RESUMO
PURPOSE: Radiation-induced lung injury limits the implementation of radiotherapy plans and severely impairs the quality of life. Crocetin has the capability to protect against radiation. This study is aimed at estimate the preventive effect and mechanism of crocetin on acute radiation induced lung injury. METHODS AND MATERIALS: In this study, we offer a strategy for radiation-induced lung injury by using crocetin, an extract of gardenia fruit. Histopathology, transcriptomics, flow cytometry, and other methods have served to examine the effect and mechanism of crocetin on acute radiation-induced lung injury. RESULTS: Crocetin effectively alleviates radiation-induced alveolar wall thickening and alveolar destruction. The number of normal alveoli and lung structure of mice is well protected by the prevention of crocetin. It is found that crocetin inhibits necroptosis to achieve effective radioprotection by down regulating the Tnfrsf10b gene in vitro. CONCLUSION: Crocetin inhibits necroptosis through transcriptional regulation of the Tnfrsf10b gene, thereby preventing radiation-induced lung injury. This work may provide a new strategy for the prevention of lung radiation injury by the extract from Chinese herbal medicine.
Assuntos
Lesão Pulmonar Aguda , Gardenia , Lesões por Radiação , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/prevenção & controle , Animais , Carotenoides , Frutas/química , Gardenia/química , Pulmão , Camundongos , Extratos Vegetais/análise , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Qualidade de Vida , Lesões por Radiação/tratamento farmacológico , Lesões por Radiação/prevenção & controle , Vitamina A/análogos & derivadosRESUMO
Rice is an important food crop in China, fertilization measures significantly affect soil properties and ultimately change rice yield. Thus, examining the effects of long-term green manure cultivation on the rice yield and the driving factors on rice yield, plays a crucial role in maintaining food security. Based on the long-term green manure cultivation, the treatments included no fertilizer (CK), chemical fertilizer (NPK), chemical fertilizer + Chinese milk vetch (NPK + GM), chemical fertilizer + Chinese milk vetch + rice straws (NPK + GM + S), and chemical fertilizer + Chinese milk vetch + pig manure (NPK + GM + M) treatments. One-way repeated ANOVA was used to determine the effects of diverse fertilizer modes on temporal variations in rice yields. The redundancy analysis (RDA) was used to calculate the magnitudes of the effects of soil properties on rice yield. Compared with the CK treatment, four fertilizer treatments led to significantly increased double-season rice yields (116.40−124.49%), with no significant difference between four fertilizer treatments (p> 0.05). There were five soil properties accounting for 66.3% variation in rice yield (p< 0.05), with available potassium (AK) being the most influential factor (32.2% variation), whereas potential of hydrogen (pH), total nitrogen (TN), total phosphorus (TP), and soil organic carbon (SOC) accounted for 15.3%, 10.5%, 5.1%, and 3.2% variation in rice yield (p< 0.05), respectively. Thus, SOC, TN, TP, AK, and pH were major factors affecting the double-season rice yield of red paddy soil under long-term green manure cultivation. However, the results suggested that the effect of green manure on soil fertility is limited by the relatively large amount of chemical fertilizer. The results reported herein can not only increase soil fertility and improve the soil ecological environment, but also enhance and stabilize the yields of double-season rice grown in the red paddy soil of southern China.
Assuntos
Esterco , Oryza , Agricultura , Animais , Carbono/análise , China , Fertilizantes/análise , Esterco/análise , Nitrogênio/análise , Oryza/química , Fósforo/análise , Solo/química , SuínosRESUMO
As a metabolic disease, gout, which seriously affects the normal life of patients, has become increasingly common in modern society. However, the existing medicines cannot completely meet the clinical needs. In the current study, a novel short peptide (named rice-derived-peptide-2 (RDP2), AAAAGAMPK-NH2, 785.97 Da) was isolated and identified from water extract of shelled Oryza sativa fruits, without toxic side effects but excellent stability. Our results indicated that RDP2 (the minimum effective concentration is 5 µg kg-1) induced a significant reduction in serum uric acid levels in hyperuricemic mice via suppressing xanthine oxidase activity and urate transporter 1 expression, as well as alleviated renal damage through inhibiting the activation of NLRP3 inflammasome. In addition, RDP2 can also alleviate paw swelling and inflammatory reactions in mice after subcutaneous injection of monosodium urate crystals. As mentioned above, we obtained a novel peptide which could work through all stages of gout, not only reducing uric acid levels and renal damage in hyperuricemic mice, but also alleviating inflammatory responses associated with acute gout attack, and thus provided a new peptide molecular template for the development of anti-gout drugs.
