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1.
Brain Commun ; 4(4): fcac157, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35813881

RESUMO

Optimal criteria for diagnosing and monitoring response to treatment for infectious and inflammatory medium-large vessel intracranial vasculitis presenting with stroke are lacking. We integrated intracranial vessel wall MRI with arterial spin labelling into our routine clinical stroke pathway to detect presumed inflammatory intracranial arterial vasculopathy, and monitor disease activity, in patients with clinical stroke syndromes. We used predefined standardized radiological criteria to define vessel wall enhancement, and all imaging findings were rated blinded to clinical details. Between 2017 and 2018, stroke or transient ischaemic attack patients were first screened in our vascular radiology meeting and followed up in a dedicated specialist stroke clinic if a diagnosis of medium-large inflammatory intracranial arterial vasculopathy was radiologically confirmed. Treatment was determined and monitored by a multi-disciplinary team. In this case series, 11 patients were managed in this period from the cohort of young stroke presenters (<55 years). The median age was 36 years (interquartile range: 33,50), of which 8 of 11 (73%) were female. Two of 11 (18%) had herpes virus infection confirmed by viral nucleic acid in the cerebrospinal fluid. We showed improvement in cerebral perfusion at 1 year using an arterial spin labelling sequence in patients taking immunosuppressive therapy for >4 weeks compared with those not receiving therapy [6 (100%) versus 2 (40%) P = 0.026]. Our findings demonstrate the potential utility of vessel wall magnetic resonance with arterial spin labelling imaging in detecting and monitoring medium-large inflammatory intracranial arterial vasculopathy activity for patients presenting with stroke symptoms, limiting the need to progress to brain biopsy. Further systematic studies in unselected populations of stroke patients are needed to confirm our findings and establish the prevalence of medium-large artery wall inflammation.

2.
QJM ; 115(3): 148-154, 2022 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-33377941

RESUMO

BACKGROUND: The impact that rare chronic disorders, such as retroperitoneal fibrosis (RPF), can have on the physical and psychological aspects of a patient's health is poorly understood. Patient-related outcome measures and experiences provide a unique opportunity to understand the impact rare chronic disorders have on a patient's life as well as allowing healthcare providers to compare and improve performance. AIM: To understand the physical and psychosocial impact that RPF has upon peoples' lives. DESIGN: An international online questionnaire was therefore created to gain insights into how patients with RPF, a rare fibro-inflammatory condition, viewed their health and experiences. METHODS: An international online questionnaire comprising 62 questions/free text options, was designed in collaboration with two patient advocates and the multi-disciplinary Renal Association Rare Disease Registry (RaDaR) RPF Group the questionnaire was anonymous and freely accessible on a GOOGLE Form online platform for 6 months. RESULTS: A total of 229 patients from 30 countries across 5 continents responded. Four key issues were identified; (i) pain; (ii) therapy-related side effects; (iii) lack of informed doctors/information about their condition and its management; and (iv) psychological burden. Variations in diagnosis and management are highlighted with 55% undergoing a biopsy to reach a diagnosis of RPF; 75% of patients underwent a further interventional procedure with 60% concurrently treated medically. CONCLUSION: This study will guide further development of clinical and academic multi-disciplinary activity and shows the importance of trying to understand the impact of rare chronic disorders on the physical and psychological aspects of a patient's health.


Assuntos
Fibrose Retroperitoneal , Biópsia , Humanos , Doenças Raras , Sistema de Registros , Fibrose Retroperitoneal/tratamento farmacológico , Fibrose Retroperitoneal/terapia
3.
Nat Commun ; 10(1): 5014, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31676784

RESUMO

Endothelial cells actively maintain an anti-thrombotic environment; loss of this protective function may lead to thrombosis and systemic coagulopathy. The transcription factor ERG is essential to maintain endothelial homeostasis. Here, we show that inducible endothelial ERG deletion (ErgiEC-KO) in mice is associated with spontaneous thrombosis, hemorrhages and systemic coagulopathy. We find that ERG drives transcription of the anticoagulant thrombomodulin (TM), as shown by reporter assays and chromatin immunoprecipitation. TM expression is regulated by shear stress (SS) via Krüppel-like factor 2 (KLF2). In vitro, ERG regulates TM expression under low SS conditions, by facilitating KLF2 binding to the TM promoter. However, ERG is dispensable for TM expression in high SS conditions. In ErgiEC-KO mice, TM expression is decreased in liver and lung microvasculature exposed to low SS but not in blood vessels exposed to high SS. Our study identifies an endogenous, vascular bed-specific anticoagulant pathway in microvasculature exposed to low SS.


