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Introduction: Both immigrant and racialized status may be associated with the pursuit of living donor kidney transplant (LDKT). Methods: This study was a secondary analysis of a convenience cross-sectional sample of patients with kidney failure in Toronto, obtained from our "Comprehensive Psychosocial Research Data System" research database. The exposures included racialized, immigrant, and combined immigrant and racialized status (White nonimmigrant, racialized nonimmigrant, White immigrant and racialized immigrant). Outcomes include the following: (i) having spoken about LDKT with others, (ii) having a potential living donor (LD) identified, (iii) having allowed others to share the need for LDKT, (iv) having directly asked a potential donor to be tested, and (v) accept a hypothetical LDKT offer. We assessed the association between exposure and outcomes using univariable, and multivariable binary or multinominal logistic regression (reference: White or White nonimmigrant participants). Results: Of the 498 participants, 281 (56%) were immigrants; 142 (28%) were African, Caribbean, and Black (ACB); 123 (25%) were Asian; and 233 (47%) were White. Compared to White nonimmigrants, racialized immigrants (relative risk ratio [RRR]: 2.98; 95% confidence interval [CI]: 1.76-5.03) and racialized nonimmigrants (RRR: 2.84; 95% CI: 1.22-6.65) were more likely not to have spoken about LDKT with others (vs. having spoken or planning to do so). Both racialized immigrant (odds ratio [OR]: 4.07; 95% CI: 2.50-6.34), racialized nonimmigrants (OR: 2.68; 95% CI: 1.31-5.51) and White immigrants (OR: 2.68; 95% CI: 1.43-5.05) were more likely not to have a potential LD identified. Conclusion: Both racialized and immigrant status are associated with less readiness to pursue LDKT. Supporting patients to communicate their need for LDKT may improve equitable access to LDKT.
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RATIONALE & OBJECTIVE: Patients with advanced chronic kidney disease (CKD) have been reported to experience profound psychosocial distress. Other work has established that patients with CKD from marginalized populations (including individuals who on the basis of race often face racism and related discrimination, termed "racialization") experience health care inequities. Given limited information on the intersection of these 2 phenomena, we assessed the association of psychosocial distress with racialized status and immigrant status in Canadians with advanced CKD. STUDY DESIGN: Secondary analysis of cross-sectional data. SETTING & PARTICIPANTS: 536 patients with advanced CKD (estimated glomerular filtration rate<30mL/min/1.73m2, with or without kidney replacement therapy) from multiple clinical centers in Toronto. EXPOSURE: Racialized status (individuals who identify as Asian or as African, Caribbean, or Black Canadian), immigrant status, and combined immigrant-racialized status. OUTCOME: Psychosocial distress, defined as the presence of depression, anxiety, or social difficulties (ie, a score of≥10 points on the Patient Health Questionnaire 9, Generalized Anxiety Disorder 7, or Social Distress 16 scales, respectively). ANALYTICAL APPROACH: The independent associations of racialized status and immigrant status with psychosocial distress, depression, anxiety, and social difficulties were examined using univariable- and multivariable-adjusted logistic regression. RESULTS: Mean age of the 536 participants was 57±16 (SD) years, 62% were male, and 45% were immigrants. Of the sample, 58% were White, 22% were African, Caribbean, or Black Canadian, and 20% were Asian. Psychosocial distress was present in 36% of participants (depression in 19%, anxiety in 12%, and social difficulties in 31%). To assess the combined impact of racialized and immigrant status, we created a variable with mutually exclusive categories: White nonimmigrant, racialized nonimmigrant, White immigrant, and racialized immigrant participants. In our final multivariable-adjusted model, compared with White nonimmigrant participants, racialized immigrant participants were more likely to have psychosocial distress (OR, 2.96 [95% CI, 1.81-4.81]), depression (OR, 1.87 [95% CI, 1.05-3.34]), and social difficulties (OR, 3.36 [95% CI, 2.03-5.57]). Overall similar associations were seen for racialized nonimmigrants and for White immigrants. LIMITATIONS: Convenience sample; small subgroups; combined exposure variable grouping Asian and African, Caribbean, and Black participants together; lack of data about mechanisms. CONCLUSIONS: Both racialized and immigrant status based on self-report of demographic characteristics were associated with psychosocial distress among patients with advanced CKD. These patients may benefit from culturally competent psychosocial support. PLAIN-LANGUAGE SUMMARY: Psychosocial distress is frequent in patients with advanced chronic kidney disease and impacts quality of life and clinical outcomes. Psychosocial distress may be especially scarring in people who are racialized (marginalized on account of their membership in a particular racial group) and/or who are immigrants. We assessed the association of psychosocial distress with racialized and immigrant status in Canadians with advanced chronic kidney disease. Among 536 participants from multiple medical centers in Toronto, we found that racialized and immigrant participants were more likely to have psychosocial distress, depression, and social difficulties compared with White nonimmigrant participants. This is likely related to the multiple intersectional challenges, including experience with racism and discrimination that racialized immigrant patients may face. Further studies are needed to elucidate the specific factors that contribute to more distress. The potential impact of culturally competent and safe support for these patients will also need to be studied.
