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A multicenter retrospective analysis of conventionally collected data. To identify the potential causes of hypoproteinemia after traumatic spinal cord injury (TSCI) and provide a diagnostic model for predicting an individual likelihood of developing hypoproteinemia. Hypoproteinemia is a complication of spinal cord injury (SCI), an independent risk factor for respiratory failure in elderly patients with SCI, and a predictor of outcomes in patients with cervical SCI. Few nomogram-based studies have used clinical indicators to predict the likelihood of hypoproteinemia following TSCI. This multicenter retrospective clinical analysis included patients with TSCI admitted to the First Affiliated Hospital of Guangxi Medical University, Wuzhou GongRen Hospital, and Dahua Yao Autonomous County People Hospital between 2016 and 2020. The data of patients from the First Affiliated Hospital of Guangxi Medical University were used as the training set, and those from the other 2 hospitals were used as the validation set. All patient histories, diagnostic procedures, and imaging findings were recorded. To predict whether patients with TSCI may develop hypoproteinemia, a least absolute shrinkage and selection operator regression analysis was conducted to create a nomogram. The model was validated by analyzing the consequences using decision curve analysis, calibration curves, the C-index, and receiver operating characteristic curves. After excluding patients with missing data, 534 patients were included in this study. Male/female sex, ageâ ≥â 60 years, cervical SCI, pneumonia, pleural effusion, urinary tract infection (UTI), hyponatremia, fever, hypotension, and tracheostomy were identified as independent risk factors of hypoalbuminemia. A simple and easy-to-replicate clinical prediction nomogram was constructed using these factors. The area under the curve was 0.728 in the training set and 0.881 in the validation set. The predictive power of the nomogram was satisfactory. Hypoalbuminemia after TSCI may be predicted using the risk factors of male/female sex, ageâ ≥â 60 years, cervical SCI, pneumonia, pleural effusion, UTI, hyponatremia, fever, hypotension, and tracheostomy.
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Hipoproteinemia , Nomogramas , Traumatismos de la Médula Espinal , Humanos , Femenino , Masculino , Traumatismos de la Médula Espinal/complicaciones , Estudios Retrospectivos , Persona de Mediana Edad , Anciano , Adulto , Hipoproteinemia/etiología , Factores de Riesgo , Curva ROC , China/epidemiologíaRESUMEN
OBJECTIVE: This study aimed to establish a nomogram-based assessment for predicting the risk of hyponatremia after spinal cord injury (SCI). DESIGN: The study is a retrospective single-center study. PARTICIPANTS: SCI patients hospitalized in the First Affiliated Hospital of Guangxi Medical University. SETTING: The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China. METHODS: We performed a retrospective clinical study to collect SCI patients hospitalized in the First Affiliated Hospital of Guangxi Medical University from 2016 to 2020. Based on their clinical scores, the SCI patients were grouped as either hyponatremic or non-hyponatremic, SCI patients in 2016-2019 were identified as the training set, and patients in 2020 were identified as the test set. A nomogram was generated, the calibration curve, receiver operating characteristic (ROC) curve, and decision curve analysis (DCA) were used to validate the model. RESULTS: A total of 895 SCI patients were retrieved. After excluding patients with incomplete data, 883 patients were finally included in this study and used to construct the nomograms. The indicators used in the nomogram included sex, completeness of SCI, pneumonia, urinary tract infection, fever, constipation, white blood cell (WBC), albumin and serum Ca2+. These indices were determined by the least absolute shrinkage and selection operator (LASSO) regression analysis. The C-index of the model was 0.81, the area under the curve (AUC) of the training set was 0.82(Cl:0.79-0.85), and the validation set was 0.79(Cl:0.73-0.85). CONCLUSIONS: Nomogram has good predictive ability, sex, completeness of SCI, pneumonia, urinary tract infection, fever, constipation, WBC, albumin and serum Ca2+ were predictors of hyponatremia after SCI.
