RESUMO
AIM: To investigate the accuracy of cardiac magnetic resonance (CMR) tissue tracking (CMR-TT) and speckle tracking echocardiography (STE) against CMR determined right ventricular (RV) ejection fraction (RVEF) and to identify an optimal cut-off value for STE and CMR-TT to determine RVEF <45% and compare this to other conventional methods for estimating RVEF in dilated cardiomyopathy (DCM) patients. MATERIALS AND METHODS: Twenty-nine DCM patients were recruited prospectively. CMR and echocardiography were performed within 48 hours and four-chamber views were used for strain analysis. Contoured CMR short axis images provided RVEF. Intraclass correlation coefficient (ICC), bias, levels of agreement, and receiver operating characteristic (ROC) curve analyses were performed. RESULTS: CMR-TT RV free-wall longitudinal strain (FLS) and STE RV global longitudinal strain (GLS) showed the best correlation with RVEF (r=-0.68, r=-0.82, p<0.001 respectively). There was moderate correlation between echocardiography RV GLS and CMR RV FLS (r=0.64, p<0.001). CMR-TT FLS showed excellent intra-observer and interobserver reliability (ICC=0.980; ICC=0.968 respectively). STE GLS correlated better with RVEF than with peak systolic annular velocity (S'; r=0.45), tricuspid annular plane systolic excursion (TAPSE; r=0.56), and fractional area change (FAC; r=0.78). CMR-TT RV FLS had better correlation with RVEF than CMR TAPSE (r=0.69 versus 0.40). ROC analysis demonstrated the optimal cut-off value for CMR-TT RV FLS and STE GLS in detection of RVEF <45% was ≥-24.4% (area under the curve=0.87, 100% sensitivity, 66.7% specificity) and ≥-20.9% (area under the curve=0.88, 100% sensitivity, 60% specificity) respectively. CONCLUSION: CMR-TT FLS and STE GLS showed potential to provide rapid assessment of RV function and had superior correlation with RVEF compared to conventional parameters.
Assuntos
Ecocardiografia/métodos , Imagem Cinética por Ressonância Magnética/métodos , Função Ventricular Direita , Idoso , Feminino , Humanos , Masculino , Estudos Prospectivos , Reprodutibilidade dos TestesRESUMO
OBJECTIVES: Because Takayasu arteritis (TA) predominantly affects females, few data regarding gender differences have been reported. The aim of the present study is to describe clinical features and angiographic findings of patients with TA according to gender. METHODS: According to the 1990 American College of Rheumatology criteria, 294 patients were diagnosed with TA between September 1994 and April 2014 at a single tertiary hospital. We reviewed clinical, laboratory, and radiologic data at the time of diagnosis. RESULTS: Among the 294 patients studied, 257 (87.4%) were female (male:female ratio=1:6.9). Female patients had a higher tendency to exhibit blood pressure differences between arms (p=0.595) and a weak pulse at the brachial artery (p=0.063). In male patients, we observed higher serum creatinine levels (p=0.038) and hypertension more frequently (p=0.061) than in females. Females exhibited more common lesions in the thoracic aorta and its branches, while males had more frequent lesions in the abdominal aorta and its branches. An analysis of angiographic classification according to the International TA Conference in Tokyo 1994 classification revealed that male patients had a higher incidence of type IV and females showed a higher incidence of types I, IIa, and IIb. CONCLUSIONS: Female patients with TA have more frequent involvement of the thoracic aorta and its branches, whereas involvement of the abdominal aorta and its branches is more common in males. Considering these gender-specific differences, adjustment of diagnostic criteria for TA according to gender may be necessary.
