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The mechanical behaviour of polycarbonate and polydimethylsiloxane (Sylgard184) is studied in this work under laser shock conditions that induce high pressure and strain rates. Laser shock, usually used to reinforce metals, is chosen here because of its capacity to produce strain rates in the 106 s1 range and pressures of GPa order. The pressure and strain rates produced are extracted from the backface velocity profiles and reproduced with the FEM simulation on Abaqus for each laser shot. These two parameters lead to a glass transition shift in the polymers that can induce significant behaviour modifications. We show that Sylgard184, an elastomer with a glass transition temperature of 147 K, exhibits glassy behaviour under such laser shock conditions. By contrast, polycarbonate is already a glassy polymer in its normal state with a glass transition temperature of 415 K; no drastic change in behaviour under shock is evidenced. To discuss these findings in relation to the different mobility domains of the polymer chains under extreme conditions, dielectric relaxation spectroscopy (DRS) measurements are performed to characterize the limits of the rubbery and glassy behaviour for both polymers. As a result, the coupling of the two techniques provides a deeper understanding of the contribution of both the strain rate and pressure to the dynamic glass transition in polymers and thus expands the experimental study range of the two polymers to a strain rate that had not previously been reached.
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BACKGROUND: Obstructive sleep apnea frequently persists in children following adenotonsillectomy, which is the first-line treatment recommended for obstructive sleep apnea with adenotonsillar hypertrophy. Drug-induced sleep endoscopy (DISE) is a diagnostic tool increasingly used to assess pediatric obstructive sleep apnea, but its use has not been standardized. The overarching goal of this study was to document the current practice of Canadian otolaryngologists managing this population. METHODS: A nation-wide online cross-sectional survey of Canadian otolaryngologist members of the Canadian Society of Otolaryngology - Head and Neck Surgery and the Association d'otorhinolaryngologie et chirurgie cervico-faciale du Québec. The 58-question electronic survey was developed based on a validated survey redaction guide with the aim to assess management and treatment of pediatric obstructive sleep apnea, as well as indications and performance of DISE. Consensus on practice items was defined by a minimum of 75% similar answers. RESULTS: One hundred and nine Canadian otolaryngologists completed the survey on management of pediatric obstructive sleep apnea, among which 12 of them completed the questions on DISE. Overall, there was a poor rate of agreement of 55% among the respondents for the 58 questions altogether. There was a consensus to assess pediatric obstructive sleep apnea clinically ± with videos (82.6%), to assess adenotonsillar hypertrophy clinically (93.6%) and with flexible scope in the office (80.7%), as well as for the airway sites examined endoscopically during DISE. However, there was no consensus regarding anesthetic protocol and scoring system. DISE was mostly performed in cases of persistent obstructive sleep apnea after adenotonsillectomy rather than before performing any surgical procedure. There was no difference in the management of obstructive sleep apnea between otolaryngologists who perform DISE and those who do not. The only difference between otolaryngologists who practice in community centers versus in tertiary care centers was the more frequently use of the Brodsky tonsil scale by the latter ones. CONCLUSION: This Canadian-wide survey highlighted a lack of consensus in the management of pediatric obstructive sleep apnea and DISE. Certain aspects regarding DISE remain unclear, including establishment of its ideal timing in order to eventually avoid unnecessary tonsillectomies.
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Apneia Obstrutiva do Sono , Canadá , Criança , Estudos Transversais , Endoscopia , Humanos , Polissonografia , Apneia Obstrutiva do Sono/diagnóstico , Apneia Obstrutiva do Sono/cirurgia , Inquéritos e QuestionáriosRESUMO
Senegalin (1), a new phenylpropanoid has been isolated from the stem bark of Ekebergia senegalensis A. Juss. along with twelve known secondary metabolites including coumarins 2-5, 4-hydroxy-3,5-methylbenzoic acid (6), pentacyclic triterpenoids 7-9, acyclic triterpenoids 10 and 11 and steroids 12 and 13, respectively. Their structures were elucidated with the help of spectroscopic techniques including 1 D- and 2 D-NMR. The antibacterial activity of the major compounds (2, 9-11) was evaluated on five bacterial strains. However, only compounds 2 and 11 showed a weak inhibition against Bacillus subtilis and Pseudomonas agarici. Furthermore, the chemotaxonomic significance of these compounds has also been elaborated.