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BACKGROUND AND AIM: Osteoporosis, a systemic metabolic bone disease, is characterized by the decline of bone mass and quality due to excessive osteoclast activity. Currently, drug-targeting osteoclasts show promising therapy for osteoporosis. In this study, we investigated the effect of cichoric acid (CA) on receptor activator of nuclear kappa-B ligand (RANKL)-induced osteoclastogenesis and the bone loss induced by ovariectomy in mice. EXPERIMENTAL PROCEDURE: Molecular docking technologies were employed to examine the interaction between CA and RANKL. CCK8 assay was used to evaluate the cell viability under CA treatment. TRAcP staining, podosome belt staining, and bone resorption assays were used to test the effect of CA on osteoclastogenesis and osteoclast function. Further, an OVX-induced osteoporosis mice model was employed to identify the effect of CA on bone loss using micro-CT scanning and histological examination. To investigate underlying mechanisms, network pharmacology was applied to predict the downstream signaling pathways, which were verified by Western blot and immunofluorescence staining. KEY RESULTS: The molecular docking analysis revealed that CA exhibited a specific binding affinity to RANKL, engaging multiple binding sites. CA inhibited RANKL-induced osteoclastogenesis and bone resorption without cytotoxic effects. Mechanistically, CA suppressed RANKL-induced intracellular reactive oxygen species, nuclear factor-kappa B, and mitogen-activated protein kinase pathways, followed by abrogated nuclear factor activated T-cells 1 activity. Consistent with this finding, CA attenuated post-ovariectomy-induced osteoporosis by ameliorating osteoclastogenesis. CONCLUSIONS AND IMPLICATIONS: CA inhibited osteoclast activity and bone loss by targeting RANKL. CA might represent a promising candidate for treating osteoclast-related diseases, such as osteoporosis.
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Resorción Ósea , Ácidos Cafeicos , Osteoporosis , Succinatos , Animales , Femenino , Humanos , Ratones , Resorción Ósea/prevención & control , Diferenciación Celular , Ratones Endogámicos C57BL , Simulación del Acoplamiento Molecular , FN-kappa B/metabolismo , Osteoclastos , Osteogénesis , Osteoporosis/patología , Ovariectomía/efectos adversos , Ligando RANK/metabolismoRESUMEN
Objective: This study aimed to explore the molecular mechanism of Momordica grosvenori (MG) in spinal cord injury (SCI) by network pharmacology analysis. Methods: We searched for potential active MG compounds using the TCMSP database and the BATMAN-TCM platform. The Swiss target prediction database was used to find MG-related targets and the targets of SCI from the CTD, GeneCards, and DrugBank databases. Following that, a protein-protein interaction (PPI) study was carried out. Cytoscape software was used to calculate the hub gene, and R software was used to evaluate the Gene Ontology (GO) and KEGG enrichment pathways. Finally, molecular docking between the hub protein and important compounds was performed. We verified STAT3, MAPK1, HSP90AA1, PIK3R1, PIK3CA, and RXRA potential targets by quantitative PCR. Results: We obtained 293 MG-anti-SCI targets with potential therapeutic utility by intersecting 346 MG-related targets and 7214 SCI-related targets. The top 10 identified genes, ranking in descending order of value, were SRC, STAT3, MAPK1, HSP90AA1, PIK3R1, PIK3CA, RXRA, AKT1, CREBBP, and JAK2. Through enrichment analysis and literature search, 10 signaling pathways were screened out. The molecular docking of important drugs and hub targets revealed that some had a higher binding affinity. The results of quantitative PCR indicated that MAPK1, RXRA, and STAT3 were expressed differently in in vitro experiments. Conclusion: In conclusion, the current work indicated that MG might play an anti-SCI role via multicomponent, multitarget, and multichannel interaction, which presents a novel idea for further research into the precise mechanism of MG-anti-SCI interaction.