Assuntos
Aorta Torácica/diagnóstico por imagem , Artéria Carótida Primitiva/diagnóstico por imagem , Artéria Subclávia/diagnóstico por imagem , Arterite de Takayasu/diagnóstico por imagem , Adolescente , Adulto , Angiografia , Sedimentação Sanguínea , Proteína C-Reativa/metabolismo , Estudos de Coortes , Creatinina/sangue , Feminino , Hemoglobinas , Humanos , Hipertensão/etiologia , Claudicação Intermitente/etiologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores Sexuais , Arterite de Takayasu/sangue , Arterite de Takayasu/complicações , Tomografia Computadorizada por Raios X , Adulto JovemRESUMO
AIM: To assess the additional value of adenosine-stress dynamic computed tomography (CT) perfusion (ASDCTP) imaging compared with coronary CT angiography (CCTA) alone to detect significant coronary artery stenosis for each threshold of 50% and 70% diameter stenosis. MATERIALS AND METHODS: The study included 34 patients (65 ± 11 years, 79% men) with suspected coronary artery diseases who underwent ASDCTP imaging using a 128-section dual-source CT (DSCT) and invasive coronary angiography (ICA). Two investigators classified coronary artery stenosis on CCTA as severe or not. If appropriate image quality could not be acquired due to artefacts, the segment was classified as a lesion with significant stenosis. After the interpretation of ASDCTP imaging, the degree of stenosis was reclassified. All parameters of diagnostic accuracy were calculated before and after ASDCTP analysis for detection of significant coronary artery stenosis with ICA as the reference standard. RESULTS: The diagnostic accuracy parameters per vessel for the detection of ≥50% stenosis before and after ASDCTP analysis changed as follows: sensitivity, from 80% to 83%; specificity, from 83% to 98%; positive predictive value (PPV), from 87% to 98%; and negative predictive value (NPV), from 75% to 80%. The addition of ASDCTP resulted in reclassification from one class of stenosis severity to another in a significant number of vessels with threshold of 50% stenosis [net reclassification improvement (NRI), 0.176; p < 0.01]. Conversely, the addition of ASDCTP did not result in significant reclassification of stenosis severity in vessels with threshold of 70% stenosis (NRI, 0.034; p = 0.51). CONCLUSIONS: ASDCTP imaging provides incremental value in the detection of significant coronary artery stenosis using a threshold of 50%.
Assuntos
Adenosina , Angiografia Coronária/métodos , Estenose Coronária/diagnóstico por imagem , Teste de Esforço/métodos , Imagem de Perfusão do Miocárdio/métodos , Idoso , Estenose Coronária/classificação , Estenose Coronária/patologia , Vasos Coronários/diagnóstico por imagem , Vasos Coronários/patologia , Feminino , Humanos , Masculino , Índice de Gravidade de Doença , Tomografia Computadorizada por Raios X/métodosRESUMO
Immune dysregulation, Polyendocrinopathy, Enteropathy X-linked (IPEX) syndrome is a unique example of primary immunodeficiency characterized by autoimmune manifestations due to defective regulatory T (Treg) cells, in the presence of FOXP3 mutations. However, autoimmune symptoms phenotypically resembling IPEX often occur in the absence of detectable FOXP3 mutations. The cause of this "IPEX-like" syndrome presently remains unclear. To investigate whether a defect in Treg cells sustains the immunological dysregulation in IPEX-like patients, we measured the amount of peripheral Treg cells within the CD3(+) T cells by analysing demethylation of the Treg cell-Specific-Demethylated-Region (TSDR) in the FOXP3 locus and demethylation of the T cell-Specific-Demethylated-Region (TLSDR) in the CD3 locus, highly specific markers for stable Treg cells and overall T cells, respectively. TSDR demethylation analysis, alone or normalized for the total T cells, showed that the amount of peripheral Treg cells in a cohort of IPEX-like patients was significantly reduced, as compared to both healthy subjects and unrelated disease controls. This reduction could not be displayed by flow cytometric analysis, showing highly variable percentages of FOXP3(+) and CD25(+)FOXP3(+) T cells. These data provide evidence that a quantitative defect of Treg cells could be considered a common biological hallmark of IPEX-like syndrome. Since Treg cell suppressive function was not impaired, we propose that this reduction per se could sustain autoimmunity.