Assuntos
Regulação da Expressão Gênica , Microvasos/metabolismo , Trombomodulina/metabolismo , Trombose/metabolismo , Regulador Transcricional ERG/metabolismo , Animais , Células Cultivadas , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Humanos , Fatores de Transcrição Kruppel-Like , Camundongos Knockout , Microvasos/citologia , Regiões Promotoras Genéticas/genética , Transdução de Sinais/genética , Estresse Mecânico , Trombomodulina/genética , Trombose/genética , Regulador Transcricional ERG/genética
4.
QJM ; 112(10): 763-769, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31225617

RESUMO

BACKGROUND: Immunoglobulin-G4-related disease (IgG4-RD) is a recently recognized fibro-inflammatory condition that can affect multiple organs. Despite growing interest in this condition, the natural history and management of IgG4-RD remain poorly understood. AIM: To describe the clinical characteristics, treatment and outcomes of IgG4-RD in a multi-ethnic UK cohort, and investigate its possible association with malignancy. DESIGN: Retrospective analysis of case-note and electronic data. METHODS: Cases were identified from sub-specialty cohorts and a systematic search of an NHS trust histopathology database using 'IgG4' or 'inflammatory pseudotumour' as search terms. Electronic records, imaging and histopathology reports were reviewed. RESULTS: In total, 66 identified cases of IgG4-RD showed a similar multi-ethnic spread to the local population of North West London. The median age was 59 years and 71% of patients were male. Presenting symptoms relating to mass effect of a lesion were present in 48% of cases and the mean number of organs involved was 2.4. Total of 10 patients had reported malignancies with 6 of these being haematological. 83% of those treated with steroids had good initial response; however, 50% had relapsing-remitting disease. Rituximab was administered in 11 cases and all achieved an initial serological response. Despite this, seven patients subsequently relapsed after a mean duration of 11 months and four progressed despite treatment. CONCLUSIONS: We report a large UK-based cohort of IgG4-RD that shows no clear ethnic predisposition and a wide range of affected organs. We discuss the use of serum IgG4 concentrations as a disease marker in IgG4-RD, the association with malignant disease and outcomes according to differing treatment regimens.


Assuntos
Doença Relacionada a Imunoglobulina G4/complicações , Imunoglobulina G/sangue , Neoplasias/complicações , Adulto , Idoso , Etnicidade , Feminino , Glucocorticoides/uso terapêutico , Humanos , Doença Relacionada a Imunoglobulina G4/sangue , Doença Relacionada a Imunoglobulina G4/tratamento farmacológico , Imunossupressores/uso terapêutico , Londres , Masculino , Pessoa de Meia-Idade , Recidiva , Estudos Retrospectivos , Rituximab/uso terapêutico
5.
Nat Commun ; 8: 16002, 2017 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-28695891

RESUMO

Notch and Angiopoietin-1 (Ang1)/Tie2 pathways are crucial for vascular maturation and stability. Here we identify the transcription factor ERG as a key regulator of endothelial Notch signalling. We show that ERG controls the balance between Notch ligands by driving Delta-like ligand 4 (Dll4) while repressing Jagged1 (Jag1) expression. In vivo, this regulation occurs selectively in the maturing plexus of the mouse developing retina, where Ang1/Tie2 signalling is active. We find that ERG mediates Ang1-dependent regulation of Notch ligands and is required for the stabilizing effects of Ang1 in vivo. We show that Ang1 induces ERG phosphorylation in a phosphoinositide 3-kinase (PI3K)/Akt-dependent manner, resulting in ERG enrichment at Dll4 promoter and multiple enhancers. Finally, we demonstrate that ERG directly interacts with Notch intracellular domain (NICD) and ß-catenin and is required for Ang1-dependent ß-catenin recruitment at the Dll4 locus. We propose that ERG coordinates Ang1, ß-catenin and Notch signalling to promote vascular stability.


