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1.
Eur J Vasc Endovasc Surg ; 60(3): 452-460, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32703634

RESUMO

OBJECTIVE: Experimental studies suggest that fenofibrate prevents abdominal aortic aneurysm (AAA) development by lowering aortic osteopontin (OPN) concentration and reducing the number of macrophages infiltrating the aortic wall. The current study examined the effects of a short course of fenofibrate on AAA pathology in people with large AAAs awaiting aortic repair. METHODS: This randomised double blind parallel trial included male and female participants aged ≥ 60 years who had an asymptomatic AAA measuring ≥ 50 mm and were scheduled to undergo open AAA repair. Participants were allocated to fenofibrate (145 mg/day) or matching placebo for at least two weeks before elective AAA repair. Blood samples were collected at recruitment and immediately prior to surgery. AAA biopsies were obtained during aortic surgery. The primary outcomes were (1) AAA OPN concentration; (2) serum OPN concentration; and (3) number of AAA macrophages. Exploratory outcomes included circulating and aortic concentrations of other proteins previously associated with AAA. Outcomes assessed at a single time point were compared using logistic regression. Longitudinal outcomes were compared using linear mixed effects models. RESULTS: Forty-three participants were randomised. After three withdrawals, 40 were followed until the time of surgery (21 allocated fenofibrate and 19 allocated placebo). As expected, serum triglycerides reduced significantly from recruitment to the time of surgery in participants allocated fenofibrate. No differences in any of the primary and exploratory outcomes were observed between groups. CONCLUSION: A short course of 145 mg of fenofibrate/day did not lower concentrations of OPN or aortic macrophage density in people with large AAAs.


Assuntos
Aorta Abdominal/efeitos dos fármacos , Aorta Abdominal/cirurgia , Aneurisma da Aorta Abdominal/terapia , Fenofibrato/administração & dosagem , Procedimentos Cirúrgicos Vasculares , Idoso , Aorta Abdominal/metabolismo , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/sangue , Aneurisma da Aorta Abdominal/patologia , Biomarcadores/sangue , Progressão da Doença , Método Duplo-Cego , Esquema de Medicação , Feminino , Fenofibrato/efeitos adversos , Humanos , Macrófagos/patologia , Masculino , Pessoa de Meia-Idade , Osteopontina/sangue , Queensland , Fatores de Tempo , Resultado do Tratamento , Triglicerídeos/sangue , Remodelação Vascular/efeitos dos fármacos , Procedimentos Cirúrgicos Vasculares/efeitos adversos
2.
Clin Sci (Lond) ; 133(21): 2203-2215, 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-31696215

RESUMO

OBJECTIVE: The role of chronic inflammation in abdominal aortic aneurysm (AAA) is controversial. CD11c+ antigen-presenting cells (APCs) (dendritic cells (DCs)) have been reported in human AAA samples but their role is unclear. The effect of conditional depletion of CD11c+ cells on experimental AAA was investigated in the angiotensin II (AngII)-infused apolipoprotein E-deficient (ApoE-/-) mouse model. APPROACH: CD11c-diphtheria toxin (DT or D.tox) receptor (DTR), ovalbumin (OVA) fragment aa 140-386, and enhanced green fluorescent protein (eGFP)-ApoE-/- (CD11c.DOG.ApoE-/-) mice were generated and CD11c+ cell depletion achieved with D.tox injections (8 ng/g body weight, i.p., every-other-day). AAA formation and growth were assessed by measurement of supra-renal aortic (SRA) diameter in vivo by serial ultrasound and by morphometry assessment of harvested aortas at the end of the study. RESULTS: Depletion of CD11c+ cells by administration of D.tox on alternative days was shown to reduce the maximum diameter of AAAs induced by 28 days AngII infusion compared with controls (D.tox, 1.58 ± 0.03 mm vs Vehicle control, 1.81 ± 0.06 mm, P<0.001). CD11c+ depletion commencing after AAA establishment by 14 days of AngII infusion, was also shown to lead to smaller AAAs than controls after a further 14 days (D.tox, 1.54 ± 0.04 mm vs Vehicle control, 1.80 ± 0.03 mm, P<0.001). Flow cytometry revealed significantly lower numbers of circulating CD44hi CD62Llo effector CD4 T cells, CD44hi CD62Llo effector CD8 T cells and B220+ B cells in CD11c+ cell-depleted mice versus controls. CD11c+ depletion attenuated SRA matrix degradation indicated by decreased neutrophil elastase activity (P=0.014), lower elastin degradation score (P=0.012) and higher collagen content (P=0.002). CONCLUSION: CD11c+ cell-depletion inhibited experimental AAA development and growth associated with down-regulation of circulating effector T cells and attenuated matrix degradation. The findings suggest involvement of autoreactive immune cells in AAA pathogenesis.