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Meliaceae , Triterpenos , Casca de Planta , PseudomonasRESUMO
Introduction: Standard treatment for early-stage invasive breast cancer (bca) consists of breast-conserving surgery and several weeks of adjuvant radiotherapy (rt). Neoadjuvant single-fraction rt is a novel approach for early-stage bca. We sought to investigate the effect of delaying surgery after neoadjuvant rt with respect to the rate of pathologic response (pr). Methods: Women 65 years of age or older with a new diagnosis of stage i luminal A bca were eligible for inclusion. A single 20 Gy dose to the primary breast tumour was given, followed by breast-conserving surgery 3 months later. The primary endpoint was the pr rate assessed by microscopic evaluation using the Miller-Payne system. Results: To date, 10 patients have been successfully treated. Median age of the patients was 72 years (range: 65-84 years). In 8 patients, neoadjuvant rt resulted in a tumour pr with median residual cellularity of 3%. No immediate rt complications other than mild dermatitis were noted. Conclusions: This study demonstrates a method for delivering single-fraction rt that can lead to a high level of pr in most patients. Continued accrual to this study and subsequent trials are needed to determine the feasibility, safety, and role of this novel technique in the management of early-stage bca.
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Neoplasias da Mama/radioterapia , Radioterapia Adjuvante/métodos , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Fatores de TempoRESUMO
Bone is the most common metastatic site for breast cancer. Estrogen-related-receptor alpha (ERRα) has been implicated in cancer cell invasiveness. Here, we established that ERRα promotes spontaneous metastatic dissemination of breast cancer cells from primary mammary tumors to the skeleton. We carried out cohort studies, pharmacological inhibition, gain-of-function analyses in vivo and cellular and molecular studies in vitro to identify new biomarkers in breast cancer metastases. Meta-analysis of human primary breast tumors revealed that high ERRα expression levels were associated with bone but not lung metastases. ERRα expression was also detected in circulating tumor cells from metastatic breast cancer patients. ERRα overexpression in murine 4T1 breast cancer cells promoted spontaneous bone micro-metastases formation when tumor cells were inoculated orthotopically, whereas lung metastases occurred irrespective of ERRα expression level. In vivo, Rank was identified as a target for ERRα. That was confirmed in vitro in Rankl stimulated tumor cell invasion, in mTOR/pS6K phosphorylation, by transactivation assay, ChIP and bioinformatics analyses. Moreover, pharmacological inhibition of ERRα reduced primary tumor growth, bone micro-metastases formation and Rank expression in vitro and in vivo. Transcriptomic studies and meta-analysis confirmed a positive association between metastases and ERRα/RANK in breast cancer patients and also revealed a positive correlation between ERRα and BRCA1mut carriers. Taken together, our results reveal a novel ERRα/RANK axis by which ERRα in primary breast cancer promotes early dissemination of cancer cells to bone. These findings suggest that ERRα may be a useful therapeutic target to prevent bone metastases.