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Gota/tratamento farmacológico , Oryza/química , Peptídeos/farmacologia , Extratos Vegetais/farmacologia , Animais , Edema/tratamento farmacológico , Feminino , Hiperuricemia/tratamento farmacológico , Inflamassomos , Inflamação/tratamento farmacológico , Interleucina-1beta/sangue , Rim/patologia , Fígado/patologia , Masculino , Camundongos , Simulação de Acoplamento Molecular , Ácido ÚricoRESUMO
Gout and hyperuricemia can seriously affect the quality of life; at present, however, existing medicines are unable to meet all clinical needs. In the current study, a novel peptide (i.e., rice-derived-peptide-3 (RDP3), AAAAMAGPK-NH2, 785.97 Da) in water extract obtained from shelled Oryza sativa fruits was identified. Testing revealed that RDP3 (minimum effective concentration 100 µg/kg) did not show both hemolytic and acute toxicity, and reduced uric acid levels in the serum of hyperuricemic mice by inhibiting xanthine oxidase activity and decreasing urate transporter 1 expression. RDP3 also alleviated renal injury in hyperuricemic mice by decreasing NLRP3 inflammasome expression. Furthermore, RDP3 alleviated formalin-induced paw pain and reduced monosodium urate crystal-induced paw swelling and inflammatory factors in mice. Thus, this newly identified peptide reduced uric acid levels and renal damage in hyperuricemic mice and showed anti-inflammatory and analgesic activities, indicating the potential of RDP3 as an antigout medicine candidate.
Assuntos
Oryza/química , Peptídeos/química , Extratos Vegetais/química , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Edema/tratamento farmacológico , Edema/metabolismo , Gota/tratamento farmacológico , Gota/metabolismo , Supressores da Gota/administração & dosagem , Supressores da Gota/química , Supressores da Gota/isolamento & purificação , Humanos , Hiperuricemia/tratamento farmacológico , Hiperuricemia/metabolismo , Camundongos , Camundongos Nus , Peptídeos/administração & dosagem , Peptídeos/isolamento & purificação , Extratos Vegetais/administração & dosagem , Extratos Vegetais/isolamento & purificação , Ácido Úrico/metabolismo , Xantina Oxidase/metabolismoRESUMO
OBJECTIVES: To determine the feasibility of a personalized music intervention with mechanically ventilated patients in the PICU. DESIGN: Pilot study with a quasi-experimental design. SETTING: Tertiary children's hospital in China with a 40-bed PICU. PATIENTS: Children, 1 month to 7 years, with mechanical ventilation were recruited and assigned to music group (n = 25) and control group (n = 25). INTERVENTIONS: Children in the music group received their own favorite music and listened for 60 minutes three times a day. The control group receive routine care without music. MEASUREMENTS AND MAIN RESULTS: Primary outcome measure was comfort measured with the COMFORT Behavior scale 5 minutes before and after the music. Secondary outcome measures were physiologic variables; heart rate, respiration, blood pressure, oxygen saturation. Mechanical ventilation time, length of stay, and sedation medication were also collected. Qualitative analysis revealed that nurses had a positive attitude in delivering the interventions and identified improvements for the main trial. Children in the music group had lower COMFORT Behavior scores (15.7 vs 17.6; p = 0.011). Children in the music group had better physiologic outcomes; heart rate (140 vs 144; p = 0.039), respiration rate (40 vs 43; p = 0.036), systolic blood pressure (93 vs 95 mm Hg; p = 0.031), oxygen saturation (96% vs 95%; p < 0.001), diastolic blood pressure was not significantly (52 vs 53 mm Hg; p = 0.11). Children in the music group had a shorter ventilation time (148.7 vs 187.6; p = 0.044) and a shorter length of stay, but not significant (11.2 vs 13.8; p = 0.071). Children in the control group had higher total amount of on-demand midazolam (29 vs 33 mg; p = 0.040). CONCLUSIONS: Our pilot study indicates that personalized music intervention is feasible and might improve the comfort of children with mechanical ventilation. Further studies are needed to provide conclusive evidence in confirming the effectiveness of music interventions comforting critically ill children in PICUs.