Assuntos
Aneurisma da Aorta Abdominal/imunologia , Células Dendríticas/fisiologia , Remodelação Vascular/imunologia , Angiotensina II , Animais , Aneurisma da Aorta Abdominal/sangue , Aneurisma da Aorta Abdominal/induzido quimicamente , Aterosclerose , Antígenos CD11 , Colesterol/sangue , Elastase de Leucócito/sangue , Contagem de Linfócitos , Masculino , Camundongos Knockout para ApoE , Distribuição Aleatória
3.
J Vasc Surg ; 67(3): 770-777, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-28843790

RESUMO

OBJECTIVE: Endoleak is a common complication of endovascular aneurysm repair (EVAR) for abdominal aortic aneurysm (AAA) but can be detected only through prolonged follow-up with repeated aortic imaging. This study examined the potential for circulating matrix metalloproteinase 9 (MMP9), osteoprotegerin (OPG), D-dimer, homocysteine (HCY), and C-reactive protein (CRP) to act as diagnostic markers for endoleak in AAA patients undergoing elective EVAR. METHODS: Linear mixed-effects models were constructed to assess differences in AAA diameter after EVAR between groups of patients who did and did not develop endoleak during follow-up, adjusting for potential confounders. Circulating MMP9, OPG, D-dimer, HCY, and CRP concentrations were measured in preoperative and postoperative plasma samples. The association of these markers with endoleak diagnosis was assessed using linear mixed effects adjusted as before. The potential for each marker to diagnose endoleak was assessed using receiver operating characteristic curves. RESULTS: Seventy-five patients were included in the study, 24 of whom developed an endoleak during follow-up. Patients with an endoleak had significantly larger AAA sac diameters than those who did not have an endoleak. None of the assessed markers showed a significant association with endoleak. This was confirmed through receiver operating characteristic curve analyses indicating poor diagnostic ability for all markers. CONCLUSIONS: Circulating concentrations of MMP9, OPG, D-dimer, HCY, and CRP were not associated with endoleak in patients undergoing EVAR in this study.


Assuntos
Aneurisma da Aorta Abdominal/cirurgia , Implante de Prótese Vascular/efeitos adversos , Proteína C-Reativa/metabolismo , Endoleak/sangue , Procedimentos Endovasculares/efeitos adversos , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Homocisteína/sangue , Metaloproteinase 9 da Matriz/sangue , Osteoprotegerina/sangue , Idoso , Idoso de 80 Anos ou mais , Aneurisma da Aorta Abdominal/sangue , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Aortografia/métodos , Área Sob a Curva , Austrália , Biomarcadores/sangue , Angiografia por Tomografia Computadorizada , Endoleak/diagnóstico por imagem , Endoleak/etiologia , Feminino , Humanos , Modelos Lineares , Masculino , Valor Preditivo dos Testes , Estudos Prospectivos , Curva ROC , Sistema de Registros , Fatores de Risco , Resultado do Tratamento
4.
J Am Heart Assoc ; 7(19): e009866, 2018 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-30371299

RESUMO

Background There is no drug therapy for abdominal aortic aneurysm ( AAA ). FAME-2 (Fenofibrate in the Management of Abdominal Aortic Aneurysm 2) was a placebo-controlled randomized trial designed to assess whether administration of 145 mg of fenofibrate/d for 24 weeks favorably modified circulating markers of AAA. Methods and Results Patients with AAA s measuring 35 to 49 mm and no contraindication were randomized to fenofibrate or identical placebo. The primary outcome measures were the differences in serum osteopontin and kallistatin concentrations between groups. Secondary analyses compared changes in the circulating concentration of AAA -associated proteins, and AAA growth, between groups using multivariable linear mixed-effects modeling. A total of 140 patients were randomized to receive fenofibrate (n=70) or placebo (n=70). By the end of the study 3 (2.1%) patients were lost to follow-up and 18 (12.9%) patients had ceased trial medication. A total of 85% of randomized patients took ≥80% of allocated tablets and were deemed to have complied with the medication regimen. Patients' allocated fenofibrate had expected reductions in serum triglycerides and estimated glomerular filtration rate, and increases in serum homocysteine. No differences in serum osteopontin, kallistatin, or AAA growth were observed between groups. Conclusions Administering 145 mg/d of fenofibrate for 24 weeks did not significantly reduce serum concentrations of osteopontin and kallistatin concentrations, or rates of AAA growth in this trial. The findings do not support the likely benefit of fenofibrate as a treatment for patients with small AAA s. Clinical Trial Registration URL : www.anzctr.org.au . Unique identifier: ACTRN 12613001039774.


Assuntos
Aneurisma da Aorta Abdominal/tratamento farmacológico , Fenofibrato/administração & dosagem , Osteopontina/sangue , Serpinas/sangue , Idoso , Idoso de 80 Anos ou mais , Aorta Abdominal/diagnóstico por imagem , Aneurisma da Aorta Abdominal/sangue , Aneurisma da Aorta Abdominal/diagnóstico , Biomarcadores/sangue , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Hipolipemiantes/administração & dosagem , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Resultado do Tratamento , Ultrassonografia
5.
Trans R Soc Trop Med Hyg ; 102 Suppl 1: S66-70, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19121692

RESUMO

Cell-mediated immunity to Burkholderia pseudomallei, the causative agent of melioidosis, provides protection from disease progression. An indirect haemagglutination assay was used to detect antibodies to B. pseudomallei in 1500 healthy donors in an endemic region of Australia. Lymphocyte proliferation, activation and cytokine expression to B. pseudomallei antigen were determined in eight donors who were seropositive and in eight age- and sex-matched controls. In North Queensland, 2.5% of the population was seropositive for B. pseudomallei, which is less than half that which was previously described. Of clinical significance was the observation that while 75% of the seropositive individuals had increased lymphocyte proliferation to B. pseudomallei antigens, there were no significant differences observed in lymphocyte activation or production of cytokines.


Assuntos
Anticorpos Antibacterianos/isolamento & purificação , Burkholderia pseudomallei/imunologia , Melioidose/imunologia , Adulto , Antígenos de Bactérias/imunologia , Proliferação de Células , Citocinas/metabolismo , Feminino , Testes de Hemaglutinação , Humanos , Imunidade Celular/imunologia , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade
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