Assuntos
Angiopoietina-1/metabolismo , Receptores Notch/metabolismo , Remodelação Vascular , Proteínas Adaptadoras de Transdução de Sinal , Animais , Proteínas de Ligação ao Cálcio , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteína Jagged-1/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Regulador Transcricional ERG/metabolismo , Via de Sinalização Wnt
6.
Ann Rheum Dis ; 75(2): 439-48, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25575725

RESUMO

AIMS: Premature cardiovascular events complicate chronic inflammatory conditions. Low-dose weekly methotrexate (MTX), the most widely used disease-modifying drug for rheumatoid arthritis (RA), reduces disease-associated cardiovascular mortality. MTX increases intracellular accumulation of adenosine monophosphate (AMP) and 5-aminoimidazole-4-carboxamide ribonucleotide which activates AMP-activated protein kinase (AMPK). We hypothesised that MTX specifically protects the vascular endothelium against inflammatory injury via induction of AMPK-regulated protective genes. METHODS/RESULTS: In the (NZW×BXSB)F1 murine model of inflammatory vasculopathy, MTX 1 mg/kg/week significantly reduced intramyocardial vasculopathy and attenuated end-organ damage. Studies of human umbilical vein endothelial cells (HUVEC) and arterial endothelial cells (HAEC) showed that therapeutically relevant concentrations of MTX phosphorylate AMPKα(Thr172), and induce cytoprotective genes including manganese superoxide dismutase (MnSOD) and haem oxygenase-1 (HO-1). These responses were preserved when HUVECs were pretreated with tumour necrosis factor-α to mimic dysfunctional endothelium. Furthermore, MTX protected against glucose deprivation-induced endothelial apoptosis. Mechanistically, MTX treatment led to cyclic AMP response element-binding protein (CREB)(Ser133) phosphorylation, while AMPK depletion attenuated this response and the induction of MnSOD and HO-1. CREB siRNA inhibited upregulation of both cytoprotective genes by MTX, while chromatin immunoprecipitation demonstrated CREB binding to the MnSOD promoter in MTX-treated EC. Likewise, treatment of (NZW×BXSB)F1 mice with MTX enhanced AMPKα(Thr172) phosphorylation and MnSOD, and reduced aortic intercellular adhesion molecule-1 expression. CONCLUSIONS: These data suggest that MTX therapeutically conditions vascular endothelium via activation of AMPK-CREB. We propose that this mechanism contributes to the protection against cardiovascular events seen in patients with RA treated with MTX.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Antirreumáticos/farmacologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Metotrexato/farmacologia , Vasculite Reumatoide/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Animais , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Heme Oxigenase-1/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Hidroximetil e Formil Transferases/metabolismo , Inflamação , Camundongos , Complexos Multienzimáticos/metabolismo , Nucleotídeo Desaminases/metabolismo , Fosforilação , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa
7.
Br J Surg ; 101(2): 43-50, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24375298