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Emigrantes e Imigrantes , Insuficiência Renal Crônica , Humanos , Masculino , Adulto , Pessoa de Meia-Idade , Idoso , Feminino , Canadá/epidemiologia , Estudos Transversais , Qualidade de Vida , Grupos Raciais , Insuficiência Renal Crônica/psicologiaRESUMO
BACKGROUND: The hepatopulmonary syndrome (HPS) is a pulmonary complication of liver disease found in 10 to 32% of patients with cirrhosis and is characterized by intrapulmonary vascular dilatations and abnormal oxygenation. Liver transplantation is the only effective therapy for this disease. Patients with HPS have significant exercise limitations, impacting their quality of life and associated with poor liver transplant outcomes. Many patients with HPS exhibit orthodeoxia-an improvement in oxygenation in the supine compared to the upright position. We hypothesize that exercise capacity will be superior in the supine compared to the upright position in such patients. METHODS: We propose a randomized controlled crossover trial in patients with moderate HPS (PaO2 < 80 mmHg) and orthodeoxia (supine to upright PaO2 decrease > 4 mmHg) comparing the effect of supine vs upright position on exercise. Patients with pulmonary hypertension, FEV1/FVC ratio < 0.65, significant coronary artery disease, disorders preventing or contraindicating use of a cycle ergometer, and/or moderate or severe ascites will be excluded. Participants will be randomized to cycle ergometry in either the supine or upright position. After a short washout period (a minimum of 1 day to a maximum of 4 weeks), participants will crossover and perform an exercise in the alternate position. Exercise will be performed at a constant work rate of 70-85% of the predicted peak work rate until the "stopping time" is reached, defined by exhaustion, profound desaturation, or safety concerns (drop in systolic blood pressure or life-threatening arrhythmia). The primary outcome will be the difference in the stopping time between exercise positions, compared with a repeated measures analysis of variance method with a mixed effects model approach. The model will be adjusted for period effects. P < 0.05 will be considered statistically significant. DISCUSSION: HPS patients have hypoxemia leading to significant exercise limitations. If our study is positive, a supine exercise regimen could become a routine prescription for patients with HPS and orthodeoxia, enabling them to exercise more effectively. Future studies could explore the corresponding effects of a supine exercise training regimen on physiologic variables such as long-term exercise capacity, quality of life, dyspnea, and liver transplantation outcomes. TRIAL REGISTRATION: ClinicalTrials.gov Protocol Registration and Results System (PRS) NCT04004104 . Registered on 1 July 2019.