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Bone homeostasis only exists when the physical function of osteoblast and osteoclast stays in the balance between bone formation and resorption. Bone resorption occurs when the two processes are uncoupled, shifting the balance in favour of bone resorption. Excessive activation of osteoclasts leads to a range of osteolytic bone diseases including osteoporosis, aseptic prosthesis loosening, rheumatoid arthritis, and osteoarthritis. Receptor activator of nuclear factor kappa-B ligand (RANKL) and its downstream signaling pathways are recognized as key mediators that drive the formation and activation of osteoclastic function. Hence, osteoclast formation and/or its function remain as dominant targets for research and development of agents reaching the treatment towards osteolytic diseases. Chrysin (CHR) is a flavonoid with a wide range of anti-inflammatory and anti-tumor effects. However, its effect on osteoclasts remains unknown. In this study, we found the effects of CHR on inhibiting osteoclast differentiation which were assessed in terms of the number and size of TRAcP positive multinucleated osteoclasts (OCs). Further, the inhibitory effects of CHR on bone resorption and osteoclast fusion of pre-OC were assessed by hydroxyapatite resorption pit assay and F-actin belts staining; respectively. Western blotting analysis of RANKL-induced signaling pathways and immunofluorescence analysis for p65 nuclear translocation in response to RANKL-induced osteoclasts were used to analyze the mechanism of action of CHR affecting osteoclasts. Lastly, the murine calvarial osteolysis model revealed that CHR could protect against particle-induced bone destruction in vivo. Collectively, our data strongly suggested that CHR with its promising anti-tumor effects would also be a potential therapeutic agent for osteolytic diseases.
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Spinal cord injury (SCI) is a public health problem in the world. The SCI usually triggers an excessive inflammatory response that brings about a secondary tissue wreck leading to further cellular and organ dysfunction. Hence, there is great potential of reducing inflammation for therapeutic strategies of SCI. In this study, we aim to investigate if Salidroside (SAD) exerts an anti-inflammatory effect and promotes recovery of motor function on SCI through suppressing nuclear factor-κB (NF-κB) and the mitogen-activated protein kinase (MAPK) pathways. In vitro, real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA) were used to examine the inhibitory effect of SAD on the expression and release of interleukin-1ß (IL-1ß), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) activated by lipopolysaccharide (LPS) in astrocytes. In addition, SAD was found to inhibit NF-κB, p38 and extracellular-regulated protein kinases (ERK) signaling pathways by western blot analysis. Further, in vivo study showed that SAD was able to improve hind limb motor function and reduce tissue damage accompanied by the suppressed expression of inflammatory cytokines IL-1ß, IL-6, and TNF-α. Overall, SAD could reduce the inflammatory response and promote motor function recovery in rats after SCI by inhibiting NF-κB, p38, and ERK signaling pathways.
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Citocinas/genética , Glucósidos/farmacología , Inflamación/tratamiento farmacológico , Fenoles/farmacología , Traumatismos de la Médula Espinal/tratamiento farmacológico , Animales , Astrocitos/efectos de los fármacos , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Inflamación/genética , Inflamación/patología , Interleucina-1beta , Interleucina-6/genética , Lipopolisacáridos/farmacología , Quinasas de Proteína Quinasa Activadas por Mitógenos/genética , FN-kappa B/genética , Ratas , Transducción de Señal/efectos de los fármacos , Traumatismos de la Médula Espinal/genética , Traumatismos de la Médula Espinal/patología , Factor de Necrosis Tumoral alfa/genética , Proteínas Quinasas p38 Activadas por Mitógenos/genéticaRESUMEN
Osteoporosis, arthritis, Peget's disease, bone tumor, periprosthetic joint infection, and periprosthetic loosening have a common characteristic of osteolysis, which is characterized by the enhanced osteoclastic bone resorptive function. At present, the treatment target of these diseases is to interfere with osteoclastic formation and function. Scutellarein (Scu), a flavonoids compound, can inhibit the progress of tumor and inflammation. However, the role of Scu in inflammatory osteolysis isn't elucidated clearly. Our study showed that Scu inhibited bone destruction induced by LPS in vivo and OC morphology and function induced by RANKL in vitro. Mechanistic studies revealed that Scu suppressed osteoclastic marker gene expression by RANKL-induced, such as Ctsk9, Mmp9, Acp5, and Atp6v0d2. In addition, we found that the inhibition effects of osteoclastogenesis and bone resorption function of Scu were mediated via attenuating NF-κB and NFAT signaling pathways. In conclusion, the results showed that Scu may become a potential new drug for the treatment of inflammatory osteolysis.