Assuntos
Estado Terminal/terapia , Unidades de Terapia Intensiva Pediátrica , Musicoterapia/métodos , Respiração Artificial/métodos , Escala de Avaliação Comportamental , Pressão Sanguínea , Criança , Pré-Escolar , China , Feminino , Frequência Cardíaca , Humanos , Hipnóticos e Sedativos/uso terapêutico , Lactente , Tempo de Internação , Masculino , Midazolam/uso terapêutico , Música , Conforto do Paciente/métodos , Projetos Piloto , Taxa Respiratória , Fatores de TempoRESUMO
Recent studies have shown that hyperbaric oxygen (HBO) has a therapeutic effect on vascular dementia (VD); however, the exact mechanism remains unclear. This article aims to reveal the protective effects and underlying mechanisms of HBO on VD. A total of 158 patients with VD were prospectively included in the study and were randomly divided into control group and HBO group. The control group was given conventional treatment and the HBO group was treated with HBO in addition to conventional treatment. The following HBO protocol was practiced: 5 days per week, 60 min each, 100% oxygen at 2 standard atmospheric pressures for 12 weeks. The Mini-Mental State Examination (MMSE) scores and serum Humanin levels were detected before and after treatments in both groups. The baseline characteristics were not different dramatically between groups (p > 0.05). There was no significant difference in MMSE scores and serum Humanin levels between the two groups before treatment (p > 0.05). After treatment, compared with the control group, the MMSE scores and serum Humanin levels in the HBO group were significantly increased (p < 0.05). Spearman correlation analysis showed that the serum Humanin levels were positively correlated with MMSE scores (r = 0.409, p < 0.05) and this correlation was independent of baseline characteristics (ß = 0.312, p < 0.05). HBO therapy can improve cognitive function in patients with VD, and its mechanism may be related to elevated serum Humanin levels.
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Cognição , Demência Vascular/fisiopatologia , Demência Vascular/terapia , Oxigenoterapia Hiperbárica , Substâncias Protetoras/uso terapêutico , Idoso , Demência Vascular/sangue , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/sangue , Modelos Logísticos , Masculino , Estatísticas não ParamétricasRESUMO
Ubiquitous cadmium (Cd) contamination in mine impacted paddy soil has been jeopardizing regional rice quality, which represents a dominant pathway of Cd exposure in populations depending on a rice diet. Two major aspects of mitigation, soil liming and Si fertilization, were integrated and investigated with a Ca-Si-rich composite mineral (CS) derived from feldspar and carbonate. With the CS amendment, bioavailable Cd in rice rhizosphere was reduced by 92-100% from tillering to maturation stage, paralleled by a marked increase in Cd bound to Fe/Mn oxides and carbonate. As indicated by XRD analysis, the much reduced labile pool of Cd in the CS-amended soil could be mainly attributed to Cd (co)precipitation (Cd(OH)2, Cd2(OH)3Cl, CH6Br3CdN) and surface complexation on more negatively charged oxides at elevated soil pH with CS addition. EDX line scan illustrated much more intensified Si deposition along root cross-section in the CS treatment, which resulted in 1.5-2.1-fold higher Cd sequestration in the CS-amended root than control. As a direct result, the root-to-shoots Cd translocation was reduced significantly by 42-51%, while a slightly less significant decrease in brown rice Cd was obtained with the CS treatment relative to control. The CS amendment showed differing effects on brown rice mineral accumulation, with 1.2-1.5-fold increase in brown rice Zn and simultaneously reduced Fe, Mn, Mg and Cu in brown rice. Our results call the readers' attention to the potential impact of soil ameliorator on grain mineral uptake, and we suggest that proper fortification with mineral fertilizers should be supplemented to assist sustainable rice production with improved mineral nutrition.
Assuntos
Oryza , Poluentes do Solo , Disponibilidade Biológica , Cádmio , Minerais , SoloRESUMO
Background: The research evaluated the impact of intravenous antimicrobial restriction strategy (IARS) on different types of hospitals in China for evidence-based management, for outpatients implemented in 2016. Methods: Based on panel data on antimicrobial use in 121 tertiary hospitals in Zhejiang, China, segmented regression analysis was used to evaluate the impact of IARS in children's hospitals (CHs), obstetrics and gynecology hospitals (OGHs), women's and children's hospitals (WCHs), traditional Chinese medicine hospitals (TCMHs) and general hospitals (GHs). Antimicrobial use was measured using the percentage of total encounters with prescribing and the percentage of total drug expenditure relating to antimicrobials (APP and AEP). Results: There was a downward baseline slope of APP in all types of hospitals and AEP in WCHs, TCMHs and GHs (P < 0.01). After IARS, a level reduction in AEP in CHs (-3.14%, 95% CI = -6.21 to 0.06), WCHs (-1.33%, 95% CI = -2.44 to 0.22) and TCMHs (-0.85%, 95%CI = -1.51 to 0.18). After IARS, the slope of AEP changed significantly in OGHs (-0.42%, 95%CI = -0.81 to 0.03) and WCHs (0.29%, 95% CI = 0.08 to 0.49), and the slope of APP changed significantly in CHs (2.35%, 95%CI = 1.20 to 3.49). Conclusions: IARS had the mixed effects including positive effect in AEP and no significant change in APP, and an unexpected rise in APP in CHs needs further study.