Assuntos
Neoplasias Ósseas/metabolismo , Neoplasias da Mama/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias Mamárias Animais/metabolismo , Proteínas de Neoplasias/metabolismo , Receptor Ativador de Fator Nuclear kappa-B/biossíntese , Receptores de Estrogênio/metabolismo , Animais , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Neoplasias Ósseas/secundário , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Humanos , Neoplasias Mamárias Animais/genética , Neoplasias Mamárias Animais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Proteínas de Neoplasias/genética , Receptor Ativador de Fator Nuclear kappa-B/genética , Receptores de Estrogênio/genética , Receptor ERRalfa Relacionado ao EstrogênioAssuntos
Cianobactérias , Endotoxinas/toxicidade , Exposição Ambiental/efeitos adversos , Gastroenteropatias/epidemiologia , Microbiologia da Água , Doença Aguda , Adolescente , Adulto , Criança , Pré-Escolar , Cianobactérias/isolamento & purificação , Endotoxinas/análise , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Recreação , Adulto JovemRESUMO
PURPOSE: Abdominal aortic aneurysms (AAAs) expand because of aortic wall destruction. Enrichment in Vascular Smooth Muscle Cells (VSMCs) stabilizes expanding AAAs in rats. Mesenchymal Stem Cells (MSCs) can differentiate into VSMCs. We have tested the hypothesis that bone marrow-derived MSCs (BM-MSCs) stabilizes AAAs in a rat model. MATERIAL AND METHODS: Rat Fischer 344 BM-MSCs were isolated by plastic adhesion and seeded endovascularly in experimental AAAs using xenograft obtained from guinea pig. Culture medium without cells was used as control group. The main criteria was the variation of the aortic diameter at one week and four weeks. We evaluated the impact of cells seeding on inflammatory response by immunohistochemistry combined with RT-PCR on MMP9 and TIMP1 at one week. We evaluated the healing process by immunohistochemistry at 4 weeks. RESULTS: The endovascular seeding of BM-MSCs decreased AAA diameter expansion more powerfully than VSMCs or culture medium infusion (6.5% ± 9.7, 25.5% ± 17.2 and 53.4% ± 14.4; p = .007, respectively). This result was sustained at 4 weeks. BM-MSCs decreased expression of MMP-9 and infiltration by macrophages (4.7 ± 2.3 vs. 14.6 ± 6.4 mm(2) respectively; p = .015), increased Tissue Inhibitor Metallo Proteinase-1 (TIMP-1), compared to culture medium infusion. BM-MSCs induced formation of a neo-aortic tissue rich in SM-alpha active positive cells (22.2 ± 2.7 vs. 115.6 ± 30.4 cells/surface units, p = .007) surrounded by a dense collagen and elastin network covered by luminal endothelial cells. CONCLUSIONS: We have shown in this rat model of AAA that BM-MSCs exert a specialized function in arterial regeneration that transcends that of mature mesenchymal cells. Our observation identifies a population of cells easy to isolate and to expand for therapeutic interventions based on catheter-driven cell therapy.
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Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/cirurgia , Transplante de Medula Óssea , Transplante de Células-Tronco Mesenquimais , Músculo Liso Vascular/transplante , Miócitos de Músculo Liso/transplante , Animais , Aorta Abdominal/metabolismo , Aorta Abdominal/transplante , Aneurisma da Aorta Abdominal/genética , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Diferenciação Celular , Células Cultivadas , Modelos Animais de Doenças , Cobaias , Imuno-Histoquímica , Masculino , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Ratos , Ratos Endogâmicos F344 , Regeneração , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Tempo , Inibidor Tecidual de Metaloproteinase-1/genética , Inibidor Tecidual de Metaloproteinase-1/metabolismoRESUMO
BACKGROUND: Determinants of extracellular matrix (ECM) destruction/reconstruction balance influencing abdominal aortic aneurysm (AAA) diameter may impact length. OBJECTIVE: Document aortic lengthening, its correlation to diameter, and determine how treatments that impact diameter also affect length. METHODS: Three hundred and fifty-five diameter and length measurements were performed in 308 rats during AAA formation, expansion and stabilisation in guinea pig aortas xenografted in rats. Impact of modulation of ECM destructive/reconstructive balance by endovascular Vascular Smooth Muscle Cell (VSMCs) seeding, TIMP-1, PAI-1 and TGF-beta1 overexpression on length has been assessed. RESULTS: Length increased in correlation with diameter during formation (correlation coefficient (cc): 0.584, P<0.0001) and expansion (cc: 0.352, P=0.0055) of AAAs. Overexpression of TIMP-1 and PAI-1 decreased lengthening (P=0.02 and 0.014, respectively) demonstrating that elongation is driven by matrix metalloproteinases and their activation by the plasmin pathway. Overexpression of TGF-beta1 controlled length in formed AAAs (17.3 ± 9.6 vs. 5.9 ± 7.4mm, P=0.022), but not VSMC seeding, although both therapies efficiently prevented further diameter increase. Length and diameter correlation was lost after biotherapies. CONCLUSION: Length increases in correlation with diameter during AAA formation and expansion, as a consequence of ECM injury driven by MMPs activated by the plasmin pathway. Correlation between length and diameter increases is not universally preserved.