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Apigenina/farmacología , Resorción Ósea/tratamiento farmacológico , Diferenciación Celular/efectos de los fármacos , Osteoclastos/efectos de los fármacos , Animales , Enfermedades Óseas Metabólicas/metabolismo , Resorción Ósea/patología , Lipopolisacáridos/farmacología , Macrófagos/metabolismo , Ratones Endogámicos C57BL , Factores de Transcripción NFATC/efectos de los fármacos , Factores de Transcripción NFATC/metabolismo , Osteoclastos/metabolismo , Osteogénesis/efectos de los fármacosRESUMEN
Osteolytic bone diseases are closely linked to the over-activation of osteoclasts and enhancement of bone resorption. It has become a major health issue in orthopedic practice worldwide. Inhibition of osteoclasts is proposed to be the main treatment for osteolytic disorders. Diosmetin (DIO) is a natural flavonoid with properties of antioxidant, anti-infection, and antishock. The effect of DIO on osteoclast differentiation is poorly understood. In this study project, we found that DIO could inhibit osteoclastic formation induced by receptor activator of nuclear factor kappa-B ligand (RANKL) in a dose-dependent manner. The expression of the osteoclast differentiation marker genes, cathepsin K, nuclear factor of activated T-cells 1 (NFATc1), Acp5, Ctr, Atp6v0d2, and Mmp9 were also decreased by the treatment of DIO. In addition, DIO attenuated the formation of actin ring and the ability of bone resorption. Further, the western blotting showed that DIO inhibits the phosphorylation of the mitogen-activated protein kinases signaling pathway induced by RANKL, accompanied by the downregulation of NFATc1 and c-Fos expression. We also found that DIO could reduce the accumulation of reactive oxygen species (ROS) induced by RANKL. In vivo, the study revealed that DIO can significantly reduce LPS-induced osteolysis in mice. Collectively, our study shows that DIO can inhibit osteoclast formation and activation, and could serve as a potential therapeutic drug for osteolytic bone diseases.
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Diferenciación Celular/efectos de los fármacos , Flavonoides/farmacología , Osteoclastos/efectos de los fármacos , Osteólisis/tratamiento farmacológico , Animales , Antioxidantes/metabolismo , Resorción Ósea/tratamiento farmacológico , Resorción Ósea/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Lipopolisacáridos/farmacología , Ratones , Ratones Endogámicos C57BL , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Factores de Transcripción NFATC/metabolismo , Osteoclastos/metabolismo , Osteólisis/inducido químicamente , Osteólisis/metabolismo , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ligando RANK/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Osteosarcoma is the most frequent primary bone tumor in children and adolescents. The phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway is an attractive anticancer target because it plays key roles in the regulation of cell growth, division and differentiation. In this study, we demonstrated high expression of PI3K/mTOR signaling pathway-related genes in patients with osteosarcoma. We thus investigated the effects of A005, a newly synthesized dual PI3K/mTOR inhibitor, on osteosarcoma cells and in a mouse xenograft tumor model. The results confirmed that A005 inhibited the proliferation, migration and invasion of human osteosarcoma cells. In addition, A005 also inhibited receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclast differentiation and bone resorption in vitro. Therefore, A005 was further applied to a SaOS-2 osteosarcoma-induced mouse osteolysis model. A005 inhibited tumor growth and prevented osteosarcoma-associated osteolysis via modulation of the PI3K/AKT/mTOR pathway. Overall, our results showed that A005 inhibited osteoclastogenesis and prevented osteosarcoma-induced bone osteolysis by suppressing PI3K/AKT/mTOR signaling. These findings indicated that A005 may be a promising candidate drug for the treatment of human osteosarcoma.