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Síndrome Hepatopulmonar , Estudos Cross-Over , Exercício Físico , Síndrome Hepatopulmonar/diagnóstico , Síndrome Hepatopulmonar/terapia , Humanos , Postura , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND: Sedative-hypnotic (SH) medications are often used to treat chronic insomnia, with potentially serious long-term side effects. The objective of this study is to evaluate an interprofessional SH deprescribing program within a community team-based, primary care practice, with or without cognitive behavioural therapy for insomnia (CBT-I). METHODS: Retrospective chart review for patients referred to the team pharmacist for SH deprescribing from February 2016 to June 2019. RESULTS: A total of 121 patients were referred for SH deprescribing, with 111 (92%) patients who attempted deprescribing (average age 69, range 29-97 years) and 22 patients who also received CBT-I. Overall, 36 patients (32%) achieved complete abstinence, and another 36 patients (32%) reduced their dosage by ≥50%. For the 36 patients who achieved complete abstinence, 26 (72%) patients remained abstinent at 6 months (9 patients resumed using SH and 1 patient was lost to follow-up). The proportion of patients achieving complete abstinence or reduced dosage of ≥50% (successful tapering) was higher with CBT-I than without CBT-I but did not reach statistical significance (77% vs 62%, p = 0.22). There were also no statistically significant differences detected in the success between those who took a benzodiazepine and those who took a Z-drug (67% vs 61%, p = 0.55) or for those who took SH daily and those who took them intermittently (67% vs 44%, p = 0.09). CONCLUSION: Almost two-thirds of patients participating in our pharmacist-led program were able to stop or taper their SH medications by ≥50%. The role of CBT-I in SH deprescribing remains to be further elucidated. Can Pharm J (Ott) 2021;154:xx-xx.
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OBJECTIVES: The ankle-brachial index is a noninvasive modality to evaluate atherosclerosis and is a predictive role for future cardiovascular events and mortality. However, few studies have evaluated its relation to long-term future ischemic stroke in hemodialysis patients. Therefore, we examined the relationship between ankle-brachial index and ischemic stroke events among hemodialysis patients in a seven-year follow-up. METHODS: A total of 84 patients were enrolled. Ankle-brachial index was assessed in January 2009. Primary outcomes included ischemic stroke. An ankle-brachial index < 0.9 was considered abnormal and 1.4 ≥ ankle-brachial index ≥ 0.9 to be normal ankle-brachial index. RESULTS: Mean values for ankle-brachial index were 0.98 ± 0.21at study entrance. In addition, 28 patients encountered ischemic stroke in the seven-year follow-up. In univariate Cox regression analysis, old age (hazard ratio (HR): 1.065, 95% confidence interval (CI): 1.030-1.102, p < 0.001), low seven-year averaged serum phosphate levels (HR: 0.473, 95% CI: 0.306-0.730, p = 0.001), and abnormal ankle-brachial index (HR: 0.035, 95% CI: 0.009-0.145, p < 0.001) were risk factors for ischemic stroke. In multivariate Cox regression analysis for significant variables in univariate analysis, abnormal ankle-brachial index (HR: 0.058, 95% CI: 0.012-0.279, p < 0.001) and low seven-year averaged serum phosphate levels (HR: 0.625, 95% CI: 0.404-0.968, p = 0.035) remained the risk factors for ischemic stroke. The risk of ischemic stroke was 3.783-fold in patients with abnormal ankle-brachial index compared with patients with normal ankle-brachial index (HR: 3.783, 95% CI: 1.731-8.269, p = 0.001). CONCLUSIONS: These findings suggest that ankle-brachial index is an impressive predictor of future ischemic stroke among hemodialysis patients.
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Índice Tornozelo-Braço , AVC Isquêmico/etiologia , Nefropatias/terapia , Doença Arterial Periférica/diagnóstico , Diálise Renal , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , AVC Isquêmico/diagnóstico , Nefropatias/complicações , Nefropatias/diagnóstico , Nefropatias/fisiopatologia , Masculino , Pessoa de Meia-Idade , Doença Arterial Periférica/complicações , Doença Arterial Periférica/fisiopatologia , Valor Preditivo dos Testes , Prognóstico , Diálise Renal/efeitos adversos , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de TempoRESUMO
Pharmacist-led medication reviews have been shown to improve medication management, reducing the adverse effects of polypharmacy among older adults. This paper quantitatively examines the medications, medication discrepancies and drug therapy problems of recipients in primary care. A convenience sample of 16 primary care team pharmacists in Ontario, Canada contributed data for patients with whom they conducted a medication review over a prior four-week period. Data were uploaded using electronic data capture forms and descriptive analyses were completed. Two hundred and thirty-seven patients (on average, 67.9 years old) were included in the study, taking an average of 9.2 prescription medications ( ± 4.7). Majority of these patients (83.5%) were categorized as polypharmacy patients taking at least five or more prescribed drugs per day. Just over half of the patients were classified as having a low level of medication complexity (52.3%). Pharmacists identified 2.1 medication discrepancies ( ± 3.9) and 3.6 drug therapy problems per patient ( ± 2.8). Half these patients had more than one medication discrepancy and almost every patient had a drug therapy problem identified. Medication reviews conducted by pharmacists in primary care teams minimized medication discrepancies and addressed drug therapy problems to improve medication management and reduce adverse events that may result from polypharmacy.