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Aneurisma da Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/cirurgia , Matriz Extracelular/patologia , Análise de Variância , Animais , Aorta Abdominal/metabolismo , Aorta Abdominal/patologia , Aorta Abdominal/cirurgia , Aneurisma da Aorta Abdominal/metabolismo , Modelos Animais de Doenças , Cobaias , Músculo Liso Vascular/citologia , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Ratos , Estatísticas não Paramétricas , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Fator de Crescimento Transformador beta1/metabolismoRESUMO
PURPOSE: The objective of this investigation was to compare transthoracic ultrasound (US) determinations of ascending aortic diameters in rats with video microscopy (VM), the current standard for measuring aortic diameters in rats. MATERIALS AND METHODS: The diameter of the ascending aorta was measured in 111 adult Lewis male rats, by VM and US, with a 9 MHz probe, before and after intervention for induction of experimental aneurysm of the ascending aorta. RESULTS: The Bland-Altman test showed a high degree of agreement between the two methods, with a bias of only 0.23 mm (95 % confidence limits - 0.86 - 0.39 mm). Also, the measurements obtained by US correlated highly (r = 0.83, p < 0.0001) with those obtained by VM. Rat ascending aortic diameters obtained both by VM and US correlated significantly with the weight (r = 0.62 and r = 0.39, respectively), and with the age of the animals (r = 0.74 and r = 0.49, respectively). CONCLUSION: This study demonstrates that noninvasive US ascending aortic measurements are a reliable supplement to VM for the development of an ascending aortic aneurysm model, and for monitoring the efficiency of novel therapeutic agents.
Assuntos
Aorta/diagnóstico por imagem , Processamento de Imagem Assistida por Computador , Microscopia de Vídeo , Animais , Aneurisma da Aorta Torácica/diagnóstico por imagem , Modelos Animais de Doenças , Masculino , Ratos , Ratos Endogâmicos Lew , Sensibilidade e Especificidade , UltrassonografiaRESUMO
BACKGROUND: Knowledge in the aetiopathogeny of aortic disease helps to characterise aortic lesions better and determine the risk of evolution and therapeutic strategies as well. This article focusses on aneurysms and dissections, and excludes causes related to infection, systemic inflammatory diseases and trauma. METHODS AND RESULTS: The biomedical literature of the past 10 years has been reviewed here. Aortic diseases are heterogeneous along the aorta as far as their genetic determinants, contribution of smooth muscle cells, inflammation and thrombus formation are concerned. Degradation of extracellular matrix by proteases causing aortic disease is a 'terminal' event, modulated by genetic background, haemodynamic strain, cellular events and thrombus formation. New genetic determinants of aortic disease have been identified. Proteases degrading the aortic wall are derived from a variety of cell types in addition to macrophages, including neutrophils on the luminal thrombus, mesenchymal and endothelial cells in the wall. Smooth muscle cells contribute to aortic wall homeostasis against inflammation and proteolysis. The degradation of the wall is followed by, or paralleled with, a failure of aortic reconstruction. CONCLUSIONS: Aortic diseases are diverse, and involve a multiplicity of biological systems in the vascular wall and at the interface with blood. Future research needs to unravel distinct cellular and molecular mechanisms causing the clinical events, in particular, dissection, expansion of already formed aneurysms and rupture.
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Doenças da Aorta/diagnóstico , Doenças da Aorta/etiologia , Músculo Liso Vascular/patologia , Dissecção Aórtica/diagnóstico , Dissecção Aórtica/etiologia , Dissecção Aórtica/terapia , Animais , Aneurisma Aórtico/diagnóstico , Aneurisma Aórtico/etiologia , Aneurisma Aórtico/terapia , Progressão da Doença , Humanos , Leucócitos/metabolismo , Leucócitos/patologia , Músculo Liso Vascular/metabolismo , Peptídeo Hidrolases/biossínteseRESUMO
Biologic and technical complications are widely reported in the dental literature and often compromise the functional and/or aesthetic features of fixed, implant-supported prostheses. Managing complications without damaging or destroying a restoration is an obvious advantage of implant-based dentistry where the option of prosthetic retrievability is almost always available. The technique of cross-pinning uses a transverse screw to secure a prosthesis to a milled implant abutment, allowing prosthetic retrievability irrespective of dental implant alignment. This study presents guidelines for cross-pinning implant-supported prostheses based on resistance form, screw mechanics and natural tooth contours. The technical aspects of cross-pinning are also discussed using examples from four implant systems.