Assuntos
Metilação de DNA , Fatores de Transcrição Forkhead/genética , Poliendocrinopatias Autoimunes/genética , Poliendocrinopatias Autoimunes/imunologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Adolescente , Adulto , Complexo CD3/imunologia , Complexo CD3/metabolismo , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Citometria de Fluxo , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Lactente , Masculino , Síndrome , Adulto JovemRESUMO
BACKGROUND AND PURPOSE: Cardiac evaluation is routinely conducted in patients with ischaemic stroke because embolisms originating from the heart are an important cause of stroke. We compared the prevalence of cardioaortic sources of cerebral embolism (CSCE) in patients with ischaemic stroke detected by transthoracic echocardiography (TTE) and/or multidetector cardiac computed tomography (MDCT). Additionaly, we investigated the frequency and severity of asymptomatic coronary artery disease (CAD) in patients who underwent MDCT. METHODS: We prospectively recruited patients with non-atrial fibrillation-related stroke who had no history of cardiac disease. Patients underwent cardiac evaluation using TTE alone (N=243, during the early phase of this study--TTE period), TTE and MDCT (N=62, midphase--transitional period) and MDCT alone (N=138, late phase--MDCT period). CSCE were defined according to the original and revised TOAST classifications. CAD was defined as 50% or more stenosis of the coronary artery. RESULTS: Patients' characteristics did not differ amongst groups; however, CSCE were more frequently detected in the MDCT period than in the TTE period (18.1% vs. 6.6%, P<0.001). In the transitional period, there were 16 patients (25.8%) who were found to be CSCE by MDCT but not TTE, whilst three patients (4.8%) were found to be CSCE by TTE but not MDCT (P=0.004). Amongst the patients who underwent MDCT, 72 (36.0%) had asymptomatic CAD, invasive coronary angiography was needed in 21 (10.5%) and 10 (5.0%) patients finally underwent coronary intervention. CONCLUSION: Multidetector cardiac computed tomography proved to be complementary to TTE for the identification of CSCE and can detect asymptomatic CAD, one of the major causes of vascular death in patients with stroke, in patients with non-atrial fibrillation-related stroke.
Assuntos
Isquemia Encefálica/complicações , Doenças Cardiovasculares/diagnóstico , Ecocardiografia/métodos , Tomografia Computadorizada Multidetectores/métodos , Acidente Vascular Cerebral/complicações , Idoso , Fibrilação Atrial/complicações , Fibrilação Atrial/diagnóstico , Doenças Cardiovasculares/complicações , Doença das Coronárias/complicações , Doença das Coronárias/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
AIM: To analyse the multidetector computed tomography (MDCT) and magnetic resonance imaging (MRI) findings in patients with atresia of the coronary sinus orifice (CSA). MATERIALS AND METHODS: MDCT findings of 15 consecutive adult patients with CSAs were retrospectively analysed. The patients underwent contrast-enhanced electrocardiography-gated MDCT (n = 13) or both CT and MRI (n = 2). RESULTS: The mean size of the coronary sinus (CS) was 14.2 mm (range 5.5-24 mm) and 11 patients (73.3%) showed CS dilatation (diameter ≥12 mm). The mean length of the atretic CS segment was 2.9 mm (range 0-8 mm). Different forms of venous collateral pathways were observed in the CSA patients. Nine (60%) of the 15 CSA patients had communication between the right atrium (RA; n = 6) or LA (n = 5) and CS via intraseptal veins; six patients (40%) had persistent left superior caval veins; communications were also observed between the CS and RA (n = 4) or LA (n = 4); two patients had collateral venous pathways between dilated cardiac veins with RA; two patients had unroofing of the CS as outlet channels. Nine patients (60%) had cardiac anomalies: coronary artery fistula to the pulmonary artery (n = 6) or left ventricular base and CS (n = 1), atrial septal defects (n = 2), and a ventricular septal defect (n = 1). CONCLUSION: CSA patients have venous collateral pathways and a high incidence of associated cardiovascular anomalies such as coronary artery fistulae and atrial septal defects.
Assuntos
Técnicas de Imagem de Sincronização Cardíaca/métodos , Seio Coronário/patologia , Anomalias dos Vasos Coronários/diagnóstico , Imageamento por Ressonância Magnética/métodos , Tomografia Computadorizada por Raios X/métodos , Adolescente , Adulto , Idoso , Circulação Colateral , Meios de Contraste , Anomalias dos Vasos Coronários/diagnóstico por imagem , Feminino , Humanos , Imageamento Tridimensional/métodos , Iopamidol/análogos & derivados , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
OBJECTIVES: The purpose of this study was to analyze the prognostic value of dynamic CT perfusion imaging (CTP) and CT derived fractional flow reserve (CT-FFR) for major adverse cardiac events (MACE). METHODS: 81 patients from 4 institutions underwent coronary computed tomography angiography (CCTA) with dynamic CTP imaging and CT-FFR analysis. Patients were followed-up at 6, 12, and 18 months after imaging. MACE were defined as cardiac death, nonfatal myocardial infarction, unstable angina requiring hospitalization, or revascularization. CT-FFR was computed for each major coronary artery using an artificial intelligence-based application. CTP studies were analyzed per vessel territory using an index myocardial blood flow, the ratio between territory and global MBF. The prognostic value of CCTA, CT-FFR, and CTP was investigated with a univariate and multivariate Cox proportional hazards regression model. RESULTS: 243 vessels in 81 patients were interrogated by CCTA with CT-FFR and 243 vessel territories (1296 segments) were evaluated with dynamic CTP imaging. Of the 81 patients, 25 (31%) experienced MACE during follow-up. In univariate analysis, a positive index-MBF resulted in the largest risk for MACE (HR 11.4) compared to CCTA (HR 2.6) and CT-FFR (HR 4.6). In multivariate analysis, including clinical factors, CCTA, CT-FFR, and index-MBF, only index-MBF significantly contributed to the risk of MACE (HR 10.1), unlike CCTA (HR 1.2) and CT-FFR (HR 2.2). CONCLUSION: Our study provides initial evidence that dynamic CTP alone has the highest prognostic value for MACE compared to CCTA and CT-FFR individually or a combination of the three, independent of clinical risk factors.