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Anti-Infecciosos/administração & dosagem , Gestão de Antimicrobianos/organização & administração , Padrões de Prática Médica/estatística & dados numéricos , Administração Intravenosa , Anti-Infecciosos/economia , Gestão de Antimicrobianos/economia , China , Medicina Baseada em Evidências , Gastos em Saúde/estatística & dados numéricos , Humanos , Ambulatório Hospitalar/economia , Ambulatório Hospitalar/estatística & dados numéricos , Padrões de Prática Médica/normas , Análise de Regressão , Centros de Atenção Terciária/economia , Centros de Atenção Terciária/estatística & dados numéricosRESUMO
Although the spatial mapping and fertility assessment of soil chemical properties (SCPs) are well studied in the Loess Plateau region of China at farmland scale, little is known about spatial mapping the SCPs and their fertility and their influence factors at urban forest scale. The objectives of this study were to (1) compare the performance of two spatial interpolation methods, Ordinary kriging (OK) and regression kriging (RK), and (2) explain the relationships of the vegetation, terrain, and soil layer depth between the eight SCPs and their fertility, and (3) find the limiting factors of soil comprehensive fertility in this study area? The Yan'an urban forest was taken as study case, used hybrid spatial interpolation methods based on OK and RK to mapping eight SCPs and the soil fertility in each soil layer (0-20 cm, 20-40 cm, and 40-60 cm) for 285 soil samples. The results indicated that RK outperformed OK for total nitrogen (TN), available potassium (AK), organic matter (OM) in 0-60 cm profile and available phosphorus (AP) in the 0-20 cm and 40-60 cm soil layers because RK considered the impact of terrain. The terrain factors, comprising the relative terrain position, slope, aspect, and relative elevation significantly affected the SCPs and spatial heterogeneity of fertility, where the vegetation cover types determined the average SCPs to some extent. On average, the six SCPs (except total potassium and AP) and the fertility decreased as the soil layer depth increased. Ten vegetation cover types comprising broadleaved mixed natural forest (BM), cultivated land (CL), economic forest (EF), grassland (GL), Platycladus orientalis natural forest (PON), Platycladus orientalis plantation (POP), Pinus tabuliformis plantation (PT), Quercus wutaishanica natural forest (QW), Robinia pseudoacacia plantation (RP), and Shrubwood (SW) were associated with significant differences in TN, OM, AN, AP, and AK, across the three soil layers. QW, PON, and BM also had higher content of TN, OM, AN, and AK contents than the other vegetation cover types. There were small differences in TK, AK, and pH among the 10 vegetation cover types. We concluded that AN, TN, and OM are the limiting factors of soil comprehensive fertility in this region. These results improve understanding of the spatial mapping, influence and limiting factors of SCPs and their fertility at urban forest scales.
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Agricultura , Florestas , Pradaria , Solo/química , Carbono/análise , China , Cupressaceae/fisiologia , Fertilidade , Nitrogênio/análise , Fósforo/análise , Pinus/fisiologia , Potássio/análise , Quercus/fisiologia , Robinia/fisiologia , Análise EspacialRESUMO
OBJECTIVE: To investigate the effect of Qiguiyishen decoction (QGYS) on the severity of nephropathy. METHODS: Twenty-four rats were randomly divided into four groups (I, II, III, IV) according to the random number table. Group I as control group did not establish nephropathy model. Groups II, III, and IV were intravenously administered Adriamycin (7.5 mg/kg) through the tail vein to establish nephropathy model. QGYS was prepared with the extracts of Huangqi (Radix Astragali Mongolici), Danggui (Radix Angelicae Sinensis), Niuxi (Radix Achyranthis Bidentatae), and Chuanxiong (Rhizoma Chuanxiong). Group IV was administered QGYS (2 mL x kg(-1) x d(-1)), group III was administered benazepril (10 mL x kg(-1) x d(-1)), and group I, II was administered water (2 mL x kg(-1) x d(-1)) once daily for eight weeks. RESULTS: QGYS reduced the excretion of urinary protein and N-acetyl-beta-D-glucosaminidase and alleviated the accumulation of extracellular matrix (ECM) in renal tissue. Additionally, QGYS effectively regulated the levels of transforming growth factor, tissue inhibitor of matrix metalloproteinase, and matrix metalloproteinases in the kidney of the rats. CONCLUSION: QGYS may reduce the accumulation of ECM in the kidneys of rats with Adriamycin-induced nephropathy.