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Implantes Dentários , Planejamento de Prótese Dentária , Retenção em Prótese Dentária/instrumentação , Prótese Dentária Fixada por Implante , Resinas Acrílicas , Dente Suporte , Ligas Dentárias , Planejamento de Prótese Dentária/métodos , Falha de Restauração Dentária , Reparação em Dentadura , Humanos , Estresse Mecânico , Propriedades de Superfície , Tecnologia OdontológicaRESUMO
Estrogens are known to activate the phosphatidyl-inosityl 3-kinase (PI3K)/Akt pathway, which is central in the cardioprotection afforded by ischemic postconditioning. Therefore, our goal was to investigate whether a phytoestrogen, genistein, could induce a pharmacological postconditioning and to investigate potential mechanisms. We used low doses of genistein in order to avoid tyrosine kinases inhibition. Thus, pentobarbital-anesthetized rabbits underwent a coronary artery occlusion followed by 4 h of reperfusion. Prior to reperfusion, they randomly received an i.v. injection of either saline (Control), 100 or 1000 microg/kg of genistein (Geni(100) and Geni(1000), respectively), and 10 or 100 microg/kg of 17beta-estradiol (17beta(10) and 17beta(100), respectively). Infarct size (IS, % area at risk) was significantly reduced in Gen(100), Gen(1000) and 17beta(100) but not in 17beta(10) (6+/-2, 16+/-5, 12+/-3 and 29+/-7%, respectively) vs. Control (35+/-4%). A significant decrease in the percentage of TUNEL-positive nuclei within infarcted area was observed in Gen(100) and 17beta(100) vs. Controls. The estrogen receptor antagonist fulvestrant (1 mg/kg i.v.) and the PI3K inhibitor wortmaninn (0.6 mg/kg) abolished the cardioprotective effect of genistein. Western blots also demonstrated an increase in Akt posphorylation in Gen(100). In the same group, in vitro mitochondrial swelling studies demonstrated a significant inhibition of calcium-induced opening of mitochondrial transition pore vs. Controls. In conclusion, genistein exerts pharmacological postconditioning with a similar potency as 17beta-estradiol through a pathway involving activation of the estrogen receptor, of PI3K/Akt and mitochondrial preservation. Therefore, genistein should not be only considered as an inhibitor of tyrosine kinase but also as a cardioprotective estrogen.
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Cardiotônicos/farmacologia , Genisteína/farmacologia , Fitoestrógenos/farmacologia , Animais , Cálcio/farmacologia , Estradiol/farmacologia , Técnicas In Vitro , Precondicionamento Isquêmico Miocárdico/métodos , Masculino , Mitocôndrias Cardíacas/efeitos dos fármacos , Dilatação Mitocondrial/efeitos dos fármacos , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Coelhos , Receptores de Estrogênio/efeitos dos fármacos , Receptores de Estrogênio/metabolismoRESUMO
This study investigates the evolutionary history of vertebrate red blood cell carbonic anhydrase (CA) by characterizing the isozyme properties and nucleotide sequence of an ancient fish, the longnose gar ( Lepisosteus osseus). The inhibitor sensitivities of gar rbc CA closely resembled those for mammalian CA II, as well as those for CAs from more recently evolved fishes. The kinetic properties of gar rbc CA were not closely aligned with either mammalian CA I and CA II, but fit well into an emerging phylogenetic pattern for early vertebrates. Gar rbc CA cDNA was also amplified from mRNA using 5' and 3'-RACE and the open reading frame consisted of 786 bp. This sequence shares approximately 65% identity with the nucleotide and amino acid sequences of both mammalian CA I and CA II. When the amino acid sequences within the active site are compared, gar rbc CA differs from mammalian CA I, CA II and CA VII by 9, 4 and 3 of the 36 amino acids, respectively. Phylogenetic analyses suggest that gar rbc CA diverged before the amniotic CAs (CA I, CA II and CA III), but after CA V and CA VII.