Assuntos
Angiografia por Tomografia Computadorizada/métodos , Angiografia Coronária/métodos , Doença da Artéria Coronariana/diagnóstico por imagem , Vasos Coronários/diagnóstico por imagem , Reserva Fracionada de Fluxo Miocárdico , Imagem de Perfusão do Miocárdio/métodos , Idoso , Inteligência Artificial , Ásia , Doença da Artéria Coronariana/mortalidade , Doença da Artéria Coronariana/fisiopatologia , Doença da Artéria Coronariana/terapia , Vasos Coronários/fisiopatologia , Europa (Continente) , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Interpretação de Imagem Radiográfica Assistida por Computador , Sistema de Registros , Medição de Risco , Fatores de Risco , Estados UnidosRESUMO
Vascular endothelial growth factor (VEGF) is a mediator of airway inflammation and remodelling in asthma. Transforming growth factor (TGF)-beta(1) plays pivotal roles in diverse biological processes, including tissue remodelling and repair in a number of chronic lung diseases. However, there are few studies elucidating the interactions between VEGF and TGF-beta(1) in allergic airway disease. A murine model of allergic airway disease was used to define the mechanism by which VEGF induces subepithelial fibrosis and to investigate a potential relationship between VEGF and TGF-beta(1) and the mechanisms by which VEGF signalling regulates TGF-beta(1) expression in allergic airway disease. The ovalbumin (OVA)-inhaled murine model revealed the following typical pathophysiological features of allergic airway disease in the lungs: increased numbers of inflammatory cells of the airways, airway hyperresponsiveness, increased peribronchial fibrosis, and increased levels of VEGF and TGF-beta(1). Administration of VEGF inhibitors reduced the pathophysiological signs of allergic airway disease and decreased the increased TGF-beta(1) levels and peribronchial fibrosis, including phosphoinositide 3-kinase (PI3K) activity after OVA inhalation. In addition, the increased TGF-beta(1) levels and collagen deposition after OVA inhalation were decreased by administration of PI3K inhibitors. These results suggest that inhibition of vascular endothelial growth factor attenuates peribronchial fibrosis, at least when mediated by regulation of transforming growth factor-beta(1) expression through phosphoinositide 3-kinase/Akt pathway in a murine model of allergic airway disease.
Assuntos
Asma/imunologia , Asma/fisiopatologia , Fator de Crescimento Transformador beta1/metabolismo , Fator A de Crescimento do Endotélio Vascular/imunologia , Animais , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fibrose Pulmonar/fisiopatologia , Transdução de Sinais , Fator de Crescimento Transformador beta1/imunologia , Fator A de Crescimento do Endotélio Vascular/fisiologiaRESUMO
PURPOSE: To test the hypothesis that a proximal arterial occlusion has a protective effect on the progression of distal arterial disease, assessed by distal runoff resistance score (DRRS). MATERIALS AND METHODS: One hundred and nineteen patients (median age 64 y, male 96%) with a unilateral iliac and/or femoral arterial occlusion caused by atherosclerosis were analyzed retrospectively. DRRS was assessed on arteriograms of the test limb (with proximal arterial occlusion) and control limb (contralateral limb). Multivariate analysis was performed to determine if a proximal arterial occlusion was an independent risk factor for the development of a difference in the DRRS between the test and control limbs. RESULTS: The clinical features of the subjects were claudication in 85%, ankle brachial index 0.52 (median), diabetes in 30% and smoker in 76%. The upper leg DRRS of the test limb was significantly lower in the iliac occlusion group than in the control limb (1.87+/-1.69 vs 2.85+/-2.75, p=0.032). However, multivariate analysis failed to identify any risk factors associated with the difference in DRRS in both limbs. CONCLUSION: There was no evidence that a proximal arterial occlusion was associated with a slower progression of distal arterial disease.