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BACKGROUND: Inorganic polyphosphate (polyP) is a fundamental and ubiquitous molecule in prokaryotes and eukaryotes. PolyP has been found in mammalian tissues with particularly high levels of long-chain polyP in bone and cartilage where critical questions remain as to its localization and function. Here, we investigated polyP presence and function in osteoblast-like SaOS-2 cells and cell-derived matrix vesicles (MVs), the initial sites of bone mineral formation. METHODS: PolyP was quantified by 4',6-diamidino-2-phenylindole (DAPI) fluorescence and characterized by enzymatic methods coupled to urea polyacrylamide gel electrophoresis. Transmission electron microscopy and confocal microscopy were used to investigate polyP localization. A chicken embryo cartilage model was used to investigate the effect of polyP on mineralization. RESULTS: PolyP increased in concentration as SaOS-2 cells matured and mineralized. Particularly high levels of polyP were observed in MVs. The average length of MV polyP was determined to be longer than 196 Pi residues by gel chromatography. Electron micrographs of MVs, stained by two polyP-specific staining approaches, revealed polyP localization in the vicinity of the MV membrane. Additional extracellular polyP binds to MVs and inhibits MV-induced hydroxyapatite formation. CONCLUSION: PolyP is highly enriched in matrix vesicles and can inhibit apatite formation. PolyP may be hydrolysed to phosphate for further mineralization in the extracellular matrix. GENERAL SIGNIFICANCE: PolyP is a unique yet underappreciated macromolecule which plays a critical role in extracellular mineralization in matrix vesicles.
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Durapatita/química , Osteoblastos/metabolismo , Polifosfatos/química , Fosfatase Alcalina/metabolismo , Animais , Osso e Ossos/metabolismo , Calcificação Fisiológica , Cálcio/química , Cartilagem/metabolismo , Linhagem Celular Tumoral , Embrião de Galinha , Matriz Extracelular/metabolismo , Humanos , Hidrólise , Indóis/química , Luz , Microscopia Confocal , Microscopia Eletrônica de Transmissão , Osteogênese , Espalhamento de Radiação , Fosfolipases Tipo C/químicaRESUMO
Polyphosphate (polyP) is abundant in bone but its roles in signaling and control of gene expression remain unclear. Here, we investigate the effect of extracellular polyP on proliferation, migration, apoptosis, gene and protein expression in human osteoblast-like SaOS-2 cells. Extracellular polyP promoted SaOS-2 cell proliferation, increased rates of migration, inhibited apoptosis and stimulated the rapid phosphorylation of extracellular-signal-regulated kinase (ERK) directly through basic fibroblast growth factor receptor (bFGFR). cDNA microarray revealed that polyP induced significant upregulation of interleukin 11 (IL-11) at both RNA and protein levels.