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Anidrases Carbônicas/sangue , Eritrócitos/enzimologia , Peixes/sangue , Sequência de Aminoácidos/genética , Animais , Sequência de Bases/genética , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/genética , Evolução Molecular , Dados de Sequência MolecularRESUMO
This main purpose of this study was to examine the subcellular distribution and isozyme characteristics of branchial carbonic anhydrase (CA) in Chaenocephalus aceratus, an Antarctic icefish that lacks erythrocytes. The Antarctic fish, Notothenia coriiceps, which possesses erythrocytes, was also studied for comparative purposes. The gills of both species were found to have measurable activity of CA. N. coriiceps also had normal levels of blood CA activity. In contrast, the icefish, C. aceratus, lacked blood CA activity, but was found to possess an endogenous plasma CA inhibitor. The large majority of branchial CA in the gills of these species was located in the cytoplasmic fraction whereas less than 3% was associated with the membrane fraction. In both species, CA from the cytoplasmic gill fraction and membrane fraction differed markedly in terms of their sensitivity to the plasma CA inhibitor from C. aceratus. In addition, treatment with the cleaving enzyme phosphatidylinositol-specific phospholipase C indicated that CA from the branchial membrane fraction of both species is anchored to the membrane via a phosphatidylinositol-glycan linkage. Taken together, these results provide evidence for a CA IV-like isozyme in the gills of Antarctic fish. At present, the functional significance of this membrane-bound CA is unknown, but the relative amount of this isozyme appeared to be greater in the gills of C aceratus, the species that lacked erythrocytes.
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Inibidores da Anidrase Carbônica/sangue , Anidrases Carbônicas/metabolismo , Peixes/metabolismo , Brânquias/enzimologia , Animais , Regiões Antárticas , Anidrases Carbônicas/análise , Citoplasma/enzimologia , Ativação Enzimática/efeitos dos fármacos , Eritrócitos/enzimologia , Microssomos/enzimologia , Fosfatidilinositol Diacilglicerol-Liase , Fosfoinositídeo Fosfolipase C , Fosfolipases Tipo C/farmacologiaRESUMO
Measuring the psychological well-being of people with physical impairments could provide relevant information to occupational therapists. The aim of this study was to verify psychometric properties of a psychological well-being test called Test de personnalité PER (PER). This test was administered to two samples of people with physical impairments. Two time measurements were collected within a group of 36 individuals and one single measure within another group of 79 individuals. Comparisons between time measurements, between groups and with the normative group of the PER were performed in an attempt to verify the sensitivity, the capacity to discriminate between known groups, and the construct validity of the PER. One section of the Sickness Impact Profile measuring psychological well-being was administered to the same groups to verify the concurrent criterion validity of the PER. The results indicate that the PER has sufficient psychometric qualities.
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Pessoas com Deficiência/psicologia , Testes de Personalidade , Humanos , Saúde Mental , Psicometria , Sensibilidade e Especificidade , Fatores de TempoRESUMO
1. The aim of the present study was to investigate left and right ventricular (LV and RV, respectively) coronary vasodilatation reserve (CVR; fluorescent microsphere technique) in rats with hypertension (spontaneously hypertensive rats (SHR)) or congestive heart failure (CHF) and the effects of early and chronic renin-angiotensin system (RAS) blockade thereupon. 2. In adult SHR, both LV and RV CVR were impaired, especially in the non-hypertrophied RV, the main factor involved being coronary vascular remodelling. Blockade of the RAS normalized both LV and RV CVR, mainly through the prevention of hypertension and suppression of the resulting pericoronary fibrosis. 3. In postischaemic CHF rats, there was an early and severe degradation of LV and RV CVR that developed before any significant vascular remodelling and appeared to be linked to the deterioration of cardiac hypertrophy and haemodynamics. This degradation in CVR further worsened over the longer term due to late-developing pericoronary fibrosis and endothelial dysfunction. Blockade of the RAS had no early effects on LV and RV CVR, but improved RV CVR over the long term, mainly by limiting RV hypertrophy and by preventing the development of pericoronary fibrosis and coronary endothelial dysfunction. 4. In kallikrein-kinin system-deficient mice, CVR was not different from that of wild-type mice, suggesting that this system is not implicated in normal CVR regulation.