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BACKGROUND/AIMS: Extensive osteoclast formation plays a critical role in bone diseases, including rheumatoid arthritis, periodontitis and the aseptic loosening of orthopedic implants. Thus, identification of agents that can suppress osteoclast formation and bone resorption is important for the treatment of these diseases. Monocrotaline (Mon), the major bioactive component of crotalaria sessiliflora has been investigated for its anti-cancer activities. However, the effect of Mon on osteoclast formation and osteolysis is not known. METHODS: The bone marrow macrophages (BMMs) were cultured with M-CSF and RANKL followed by Mon treatment. Then the effects of Mon on osteoclast differentiation were evaluated by counting TRAP (+) multinucleated cells. Moreover, effects of Mon on hydroxyapatite resorption activity of mature osteoclast were studied through resorption areas measurement. The involved potential signaling pathways were analyzed by performed Western blotting and quantitative real-time PCR examination. Further, we established a mouse calvarial osteolysis model to measure the osteolysis suppressing effect of Mon in vivo. RESULTS: In this study, we show that Mon can inhibit RANKL-induced osteoclast formation and function in a dose-dependent manner. Mon inhibits the expression of osteoclast marker genes such as tartrate-resistant acid phosphatase (TRAP) and cathepsin K. Furthermore, Mon inhibits RANKL-induced the activation of p38 and JNK. Consistent with in vitro results, Mon exhibits protective effects in an in vivo mouse model of LPS-induced calvarial osteolysis. CONCLUSION: Taken together our data demonstrate that Mon may be a potential prophylactic anti-osteoclastic agent for the treatment of osteolytic diseases caused by excessive osteoclast formation and function.
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Diferenciación Celular/efectos de los fármacos , Monocrotalina/farmacología , Osteogénesis/efectos de los fármacos , Osteólisis/prevención & control , Sustancias Protectoras/uso terapéutico , Ligando RANK/farmacología , Animales , Células de la Médula Ósea/citología , Células Cultivadas , Modelos Animales de Enfermedad , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Lipopolisacáridos/toxicidad , Macrófagos/citología , Macrófagos/metabolismo , Ratones , Ratones Endogámicos C57BL , Monocrotalina/química , Monocrotalina/uso terapéutico , Osteoclastos/citología , Osteoclastos/metabolismo , Osteólisis/etiología , Sustancias Protectoras/química , Sustancias Protectoras/farmacología , Proteínas Proto-Oncogénicas c-fos/genética , Proteínas Proto-Oncogénicas c-fos/metabolismo , ATPasas de Translocación de Protón/genética , ATPasas de Translocación de Protón/metabolismo , Cráneo/diagnóstico por imagen , Cráneo/patología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Osteoclasts are multinuclear giant cells responsible for bone resorption in lytic bone diseases such as osteoporosis, arthritis, periodontitis, and bone tumors. Due to the severe side-effects caused by the currently available drugs, a continuous search for novel bone-protective therapies is essential. Artesunate (Art), the water-soluble derivative of artemisinin has been investigated owing to its anti-malarial properties. However, its effects in osteoclastogenesis have not yet been reported. In this study, Art was shown to inhibit the nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis, the mRNA expression of osteoclastic-specific genes, and resorption pit formation in a dose-dependent manner in primary bone marrow-derived macrophages cells (BMMs). Furthermore, Art markedly blocked the RANKL-induced osteoclastogenesis by attenuating the degradation of IκB and phosphorylation of NF-κB p65. Consistent with the in vitro results, Art inhibited lipopolysaccharide (LPS)-induced bone resorption by suppressing the osteoclastogenesis. Together our data demonstrated that Art inhibits RANKL-induced osteoclastogenesis by suppressing the NF-κB signaling pathway and that it is a promising agent for the treatment of osteolytic diseases.