RESUMO

BACKGROUND: Takayasu arteritis (TA) predisposes to the development of arterial stenoses and aneurysms, and is associated with considerable morbidity and mortality amongst young patients. The aims of this study were to analyse indications and outcomes of surgical intervention, and to assess the potential benefits of immunosuppression and the use of perioperative imaging. METHODS: This was a retrospective review of patients with TA referred between 2001 and 2012. RESULTS: A series of 97 patients with TA, seen at a single tertiary centre, is reported. Immunosuppression was required in 87 patients (90 per cent). Thirty-seven (38 per cent) underwent 64 procedures: 27 patients underwent 33 open surgical procedures and 20 patients had 31 endovascular procedures. After a median follow-up of 6 years, the overall success rate was 79 per cent for open surgery (mean graft patency 9.4 years) and 52 per cent for endovascular procedures (P = 0.035). Procedural failure was significantly reduced in patients receiving preoperative immunosuppression, and particularly endovascular procedures (P = 0.001). In addition to clinical examination and measurement of acute-phase reactants, combination non-invasive imaging including Doppler ultrasonography, [18F]fluorodeoxyglucose combined positron emission and computed tomography (CT), magnetic resonance angiography and CT angiography was used to identify arterial lesions, establish the diagnosis and monitor treatment outcomes. CONCLUSION: Outcomes of vascular intervention in TA may be improved by detailed preoperative assessment including measurement of disease activity, and by ensuring optimal immunomodulatory therapy before and after the procedure.


Assuntos
Procedimentos Endovasculares/métodos , Arterite de Takayasu/cirurgia , Adulto , Angioplastia/métodos , Aneurisma da Aorta Torácica/patologia , Aneurisma da Aorta Torácica/fisiopatologia , Aneurisma da Aorta Torácica/cirurgia , Doenças das Artérias Carótidas/patologia , Doenças das Artérias Carótidas/fisiopatologia , Doenças das Artérias Carótidas/cirurgia , Terapia Combinada , Constrição Patológica/patologia , Constrição Patológica/fisiopatologia , Constrição Patológica/cirurgia , Doença das Coronárias/patologia , Doença das Coronárias/fisiopatologia , Doença das Coronárias/cirurgia , Dilatação Patológica/patologia , Dilatação Patológica/fisiopatologia , Dilatação Patológica/cirurgia , Feminino , Fluordesoxiglucose F18 , Humanos , Terapia de Imunossupressão/métodos , Angiografia por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Cuidados Pré-Operatórios , Compostos Radiofarmacêuticos , Recidiva , Obstrução da Artéria Renal/patologia , Obstrução da Artéria Renal/fisiopatologia , Obstrução da Artéria Renal/cirurgia , Reoperação , Estudos Retrospectivos , Stents , Arterite de Takayasu/patologia , Arterite de Takayasu/fisiopatologia , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Ultrassonografia Doppler , Grau de Desobstrução Vascular/fisiologia
8.
Int J Vasc Med ; 2013: 618910, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23986869

RESUMO

Takayasu aortoarteritis is a rare, chronic granulomatous panarteritis with significant morbidity amongst young patients. Current challenges include a lack of awareness about the condition, delays in diagnosis due to its varied presentation, and suboptimal methods for assessing disease activity. The development of noninvasive imaging including magnetic resonance angiography and positron emission tomography is aiding earlier diagnosis. Early initiation of immunosuppressive treatment is crucial to control active inflammation and minimize arterial injury. Recent studies investigating biological agents such as tumour necrosis factor- α antagonists are encouraging. Surgical revascularization should only be undertaken following careful consideration, as restenosis is common. The indications for considering intervention include uncontrolled hypertension due to renal artery stenosis, severe symptomatic coronary artery or cerebrovascular disease, severe aortic regurgitation, stenotic or occlusive lesions resulting in critical limb ischemia, and aneurysms at risk of rupture. In these cases, the risk benefit ratio for intervention is good. Open surgery, at present, has better outcomes compared to endovascular techniques. However, technological advances in endovascular treatment are continually improving. Controlling disease activity prior to and following revascularization is key to preventing complications. A multidisciplinary approach to the diagnosis and management of Takayasu arteritis is essential to achieve satisfactory patient outcomes.

