke, systemic embolism, major bleeding, and nonmajor clinically relevant bleeding. CONCLUSIONS: Compared to standard-dose rivaroxaban, low-dose rivaroxaban in Asian patients with AF was associated with similar risks of thromboembolism and bleeding except myocardial infarction.

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