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Artemisininas/farmacología , Resorción Ósea/tratamiento farmacológico , Lipopolisacáridos , Osteoclastos/efectos de los fármacos , Osteogénesis/efectos de los fármacos , Osteólisis/prevención & control , Ligando RANK/metabolismo , Animales , Artesunato , Resorción Ósea/genética , Células Cultivadas , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Regulación de la Expresión Génica , Proteínas I-kappa B/metabolismo , Masculino , Ratones Endogámicos C57BL , Osteoclastos/metabolismo , Osteogénesis/genética , Osteólisis/inducido químicamente , Osteólisis/metabolismo , Osteólisis/patología , Fosforilación , Proteolisis , Transducción de Señal/efectos de los fármacos , Factores de Tiempo , Factor de Transcripción ReIA/metabolismo , Microtomografía por Rayos XRESUMEN
Effects of salt stress on Artemisia scoparia and A. vulgaris "Variegate" were examined. A. scoparia leaves became withered under NaCl treatment, whereas A. vulgaris "Variegate" leaves were not remarkably affected. Chlorophyll content decreased in both species, with a higher reduction in A. scoparia. Contents of proline, MDA, soluble carbohydrate, and Na(+) increased in both species under salt stress, but A. vulgaris "Variegate" had higher level of proline and soluble carbohydrate and lower level of MDA and Na(+). The ratios of K(+)/Na(+), Ca(2+)/Na(+), and Mg(2+)/Na(+) in A. vulgaris "Variegate" under NaCl stress were higher. Moreover, A. vulgaris "Variegate" had higher transport selectivity of K(+)/Na(+) from root to stem, stem to middle mature leaves, and upper newly developed leaves than A. scoparia under NaCl stress. A. vulgaris "Variegate" chloroplast maintained its morphological integrity under NaCl stress, whereas A. scoparia chloroplast lost integrity. The results indicated that A. scoparia is more sensitive to salt stress than A. vulgaris "Variegate." Salt tolerance is mainly related to the ability of regulating osmotic pressure through the accumulation of soluble carbohydrates and proline, and the gradient distribution of K(+) between roots and leaves was also contributed to osmotic pressure adjustment and improvement of plant salt tolerance.
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Artemisia/metabolismo , Cloroplastos/metabolismo , Presión Osmótica/efectos de los fármacos , Hojas de la Planta/metabolismo , Raíces de Plantas/metabolismo , Cloruro de Sodio/farmacología , Artemisia/crecimiento & desarrollo , Cationes Bivalentes/metabolismo , Cationes Monovalentes/metabolismo , Metales/metabolismo , Hojas de la Planta/crecimiento & desarrollo , Raíces de Plantas/crecimiento & desarrollo , Tolerancia a la Sal/efectos de los fármacosRESUMEN
OBJECTIVE: To quantitatively analyze the three-dimensional kinematic features of the motion of lower limb joints in stroke patients with chronic hemiplegia. METHODS: A three-dimensional motion analysis system was used to measure the gait of 39 patients with chronic hemiplegia due to stroke, 12 males and 15 females, aged 57.11 +/- 9.58 (43 - 75), who could walk at least 10 m independently without a walking aid, and 27 sex and age-matched non-disabled controls. RESULTS: The values of range of motion (ROM) of hip and knee of the stroke patients were 34 - 39 degrees and 50 - 58 degrees respectively, both significantly lower than those of the controls (40 - 45 degrees and 65 - 72 degrees respectively, both P < 0.01), however, the ROM of ankle of the stroke patients was 22 - 28 degrees, not significantly different from that of the controls (26 - 30 degrees, P > 0.05). The hip extension and ankle dorsiflexion of the stroke patients were 1 - 4 degrees and 8 - 10 degrees respectively, both significantly lower than those of the controls (14 - 19 degrees and 14 - 16 degrees respectively, both P < 0.01), however, the genuflex of the stroke patients was 59 - 66 degrees, not significantly different from that of the controls (65 - 69 degrees, P > 0.05). The ratio of the weak and sound sides (W/S) of hip extension and the W/S value of ankle dorxiflexion of the stroke patients were 0.33 +/- 0.40 and 0.65 +/- 0.22, both significantly lower than those of the controls (1.06 +/- 0.29 and 0.99 +/- 0.27, both P < 0.01), however, the W/S value of genuflex of the stroke patients was 0.90 +/- 0.23, not significantly different from that of the controls (1.01 +/- 0.07, P < 0.05). CONCLUSION: Lack of motion of lower limb joints in the weak side and asymmetry of lower limb motion between the weak and sound sides are the characteristics of the hemiplegic gait in stroke.