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Interleucina-11/genética , Interleucina-11/metabolismo , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Polifosfatos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Análise de Sequência com Séries de Oligonucleotídeos , Osteoblastos/citologia , Fosforilação , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Regulação para Cima/efeitos dos fármacosRESUMO
BACKGROUND & AIMS: Largazole is a novel histone deacetylase (HDAC) inhibitor. This study investigated the effects of largazole against liver fibrosis. METHODS: The in vitro effects of largazole were examined using hepatic stellate cells (HSCs). In vivo effects of largazole were studied using a mouse liver fibrotic model induced by CCl4 . RESULTS: Largazole augmented acetylation of histone H3 (H3) and histone H4 (H4) in HSCs. It directly inhibited the activation of HSCs owing to HDAC inhibitory activity as the antifibrotic effect of largazole was significantly decreased in cells with HDAC1, HDAC2 and HDAC3 knockdown. Largazole also induced apoptosis of HSCs. Largazole not only inhibited the expression of TGFßR2, but also reduced phosphorylation of Smad2 and Akt induced by TGF-ß1. Largazole also inhibited the expression of vascular endothelial growth factor (VEGF) and its receptor. VEGF-induced proliferation of HSCs and activation of Akt and p38MAPK were also suppressed by largazole. In vivo, largazole reduced the expression of collagen I, α-smooth muscle actin and tissue inhibitor of metalloproteinase-1 in CCl4 -induced fibrosis, and these antifibrotic effects were associated with increased acetylation of H3 and H4. Largazole also induced HSCs to undergo apoptosis in vivo, which was correlated with downregulation of bcl-2 and bcl-xL. Furthermore, largazole inhibited angiogenesis in vivo as evidenced by reduced expression of CD34, VEGF and VEGFR. In addition to its antifibrotic activity, the drug reduced inflammatory activity in CCl4 -induced liver fibrosis. CONCLUSIONS: Our findings revealed a novel role of largazole in the treatment of liver fibrosis. Through multiple mechanisms, largazole could be a potentially effective antifibrotic agent.
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Inibidores da Angiogênese/farmacologia , Depsipeptídeos/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Cirrose Hepática Experimental/prevenção & controle , Fígado/efeitos dos fármacos , Neovascularização Fisiológica/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Tiazóis/farmacologia , Fator de Crescimento Transformador beta/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Acetilação , Animais , Apoptose/efeitos dos fármacos , Tetracloreto de Carbono , Linhagem Celular , Relação Dose-Resposta a Droga , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/enzimologia , Células Estreladas do Fígado/patologia , Histona Desacetilases/genética , Histonas/metabolismo , Humanos , Fígado/irrigação sanguínea , Fígado/enzimologia , Fígado/patologia , Cirrose Hepática Experimental/induzido quimicamente , Cirrose Hepática Experimental/enzimologia , Cirrose Hepática Experimental/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Interferência de RNA , Ratos , Fatores de Tempo , TransfecçãoRESUMO
Notch signaling, a critical pathway for tissue development, also contributes to tumorigenesis in many cancers, but its pathological function in liver cancer is not well defined. In our study, Notch1 expression and its clinicopathological parameters were evaluated in 82 human hepatocellular carcinoma (HCC) patients. Plasmid-based siNotch1 shRNA was transiently or stably transfected into metastatic HCC cells and subsequently evaluated for the effects on orthotopic liver tumor metastasis in a mouse model as well as the effects on downstream pathways. Aberrant high expression of Notch1 was significantly associated with metastatic disease parameters in HCC patients, such as tumor-node-metastasis Stages III-IV and tumor venous invasion. Knocking-down Notch1 reduced cell motility in vitro and orthotopic tumor metastasis from the liver to the lung in vivo in a mouse model. In metastatic HCC cells, abnormal expression of Notch1 was associated with increased expression of Snail1 and repressed expression of E-cadherin; the Notch1-Snail1-E-cadherin association can also be found in HCC patient tumors. Inhibition of Notch1 by shRNA abolished Snail1 expression, which further resulted in the re-establishment of repressed E-cadherin in metastatic HCC cells. Thus, abnormal Notch1 expression was strongly associated with HCC metastatic disease, which might be mediated through the Notch1-Snail1-E-cadherin pathway. Knock-down of Notch1 reversed HCC tumor metastasis in a mouse model. Therefore, these data suggest that effective targeting of Notch signaling might also inhibit tumor metastasis.