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Doxorrubicina/efeitos adversos , Medicamentos de Ervas Chinesas/administração & dosagem , Matriz Extracelular/metabolismo , Nefropatias/tratamento farmacológico , Animais , Regulação para Baixo/efeitos dos fármacos , Matriz Extracelular/enzimologia , Humanos , Rim/efeitos dos fármacos , Rim/enzimologia , Rim/metabolismo , Nefropatias/induzido quimicamente , Nefropatias/metabolismo , Masculino , Metaloproteases/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
Evidence-based medicine is advocated by WHO and adopted by developed countries for many years. In China, however, the selection of essential medicine and various medical insurance reimbursement schemes medicine is usually based on experts' experience of prescription practice which is under heavy critics resulting from the lack of related comparative efficacy and evidence-based research. The efficacy of Jian'ganle in prevention of drug-induced liver injury (DILI) caused by antituberculotics was evaluated in this study by comparison with Hugan Pian, glucuronolactone and reduced glutathione. Evidence was provided for relevant sectors such as Ministry for Human Resources and Social Security of the People's Republic of China and National Health and Family Planning Commission of the People's Republic of China to select and renew the Essential Medicine List (EML), the new rural cooperative medical scheme in China (NRCMS) list or the reimbursement list of industrial injury insurance. A total of 189 patients with initial pulmonary tuberculosis were divided into four groups who took antituberculotics combined with Jian'ganle, Hugan Pian, glucuronolactone and reduced glutathione respectively. Their liver function profile including alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), direct bilirubin (DBIL), total protein (TP), albumin (A) and globulin (G) were detected at admission as baseline and after treatment. The Jian'ganle group was compared with the three others by chi-square tests. In an aspect of maintaining bilirubin indexes normal, Jian'ganle was more efficacious than glucuronolactone. And Jian'ganle had a little more efficacy than reduced glutathione to maintain protein indexes normal as well. And the therapeutic regimen of antituberculotics combined with Jian'ganle was the best in treating tuberculosis and preventing DILI at the same time. The study showed that among the four hepatinicas which demonstrated similar prevention of DILI caused by antituberculotics, Jian'ganle has more advantages over the three others to some extent, which provides a reliable basis for health sectors to select and renew the EML, NRCMS List or the reimbursement list of industrial injury insurance.
Assuntos
Antituberculosos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Glucuronatos/uso terapêutico , Glutationa/uso terapêutico , Medicina Tradicional Chinesa , Tuberculose Pulmonar/tratamento farmacológico , Adulto , Alanina Transaminase/metabolismo , Antituberculosos/uso terapêutico , Povo Asiático/estatística & dados numéricos , Aspartato Aminotransferases/metabolismo , Bilirrubina , Doença Hepática Induzida por Substâncias e Drogas/etiologia , China , Medicina Baseada em Evidências/estatística & dados numéricos , Feminino , Humanos , Fígado/efeitos dos fármacos , Fígado/patologia , Fígado/fisiopatologia , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Tuberculose Pulmonar/etnologiaRESUMO
RATIONALE, AIMS AND OBJECTIVES: The Ministry of Health in China has enacted a revised National Tuberculosis Control Program (NTP) guidelines and clinical pathway (CP) on new smear-positive pulmonary tuberculosis (TB) inpatients to improve the quality of TB care and asked doctors' compliance to them on the treatment of TB inpatients. However, it remains unknown whether doctors adhere to them well. So this study focuses on evaluating the doctors' compliance with them in one representative TB hospital for medical quality improvement. METHODS: A hospital-based retrospective study involving all medical records of newly diagnosed smear-positive pulmonary TB inpatients from July 2011 to July 2013. Analysis indicators including adequate drug regimens rate, adequate drug dosages rate and adequate length of hospital stay rate were chosen to assess doctors' compliance with NTP guidelines and CP on the treatment of new smear-positive pulmonary TB inpatients. The optimal value of these indicators is 100%. RESULTS: Of the 334 inpatients selected, the rate of adequate drug regimens prescribed is 26.95% (90/334), and the rate of adequate drug dosages is 0% (0/90). For the dosage of single drug, the rates of adequate dosage of isoniazid, rifampicin, pyrazinamide and ethambutol are 24.44% (22/90), 85.56% (77/90), 70% (63/90) and 13.33% (12/90). Moreover, 75.56% (68/90) of isoniazid was prescribed too high and 83.34% (75/90) of ethambutol was prescribed too low. The rate of adequate length of hospital stay provided is 28.44% (95/334). CONCLUSION: Doctors' compliance with NTP guidelines and CP on new smear-positive pulmonary TB inpatients is depressed and needs improvement.