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Vasos Coronários/patologia , Insuficiência Cardíaca/patologia , Hipertensão/patologia , Sistema Renina-Angiotensina/fisiologia , Vasodilatação , Animais , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/farmacologia , Compostos de Bifenilo/administração & dosagem , Compostos de Bifenilo/farmacologia , Vasos Coronários/fisiopatologia , Deleção de Genes , Coração/efeitos dos fármacos , Insuficiência Cardíaca/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Hipertensão/fisiopatologia , Irbesartana , Sistema Calicreína-Cinina/fisiologia , Calicreínas/genética , Calicreínas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Isquemia Miocárdica/patologia , Isquemia Miocárdica/fisiopatologia , Perindopril/administração & dosagem , Perindopril/farmacologia , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Receptor B2 da Bradicinina , Receptores da Bradicinina/genética , Receptores da Bradicinina/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Tetrazóis/administração & dosagem , Tetrazóis/farmacologia , Vasodilatação/efeitos dos fármacosRESUMO
Expression of the Saccharomyces cerevisiae nuclear gene CYB2 encoding the mitochondrial enzyme L-(+)-lactate-cytochrome c oxidoreductase (EC 1.2.2.3) is subject to several strict metabolic controls at the transcriptional level: repression due to glucose fermentation, derepression by ethanol, induction by lactate and inhibition under anaerobic conditions or in response to deficiency of haem biosynthesis. In this respect, the data obtained from the transcriptional analysis of the CYB2 gene contribute to a better understanding of the control of mitochondrial biogenesis. In this study, we show that Hap1p is the main transcriptional activator involved in the control of CYB2 transcription. We found that Hap1p activity, known to be oxygen dependent, is effected by DNA-protein interaction with two binding sites present in the CYB2 promoter. Control is moreover dependent on carbon sources. This regulation by the carbon substrates is subordinate to the activity of the complex Hap2/3/4/5p, which counteracts the negative effect of the URS1 element. Finally, our results suggest that the Adr1p transcriptional activator is also required in CYB2 transcription control. This work provides new data which allows a better understanding of the molecular mechanisms implicated in the co-regulation at the transcriptional level of the genes encoding proteins involved in various aspects of oxidative metabolism.
Assuntos
Regulação Bacteriana da Expressão Gênica , Regulação Enzimológica da Expressão Gênica , L-Lactato Desidrogenase/genética , Proteínas de Saccharomyces cerevisiae , Fatores de Transcrição/metabolismo , Animais , Sítios de Ligação , Fator de Ligação a CCAAT/genética , Fator de Ligação a CCAAT/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Deleção de Genes , L-Lactato Desidrogenase (Citocromo) , Regiões Promotoras Genéticas , Ligação Proteica , Coelhos , Transativadores/genética , Transativadores/metabolismo , Fatores de Transcrição/genéticaRESUMO
Angiotensin II AT1-receptor blockers (AT1-s) prolong survival in experimental postischemic (coronary artery ligation) heart failure (CHF) in rats. The goal of this study was to investigate whether potential beneficial effects of short- and/or long-term treatment with AT1-s on coronary dynamics, function, and structure develop along with the drug-induced survival prolongation in this model. Coronary blood flow was measured (fluorescent microspheres) in conscious sham, untreated, and irbesartan-treated (50 mg/kg daily for 6 weeks or 6 months, starting 8 days after surgery) CHF rats at baseline and at maximal vasodilatation induced by dipyridamole, and coronary dilatation reserve (CDR) was calculated as the ratio of maximal to baseline coronary flow. Coronary endothelial function was assessed in vitro by measuring the coronary relaxant responses to acetylcholine in the three groups of animals. Finally, cardiac hypertrophy and pericoronary fibrosis also were investigated. In CHF rats, left (LV) and right (RV) ventricular CDR were markedly depressed at both 7 weeks and 6 months after ligation, whereas coronary endothelial function was significantly impaired only after 6 months. Short-term AT1-receptor blockade with irbesartan did not prevent CDR deterioration at 7 weeks, nor did it significantly oppose cardiac hypertrophy and pericoronary fibrosis development. Prolonged AT1-receptor blockade prevented both RV CDR deterioration and coronary endothelial function impairment. It also limited significantly the increase in LV end diastolic pressure and the development of cardiac hypertrophy and pericoronary fibrosis. In conclusion, in postischemic CHF in rats, alterations of CDR precede those of coronary endothelial function. Long-, but not short-term AT1-receptor blockade prevents endothelial function degradation, opposes RV CDR impairment, prevents pericoronary fibrosis development, and improves systemic hemodynamics. These effects of AT1-s on coronary dynamics, function, and structure (i.e., on myocardial perfusion) may contribute to the drug-induced survival prolongation in this model.