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Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/secundário , Neoplasias Hepáticas/metabolismo , Receptor Notch1/metabolismo , Fatores de Transcrição/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Caderinas/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Transição Epitelial-Mesenquimal , Feminino , Humanos , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Metástase Neoplásica , Transplante de Neoplasias , Interferência de RNA , RNA Interferente Pequeno , Receptor Notch1/genética , Transdução de Sinais , Fatores de Transcrição da Família SnailRESUMO
The field of plasmonics has emerged as an interesting area for fundamental studies, with important application possibilities in miniaturized photonic components. Plasmonic crystals are of particular relevance because of large field enhancements and extraordinary transmission that arise from plasmonic interactions between periodic arrays of metallic elements. Here we report methods to enhance and modify the plasmonic resonances in such structures by strongly coupling them to optical modes of Fabry-Perot type cavities. First, we illustrate a type of plasmonic, narrow-band (~15 nm), high-contrast (>20 dB) absorber and an opto-fluidic modulator based on this component. Second, we use optimized samples as substrates to achieve strong amplification (>350%) and modulation (>4×) of surface-enhanced Raman scattering from surface-bound monolayers. Cavity-coupling strategies appear to be useful not only in these two examples, but also in applications of plasmonics for optoelectronics, photovoltaics and related technologies.
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Inorganic polyphosphate (polyP) plays a number of critical roles in bacterial persistence, stress, and virulence. PolyP intracellular metabolism is regulated by the polyphosphate kinase (PPK) protein families, and inhibition of PPK activity is a potential approach to disrupting polyP-dependent processes in pathogenic organisms. Here, we biochemically characterized Mycobacterium tuberculosis (MTB) PPK2 and developed DNA-based aptamers that inhibit the enzyme's catalytic activities. MTB PPK2 catalyzed polyP-dependent phosphorylation of ADP to ATP at a rate 838 times higher than the rate of polyP synthesis. Gel filtration chromatography suggested MTB PPK2 to be an octamer. DNA aptamers were isolated against MTB PPK2. Circular dichroism revealed that aptamers grouped into two distinct classes of secondary structure; G-quadruplex and non-G-quadruplex. A selected G-quadruplex aptamer was highly selective for binding to MTB PPK2 with a dissociation constant of 870 nM as determined by isothermal titration calorimetry. The binding between MTB PPK2 and the aptamer was exothermic yet primarily driven by entropy. This G-quadruplex aptamer inhibited MTB PPK2 with an IC(50) of 40 nM and exhibited noncompetitive inhibition kinetics. Mutational mechanistic analysis revealed an aptamer G-quadruplex motif is critical for enzyme inhibition. The aptamer was also tested against Vibrio cholerae PPK2, where it showed an IC(50) of 105 nM and insignificant inhibition against more distantly related Laribacter hongkongensis PPK2.
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Aptâmeros de Nucleotídeos/farmacologia , Inibidores Enzimáticos/farmacologia , Mycobacterium tuberculosis/enzimologia , Fosfotransferases (Aceptor do Grupo Fosfato)/antagonistas & inibidores , Aptâmeros de Nucleotídeos/química , Aptâmeros de Nucleotídeos/genética , Aptâmeros de Nucleotídeos/metabolismo , Sequência de Bases , Clonagem Molecular , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Quadruplex G , Cinética , Modelos Moleculares , Mutação , Fosfotransferases (Aceptor do Grupo Fosfato)/química , Fosfotransferases (Aceptor do Grupo Fosfato)/genética , Fosfotransferases (Aceptor do Grupo Fosfato)/metabolismo , Conformação Proteica , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismoRESUMO
BACKGROUND & AIMS: Nilotinib is a novel tyrosine kinase inhibitor of Bcr-Abl and other kinases. In this study, we have examined its activity as an anti-fibrotic agent. METHODS: The in vitro effect of Nilotinib on rat and human HSCs was assessed using proliferation assays and Western blotting. The in vivo antifibrotic efficacy of Nilotinib was assessed in mice with liver fibrosis induced by CCl(4) and bile duct ligation (BDL). RESULTS: Nilotinib inhibited proliferation, migration, and actin filament formation, as well as the expression of α-SMA and collagen in activated HSCs. Nilotinib induced apoptosis of HSCs, which was correlated with reduced bcl-2 expression, increased p53 expression, cleavage of PARP, as well as increased expression of PPARγ and TRAIL-R. Nilotinib also induced cell cycle arrest, accompanied by increased expression of p27 and downregulation of cyclin D1. Interestingly, Nilotinib not only inhibited activation of PDGFR, but also TGFRII through Src. Nilotinib significantly inhibited PDGF and TGFß-simulated phosphorylation of ERK and Akt. Furthermore, PDGF- and TGFß-activated phosphorylated form(s) of Abl in human HSCs were inhibited by Nilotinib. In vivo, Nilotinib reduced collagen deposition and α-SMA expression in CCl(4) and BDL-induced fibrosis. These beneficial effects were associated with suppressed expression of procollagen-(I), TIMP-1, CD31, CD34, VEGF, and VEGFR. Nilotinib could induce HSC undergoing apoptosis in vivo, which was correlated with downregulation of bcl-2. We also observed reduced expression of phosphorylated ERK, Akt, and Abl in the Nilotinib-treated CCl(4) and BDL livers. In addition to its antifibrotic activity, the drug was hepatoprotective and reduced the elevations of ALT and AST after CCl(4) and BDL. CONCLUSIONS: These studies uncover a novel role of Bcr-Abl activity in treatment of liver fibrosis through multiple mechanisms and indicate that Nilotinib represents a potentially effective antifibrotic agent.
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Genes abl/efeitos dos fármacos , Cirrose Hepática/patologia , Fator de Crescimento Derivado de Plaquetas/efeitos dos fármacos , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta/efeitos dos fármacos , Actinas/metabolismo , Animais , Apoptose/efeitos dos fármacos , Ductos Biliares , Tetracloreto de Carbono , Proliferação de Células/efeitos dos fármacos , Colágeno/metabolismo , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Ligadura , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , PPAR gama/metabolismo , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismoRESUMO
The clinical course of heel pain can be frustrating to the clinician and the patient. Most heel pain responds to conservative care in a short period of time. However, other causes should be considered, especially if the heel pain is recalcitrant to treatment. A detailed history and physical examination, along with appropriate laboratory tests and radiological studies, can direct the physician toward the correct diagnosis. There are many systemic causes of heel pain, some common and others uncommon. Regardless of the incidence, a strong index of suspicion is raised whenever the heel pain fails to respond as routine plantar fasciitis should.
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Calcanhar , Dor/etiologia , Anemia Falciforme/complicações , Artrite/complicações , Artrite/etiologia , Artrite Reativa/complicações , Gota/complicações , Humanos , Hiperparatireoidismo/complicações , Doenças Inflamatórias Intestinais/complicações , Neoplasias/complicações , Osteíte Deformante/complicações , Osteomielite/complicações , Sarcoidose/complicaçõesRESUMO
BACKGROUND: Various techniques may be used to repair Achilles tendon ruptures; however, we contend that using the strongest suture with the least amount of suture material is ideal. METHODS: To compare the strength of 2-0 FiberLoop (Arthrex Inc, Naples, Florida) and #2 Ethibond (Ethicon Inc, Somerville, New Jersey) suture materials in Achilles tendon repairs, 12 Achilles tendons were harvested from cadavers aged 18 to 62 years (median age, 42 years). The tendons were transected and repaired using a modified Krackow suture technique. All of the right limbs were repaired with 2-0 FiberLoop, and the contralateral side was repaired with #2 Ethibond. The specimens were mounted to a materials testing system, and the repairs were pulled to failure in an anatomical direction. RESULTS: The mean +/- SD yield loads of 2-0 FiberLoop and #2 Ethibond were 233 +/- 48 N and 134 +/- 34 N, respectively (P = .002). The mean +/- SD ultimate load of 2-0 FiberLoop was 282 +/- 58 N, and that of #2 Ethibond was 135 +/- 33 N (P < .001). The cross-sectional area of one pass of 2-0 FiberLoop was calculated to be 0.21 mm(2), and one pass of #2 Ethibond was 0.28 mm(2). CONCLUSIONS: The smaller-caliber 2-0 FiberLoop was significantly stronger than #2 Ethibond. This study suggests that there is no advantage to using the traditional larger suture material for Achilles tendon repairs; however, further clinical testing is needed to determine the optimal repair technique.