Assuntos
Arteriopatias Oclusivas/fisiopatologia , Aterosclerose/fisiopatologia , Artéria Femoral , Artéria Ilíaca , Resistência Vascular , Idoso , Arteriopatias Oclusivas/epidemiologia , Aterosclerose/complicações , Comorbidade , Progressão da Doença , Feminino , Artéria Femoral/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Artéria Poplítea/fisiopatologia , Estudos Retrospectivos , Fatores de Risco , Estatísticas não Paramétricas , Artérias da Tíbia/fisiopatologiaRESUMO
BACKGROUND: Multidetector computerized tomography (MDCT) is considered to be a fast noninvasive diagnostic technique for the evaluation of postoperative complications in patients with liver transplantation (LT). However, its role has not been fully established in the diagnosis for detecting complications after liver transplantation. The aim of this work was to evaluate the diagnostic performance of MDCT for detecting abdominal complications in the early and late periods after LT. METHODS: We retrospectively enrolled 75 patients who had undergone LT from March 2006 to January 2010, followed by MDCT from March 2006 to November 2017. Patients were divided into 2 groups according to the timing after LT: within the first 3 months (early period) or ≥3 months after LT (late period). We evaluated vascular, biliary, and other complications on MDCT. Angiography, endoscopic retrograde cholangiography, and percutaneous transhepatic cholangiography were used as reference standards. RESULTS: We initially found 77 complications in 45 patients (60.0%) with the use of MDCT. After comparison with the reference standards, 83 complications were diagnosed in 49 patients (65.3%). Forty-seven complications (34 vascular, 10 biliary, 3 other complications) were diagnosed in 33 patients (44.0%) during the early period, and 36 complications (6 vascular, 20 biliary, 10 other complications) were detected in 27 patients (36.0%) in the late period. The sensitivity, specificity, and diagnostic accuracy of MDCT for diagnosing overall complications were, respectively, 93.6%, 90.2%, and 92.0% in the early period (for vascular complications: 97.1%, 92.6%, and 94.3%,; for biliary complications: 80.0%, 100%, and 97.7%) and 77.8%, 98.1%, and 89.8% in the late period (for vascular complications: 83.3%, 100%, and 98.9%; for biliary complications: 65.0%, 98.6%, and 90.9%). CONCLUSIONS: Although MDCT in the late period should be interpreted with caution in patients with suspected biliary complication, MDCT is a reliable diagnostic technique for the identification of early and late abdominal complications after LT.
Assuntos
Transplante de Fígado/efeitos adversos , Tomografia Computadorizada Multidetectores/métodos , Complicações Pós-Operatórias/diagnóstico por imagem , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos , Sensibilidade e EspecificidadeRESUMO
A phase I dose-escalation clinical trial of peritumoral injections of interleukin 12 (IL-12)-transduced autologous fibroblasts was performed in patients with disseminated cancer for whom effective treatment does not exist. The goals of this study were to assess the safety and toxicities as well as the efficacy, and ancillarily the immunomodulatory effects, of peritumoral IL-12 gene transfer. Primary dermal fibroblasts cultured from the patients were transduced with retroviral vector carrying human IL-12 genes (p35 and p40) as well as the neomycin phosphotransferase gene (TFG-hIL-12-Neo). Patients received four injections at intervals of 7 days. Nine patients were enrolled in this dose-escalation study, with secreted IL-12 doses ranging from 300 ng/24 hr for the first three patients to 1000, 3000, and 5000 ng/24 hr for two patients in each subsequent dosage level. Although a definite statement cannot be made, there appears to be perturbation of systemic immunity. Also, the locoregional effects mediated by tumor necrosis factor alpha (TNF-alpha) and CD8+ T cells were observed with tumor regression. Treatment-related adverse events were limited to mild to moderate pain at the injection site; clinically significant toxicities were not encountered. Transient but clear reductions of tumor sizes were observed at the injected sites in four of nine cases, and at noninjected distant sites in one melanoma patient. Hemorrhagic necrosis of tumors was observed in two melanoma patients. These data indicate that gene therapy by peritumoral injection of IL-12-producing autologous fibroblasts is feasible, and promising in patients with advanced cancer.