Assuntos
Antagonistas de Receptores de Angiotensina , Compostos de Bifenilo/farmacologia , Vasos Coronários/efeitos dos fármacos , Insuficiência Cardíaca/tratamento farmacológico , Isquemia Miocárdica/fisiopatologia , Tetrazóis/farmacologia , Animais , Vasos Coronários/patologia , Vasos Coronários/fisiopatologia , Relação Dose-Resposta a Droga , Fibrose , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Irbesartana , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/fisiopatologia , Ratos , Ratos Wistar , Receptor Tipo 1 de Angiotensina , Receptor Tipo 2 de Angiotensina , VasodilataçãoRESUMO
Assessment of systemic and regional hemodynamic phenotypes in genetically engineered mice by nonradioactive methods is yet an unsolved problem. We therefore investigated whether the reference sample method using fluorescent microspheres (FMs), already validated in rats, might be used for this purpose in C57BL/6 and in apolipoprotein E (ApoE)-deficient mice. FMs were injected into the left ventricle of instrumented anesthetized mice. In 10-week-old C57BL/6, cardiac output was 18-19 ml/min, and its regional distribution under basal conditions was approximately 1.5% (brain), 3.5% (heart), 9. 1% (left kidney), 9.8% (right kidney), 1% (spleen), and 0.8% (stomach) (i.e., values similar to those previously reported with radioactive microspheres). Proper mixing of FMs was achieved as both kidneys had identical flows; distribution of two differently labeled FMs injected simultaneously was shown to be identical by an agreement study, and FM trapping in the capillary bed was demonstrated both histologically and by the recovery in the lungs of 90% of intravenously injected FMs. In addition, identical values for cardiac output and its distribution were obtained in different age-matched groups of C57BL/6. The FM technique also proved to be able to evidence angiotensin II and isoprenaline classic systemic and regional hemodynamic effects. Finally, applied to 30-week-old ApoE-deficient mice and age-matched C57BL/6, the FM technique showed no major hemodynamic difference between the two groups, except for coronary blood flow, which was significantly decreased in ApoE-deficient mice. In conclusion, we demonstrated for the first time the feasibility, accuracy, and reliability of the FM technique at characterizing the cardiovascular phenotype of genetically engineered mice.
Assuntos
Hemodinâmica , Angiotensina II/farmacologia , Animais , Apolipoproteínas E/deficiência , Fluorescência , Engenharia Genética , Rim/fisiologia , Pulmão/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microesferas , FenótipoRESUMO
We investigated whether angiotensin I-converting enzyme inhibition (ACEI) and angiotensin II AT1-receptor blockade (AT1-) would exert beneficial additive effects on coronary hemodynamics and on cardiac remodeling in post-myocardial infarction (MI) heart failure in rats. Wistar rats with MI were treated daily for 6 weeks with either trandolapril (0.1 mg/kg), losartan (3 mg/kg), or their combination, after which coronary hemodynamics (basal and at maximal vasodilation, fluospheres), systemic hemodynamics, and cardiac remodeling were investigated. Neither trandolapril nor losartan (both in nonantihypertensive doses) nor their combination (which significantly decreased blood pressure) proved to be effective at improving MI-induced impairments of basal coronary hemodynamics and of coronary flow reserve, and at preventing cardiac fibrosis development. In contrast, both trandolapril and losartan significantly improved the hemodynamic status [e.g., left ventricular end diastolic pressure: -27% and -39%, urinary cyclic guanosine monophosphate (GMP): -37%, and -26%, respectively] and slightly limited cardiac hypertrophy (-5% and -3%, respectively), and, in their combination, tended to exert additive effects on these three parameters (-49, -42, and -10%, respectively). Thus whereas the ACEI/AT1- combination tended to exert additive effects on systemic hemodynamics and cardiac hypertrophy in post-MI heart failure rats, no such effect was found for coronary hemodynamics, probably in relation to the lack of prevention of cardiac fibrosis. We conclude that an early (6 weeks) drug-induced improvement in coronary hemodynamics does not contribute to the long-term survival prolongation observed in this experimental model after either ACEI or AT1-.