Assuntos
Tendão do Calcâneo/lesões , Traumatismos do Tornozelo/cirurgia , Procedimentos Ortopédicos/métodos , Poliésteres , Polietileno , Técnicas de Sutura/instrumentação , Suturas , Tendão do Calcâneo/fisiopatologia , Tendão do Calcâneo/cirurgia , Adolescente , Adulto , Traumatismos do Tornozelo/fisiopatologia , Fenômenos Biomecânicos , Cadáver , Desenho de Equipamento , Humanos , Pessoa de Meia-Idade , Ruptura , Adulto JovemRESUMO
Stimulation of hepatic stellate cells (HSCs) by platelet-derived growth factor (PDGF) and transforming growth factor-beta1 (TGF-beta1) is an essential pathway of proliferation and fibrogenesis, respectively, in liver fibrosis. We provide evidence that PTK787/ZK222584 (PTK/ZK), a potent tyrosine kinase inhibitor that blocks vascular endothelial growth factor receptor (VEGFR), significantly inhibits PDGF receptor expression, as well as PDGF-simulated HSC proliferation, migration and phosphorylation of ERK1/2, Akt and p70S6 kinase. Interestingly, PTK/ZK also antagonizes the TGF-beta1-induced expression of VEGF and VEGFR1. Furthermore, PTK/ZK downregulates TGF-beta receptor expression, which is associated with reduced Akt, ERK and p38MAPK phosphorylation. Furthermore, PDGF-induced TGF-beta1 expression is inhibited by PTK/ZK. These findings provide evidence that PTK/ZK targets multiple essential pathways of stellate cell activation that provoke proliferation and fibrogenesis. Our study underscores the potential use of PTK/ZK as an antifibrotic drug in chronic liver disease.
Assuntos
Células Estreladas do Fígado/efeitos dos fármacos , Ftalazinas/farmacologia , Fator de Crescimento Derivado de Plaquetas/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Fator de Crescimento Transformador beta1/metabolismo , Animais , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Regulação para Baixo/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Células Estreladas do Fígado/metabolismo , Cirrose Hepática/tratamento farmacológico , Ftalazinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Piridinas/uso terapêutico , RNA Mensageiro/metabolismo , Ratos , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína Smad2/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Quinases raf/metabolismoRESUMO
Liver fibrosis due to hepatic stellate cell (HSC) activation represents a common response to chronic liver injury. PTK787/ZK222584 (PTK/ZK) is a pan-VEGFR tyrosine kinase inhibitor. The aim of this study was to examine the effect of PTK/ZK in liver fibrosis. In primary HSCs, PTK/ZK inhibited the expression of alpha-smooth muscle actin (alpha-SMA), collagen, tissue inhibitor of metalloproteinase-1 (TIMP-1), as well as cell proliferation, migration and actin filament formation. PTK/ZK-induced apoptosis of HSCs, which was correlated with increased caspase-3 activation and suppressed Bcl-2 expression. PTK/ZK also induced cell cycle arrest, accompanied by increasing the expression of p27(Kip1) and downregulation of cyclin D1 and cyclin E. PTK/ZK significantly inhibited vascular endothelial growth factor (VEGF) expression, as well as VEGF-simulated cell proliferation and phosphorylation of Akt in activated HSCs. In a murine fibrotic liver, PTK/ZK attenuated collagen deposition and alpha-SMA expression in carbon tetrachloride-induced fibrosis in both a 'prevention' and 'treatment' dosing scheme. These beneficial effects were associated with reduced phosphorylation of Akt and suppressed mRNA expression of procollagen-(I), TIMP-1, matrix metalloproteinase-9 and CD31. These findings provide novel insights into the potential value of blocking VEGF signaling by a small molecule tyrosine kinase inhibitor in treating hepatic fibrosis.