Assuntos
Fibroblastos/transplante , Terapia Genética/métodos , Interleucina-12/genética , Melanoma/terapia , Retroviridae/genética , Neoplasias Cutâneas/terapia , Adulto , Linfócitos T CD8-Positivos/imunologia , Feminino , Fibroblastos/metabolismo , Técnicas de Transferência de Genes , Humanos , Técnicas Imunoenzimáticas , Interleucina-12/imunologia , Interleucina-12/fisiologia , Células Matadoras Naturais/imunologia , Masculino , Melanoma/imunologia , Pessoa de Meia-Idade , Neoplasias Cutâneas/imunologia , Linfócitos T/imunologia , Fator de Crescimento Transformador beta/metabolismo , Células Tumorais Cultivadas , Fator de Necrose Tumoral alfa/metabolismoRESUMO
A novel methodology for the synthesis of poly(ethylene glycol) (PEG) prodrugs of amino-containing compounds has been developed which is based on the trimethyl lock lactonization reaction. These PEG-modified double prodrugs are water soluble, and by selective modification of the specifier or trigger, plasma half-lives can be adjusted at will to result in a wide range of values. Facile syntheses of ester, carbonate, and carbamate functionalities were accomplished and combined with greater or lesser degrees of steric hindrance in the spacer group, or on the aromatic framework, to achieve predictable ranges of drug concentration in plasma. In vivo screening of PEG prodrugs was done using a M109 syngeneic solid mouse tumor model. One of the PEG-daunorubicin prodrugs, with a half-life of 2 h, was evaluated in an in vivo solid tumor panel and found to be more efficacious against ovarian tumors (SKOV3) than equivalent amounts of daunorubicin.
Assuntos
Sistemas de Liberação de Medicamentos , Lactonas/síntese química , Polietilenoglicóis/química , Pró-Fármacos/síntese química , Animais , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/química , Daunorrubicina/administração & dosagem , Daunorrubicina/química , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Lactonas/química , Lactonas/farmacocinética , Lactonas/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Transplante de Neoplasias , Pró-Fármacos/química , Pró-Fármacos/farmacocinética , Pró-Fármacos/farmacologia , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
A general methodology for synthesizing poly(ethylene glycol) (PEG) prodrugs of amino-containing compounds has been developed and constitutes the basis for solubilization of insoluble drugs, extending plasma circulating half-lives and, in the case of anticancer agents, apparent tumor accumulation. Thus, we have successfully designed PEG conjugated specifiers or "triggers" as part of a double-prodrug strategy that relies, first, on enzymatic separation of PEG followed by the classical and rapid 1,4- or 1, 6-benzyl elimination reaction releasing the amine (drug) bound in the form of a carbamate. The prodrug trigger was comprised of ester, carbonate, carbamate, or amide bonds in order to secure predictable rates of hydrolysis. Further refinement of the hydrolysis was accomplished by the introduction of steric hindrance through the use of ortho substituents on the benzyl component of the prodrug. This modification led to longer circulating plasma half-lives of the final tripartate form. The "ortho" effect also had the beneficial effect of directing nucleophilic attack almost exclusively to the activated benzyl 6-position of the heterobifunctional intermediates. In vivo testing of the PEG daunorubicin prodrugs (transport forms) prepared in the course of this study ultimately identified the type 1 carbamate (34b), with a circulating t(1/2) of 4 h, as the most effective derivative for solid tumor growth inhibition.
Assuntos
Aminas/síntese química , Sistemas de Liberação de Medicamentos , Polietilenoglicóis/síntese química , Pró-Fármacos/síntese química , Aminas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Carbamatos/síntese química , Carbonatos/síntese química , Divisão Celular/efeitos dos fármacos , Daunorrubicina/análogos & derivados , Ésteres/síntese química , Hidrólise , Camundongos , Camundongos Endogâmicos , Polietilenoglicóis/farmacologia , Pró-Fármacos/farmacologia , Ratos , Ratos Endogâmicos , Solubilidade , Células Tumorais CultivadasRESUMO
Low molecular weight Poly(ethylene glycol) (PEG) (< 20,000)-drug conjugates, prepared over a 20-year period, have been scrutinized and their properties and efficacy reviewed. No commercial products have thus far been reported for these types of compounds. However, during the past 5 years a renaissance in the field of PEG-(anticancer) drug conjugates has taken place, initiated by the use of higher molecular weight PEGs (> 20,000), especially 40,000, which is estimated to have a plasma circulating half-life of approximately 8-9 h. This recent resuscitation of small organic molecule delivery by high molecular weight PEG conjugates was founded on meaningful in vivo testing using established tumor models and has led to a clinical candidate. Recent applications of high molecular weight PEG prodrug strategies to amino-containing drugs are also detailed.