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Antituberculosos/administração & dosagem , Fidelidade a Diretrizes , Guias de Prática Clínica como Assunto , Padrões de Prática Médica , Tuberculose Pulmonar/tratamento farmacológico , China , Procedimentos Clínicos/normas , Hospitalização , Humanos , Auditoria Médica , Estudos RetrospectivosRESUMO
OBJECTIVE: To evaluate mechanical properties of zirconia toughened composite alumina (ZTCA) ceramic used for dental application, characterize the effect of different zirconia contents on mechanical properties of ZTCA. METHODS: Dental alumina ceramic powder was prepared by sol-gel method, and four groups of ZTCA powders with different zirconia contents were prepared via surface-induced precipitation method. All five groups of powders were dry-pressed and then sintered to make standard specimens for mechanical tests. The flexural strength and fracture toughness of these specimens were evaluated, and the fractography was characterized by scanning electronic microscope (SEM). Phases of ZTCA were also determined using X-ray diffraction (XRD). RESULTS: It was found that the flexural strength of ZTCA ceramics increases with ZrO2 content up to 30%, and decreases thereafter. ZTCA specimens containing 30% ZrO2 show the highest flexural strength, and the corresponding fracture toughness was 1.85 MPa x m(1/2). The XRD results of ZTCA ceramics showed the phase constituents of alpha-Al2O3, t-ZrO2 and a small amount of m-ZrO2. CONCLUSION: The strengthening and toughening mechanisms of ZTCA depend on ZrO2 content. In the range of 15%-30% ZrO2, the stress-induced phase transformation toughening mechanism is dominant, while microcrack and deflection exist as the additional toughening mechanism when ZrO2 addition amount is above 30%.
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Óxido de Alumínio , Cerâmica , Porcelana Dentária , Teste de Materiais , ZircônioRESUMO
As dominant regulators of osteoclastogenesis and bone resorption, receptor activator of NFkappaB (RANK), receptor activator of NFkappaB ligand, and OPG have been identified as ideal drug targets for the treatment of metabolic bone disease. One concern regarding the therapeutic use of RANK signaling inhibitors is their effect on fracture healing. Therefore we tested if uncoupling and osteoclast depletion via RANK blockade affects callus formation, maturation and matrix remodeling, as well as union rates in a mouse tibia fracture model. Low dose (1 mg/kg i.p.) RANK:Fc therapy had no effect on callus formation, matrix maturation and remodeling, and resulted in 100% bony union by day 28. High dose RANK:Fc treatment (10 mg/kg i.p.) effectively eliminated osteoclasts at the fracture site on day 14, with no significant effects on fracture healing. When therapy was discontinued, normal numbers of osteoclasts were observed at the fracture site by day 28. However, continuous therapy resulted in a large osteopetrotic callus consisting of both mineralized and unmineralized matrix that was void of osteoclasts, but bony union was unaffected at day 28. We also evaluated this process in the complete absence of RANK signaling using RANK -/- mice. These animals exhibited significant radiographic and histologic evidence of callus formation, indicating that RANK signaling is not required for fracture callus formation. However, only 33% of RANK -/- animals formed bony unions compared to 100% of the osteopetrotic control mice. This defect was most likely a result of decreased blood flow, as evidenced by fewer blood vessels in the RANK -/- animals. Together, these data imply that osteoclast depletion via inhibition of RANK signaling is a viable option for the treatment of pathological bone loss since no adverse effects on fracture healing are observed when therapy is discontinued.