Assuntos
Polietilenoglicóis , Pró-Fármacos , Amidas , Aminas , Carbamatos , Carbonatos , Ésteres , Éteres , Hidrazonas , Cetonas , Peso Molecular , Polietilenoglicóis/químicaRESUMO
This paper reports on the synthesis and in vivo oncolytic activity of a series of water-soluble acyl derivatives of polyethylene glycol (PEG) conjugated podophyllotoxin. Some analogs of the polymer conjugate showed significantly better activity in a murine leukemia model than native podophyllotoxin suspended in an intralipid emulsion. Additionally, when tested intravenously against a solid lung tumor (A549) model, some conjugated analogs were equivalent to the podophyllotoxin/intralipid emulsion, while those compounds demonstrating slower rates of plasma hydrolysis (in vitro) appeared to cause greater toxicity. There appeared to be an overall correlation between the in vivo antitumor activity of the conjugate and its rate of hydrolysis in vitro, with those showing faster release possessing greater antitumor activity. In conclusion, the solubilization and predictable release of podophyllotoxin from a PEG carrier was achieved and resulted in some derivatives demonstrating, at a minimum, equivalency with podophyllotoxin when administered on an equal molar basis. Further studies may be warranted to assess the PEG-conjugates pharmacokinetics and therapeutic indices in leukemic models.
Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Podofilotoxina/análogos & derivados , Podofilotoxina/administração & dosagem , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/química , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Portadores de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Concentração Inibidora 50 , Leucemia P388/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Camundongos , Camundongos Nus , Transplante de Neoplasias , Ressonância Magnética Nuclear Biomolecular , Podofilotoxina/química , Podofilotoxina/farmacologia , Polietilenoglicóis/farmacologia , Solubilidade , Transplante Heterólogo , Células Tumorais Cultivadas , ÁguaRESUMO
Conventional angiography has been used for diagnosis of Takayasu arteritis (TA). In early stage of TA, subtle inflammatory wall thickening of the aorta and its branches without significant stenosis may be the only morphologic change of TA. Magnetic resonance (MR) imaging appears to be useful in the diagnosis of early stage TA by visualizing concentric wall thickening of the vessels. T2-weighted images may show bright signal of edema in and around the inflamed vessel. Contrast media-enhanced MR shows enhanced wall of vessels even in chronic stage, which may indicate the activity of TA at the tissue level. MR angiography allows us noninvasive assessment of the vascular tree and it may replace conventional angiography.
Assuntos
Aorta Abdominal/patologia , Aorta Torácica/patologia , Imageamento por Ressonância Magnética , Arterite de Takayasu/diagnóstico , Adulto , Meios de Contraste/administração & dosagem , Feminino , Gadolínio DTPA/administração & dosagem , Humanos , Aumento da Imagem , Injeções Intravenosas , Angiografia por Ressonância MagnéticaRESUMO
The purpose of this study was to determine the relationships between serum apolipoprotein concentration and family history of coronary or cerebral events in schoolchildren. In 269 primary schoolchildren aged 6-11 years (145 boys and 124 girls) we measured the blood concentrations of total cholesterol, apolipoproteins B and A-1, and lipoprotein(a), and questioned their parents about coronary or cerebral vascular events. Serum concentrations of apo B, A-1 and Lp(a) significantly increased with age. In children with serum cholesterol concentration > 5.18 mmol/L the concentrations of apo B, A-1, Lp(a) and apo B/apo A-1 ratio were significantly higher. The concentrations of total cholesterol, apo B, Lp(a), and apo B/apo A-1 ratio in the obese group (body weight 20% above the median body weight for age and height) differed significantly from those in the non-obese group. Serum concentrations of Lp(a) in the children who had positive family histories of coronary or cerebral events (geometric mean = 0.174 x/divided by 0.036g/L) and was significantly higher than that in the children with negative history (geometric mean = 0.086 x/divided by 0.36g/L). Family history was an independent and major contributor to high Lp(a). In evaluating children's lipid profiles, measurement of Lp(a) may help to identify children and their families at increased risk and this may facilitate the targeting of preventive measures.
Assuntos
Transtornos Cerebrovasculares/genética , Doença das Coronárias/genética , Lipoproteína(a)/sangue , Criança , Feminino , Humanos , Hipercolesterolemia/complicações , Coreia (Geográfico) , Masculino , Obesidade/complicaçõesRESUMO
Erdheim-Chester disease is a rare systemic disorder characterized by a fibrosing xanthogranulomatous infiltration of multiple organs. We report a case of Erdheim-Chester disease with diffuse necrosis leading to difficulty in making a prompt diagnosis. Radiologically, osteosclerotic lesions with osteolytic element involved metadiaphyses of both proximal tibia, and retroperitoneal infiltrations encasing both kidneys, both adrenals, and aorta were found. A biopsy of the tibia showed diffuse infiltration of foamy histiocytes, Touton-type giant cells, and fibroblastic cells associated with extensive coagulative necrosis. Immunohistochemically, foamy histiocytes were positive for CD68 and peanut agglutinin and negative for S-100 protein. A few Langerhans' cells, which were difficult to identify in hematoxylin-eosin stain, were highlighted by immunostain for S-100 protein. The patient received supportive therapy and was alive 1 1/2 years after diagnosis, with newly developed bilateral retrobulbar lesions and worsened heart failure.
Assuntos
Doenças Ósseas/patologia , Medula Óssea/patologia , Granuloma/patologia , Histiocitose de Células de Langerhans/patologia , Doenças Ósseas/terapia , Células Espumosas/metabolismo , Células Espumosas/patologia , Células Gigantes/metabolismo , Células Gigantes/patologia , Granuloma/terapia , Histiocitose de Células de Langerhans/terapia , Humanos , Imuno-Histoquímica , Células de Langerhans/metabolismo , Células de Langerhans/patologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Necrose , Osteosclerose/diagnóstico por imagem , Osteosclerose/patologia , Proteínas S100/metabolismo , Tíbia/diagnóstico por imagem , Tíbia/patologia , Tomografia Computadorizada por Raios XRESUMO
Hepatitis B virus (HBV) prophylaxis is necessary to prevent de novo hepatitis B infection from HbcAb-positive donors. However, which protocol is more effective is somewhat controversial. Also, it is uncertain whether it is necessary to administer HBV prophylaxis for HbsAb-positive recipients. This study attempted to determine whether it is necessary to administer HBV prophylaxis for HbsAb-positive patients and to evaluate the efficacy of an HBIG monotherapy protocol. From May 1996 to July 2001, among 128 donors examined for HbcAb, 58 donors (45.3%) were HbcAb-positive. Eighteen HbcAb-positive grafts were transplanted to HbsAg-negative recipients. The 4 patients who died of unrelated causes were excluded from this study. Of 14 study cases, 12 recipients were HbsAb-positive, and 2 were HbsAb-naive. Prior to late 1998, we used HBV vaccination only for de novo infection prophylaxis. However, starting from December 1998, HBIG was administered from the time of the liver transplantation regardless of HBsAb positivity. The overall rate of de novo HBV infections from HbcAb-positive donors was 21.4% (3 of 14). All 3 recipients without HBIG prophylaxis presented with de novo HBV infections. Two were HbsAb-positive preoperatively. No de novo HBV infections occurred among recipients with HBIG prophylaxis. Therefore, it is essential to administer HBV prophylaxis even for vaccinated HbsAb-positive patients. HBIG monotherapy is effective to prevent de novo hepatitis B infections from HbcAb-positive donors in living donor liver transplantation.
Assuntos
Antígenos do Núcleo do Vírus da Hepatite B/sangue , Vacinas contra Hepatite B , Hepatite B/prevenção & controle , Transplante de Fígado , Doadores Vivos , Complicações Pós-Operatórias/virologia , Criança , Hepatite B/transmissão , Humanos , Complicações Pós-Operatórias/epidemiologiaRESUMO
Until recently, situs inversus was considered to be an absolute contraindication for liver transplantation. However, recent reports have suggested that situs inversus should not be considered a contraindication. This study presents a successful living donor liver transplantation performed in a 4-month-old male infant with biliary atresia and situs inversus. The surgical findings revealed abdominal situs inversus with polysplenia and an absent retrohepatic inferior vena cava and intestinal malrotation.