9.
J Thromb Haemost ; 5(12): 2537-46, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17927807

RESUMO

BACKGROUND: Heme oxygenase-1 (HO-1), by exerting anti-inflammatory, antiproliferative, antiapoptotic and antioxidant effects in the vasculature, protects against atherosclerosis and post-transplant vasculopathy. We noted the overlap between the effects of HO-1 and those attributed to 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins). This led to an investigation of the role of HO-1 in statin-mediated cytoprotection in primary human endothelial cells (ECs), and the ability of Kruppel-like factor 2 (KLF2) to regulate HO-1 function. METHODS/RESULTS: Treatment of human umbilical vein and aortic ECs with atorvastatin significantly upregulated HO-1 promoter activity, mRNA expression and protein expression, increasing HO-1 enzymatic activity as shown by raised intracellular bilirubin IXalpha. This effect was indirect, dependent upon inhibition of HMG-CoA reductase and geranylgeranylation, and independent of nitric oxide or changes in mRNA stability. Atorvastatin protected ECs against the generation of reactive oxygen species and H(2)O(2)-induced injury. HO-1 inhibition, with small interfering RNA (siRNA) or zinc protoporphyrin IX, abrogated atorvastatin-mediated cytoprotection. Atorvastatin upregulated KLF2 expression, whereas KLF2 siRNA attenuated statin-induced HO-1 and its associated antioxidant cytoprotective effects. Iron chelation, adenoviral-mediated overexpression of ferritin or supplementation of culture media with biliverdin reversed the inhibitory effects of HO-1 and KLF2 siRNA, suggesting that bile pigments and ferritin mediate the antioxidant actions of statin-induced HO-1. CONCLUSIONS: We have identified a novel link between KLF2 and HO-1 in human vascular ECs, demonstrating that atorvastatin-mediated HO-1 upregulation, and its associated antioxidant effect, is KLF2-dependent. The relationship between KLF2 and HO-1 is likely to represent an important component of the vasculoprotective profile of statins.


Assuntos
Antioxidantes/farmacologia , Citoproteção , Células Endoteliais/efeitos dos fármacos , Heme Oxigenase-1/biossíntese , Ácidos Heptanoicos/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Fatores de Transcrição Kruppel-Like/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Pirróis/farmacologia , Atorvastatina , Bilirrubina/metabolismo , Biliverdina/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Células Endoteliais/enzimologia , Células Endoteliais/metabolismo , Indução Enzimática , Inibidores Enzimáticos/farmacologia , Ferritinas/genética , Ferritinas/metabolismo , Heme Oxigenase-1/antagonistas & inibidores , Heme Oxigenase-1/genética , Humanos , Peróxido de Hidrogênio/farmacologia , Quelantes de Ferro/farmacologia , Fatores de Transcrição Kruppel-Like/genética , Ácido Mevalônico/farmacologia , Oxidantes/farmacologia , Prenilação , Regiões Promotoras Genéticas/efeitos dos fármacos , Protoporfirinas/farmacologia , Interferência de RNA , RNA Mensageiro/biossíntese , RNA Interferente Pequeno/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Terpenos/farmacologia
10.
Clin Rheumatol ; 26(4): 584-6, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16416032

RESUMO

The presence of an acute phase response may pre-date the eventual diagnosis of malignant disease by months or even years. We describe two patients referred to the rheumatology clinic, in which extensive investigation failed to identify an underlying cause to account for the presenting symptoms and an associated acute phase response. Several months later, repeated abdominal CT scans revealed an abnormality and subsequent laparoscopic biopsy confirmed a diagnosis of peritoneal mesothelioma.


Assuntos
Reação de Fase Aguda/etiologia , Mesotelioma/patologia , Peritônio/patologia , Feminino , Humanos , Masculino , Mesotelioma/complicações , Mesotelioma/diagnóstico , Pessoa de Meia-Idade
11.
Rheumatology (Oxford) ; 46(1): 6-15, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17043053

RESUMO

Takayasu's arteritis (TA), a rare large vessel vasculitis of unknown aetiology, remains a difficult disease to manage with diagnosis often delayed until the late occlusive stage when irreversible vascular damage has occurred. Recent studies suggest that non-invasive imaging modalities including magnetic resonance imaging, ultrasound and 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) allow diagnosis of TA earlier in the disease course than standard angiography and provide a means for monitoring disease activity. Choice of appropriate therapy for TA is limited by a lack of evidence and a combination of corticosteroids and immunosuppressive drugs is most commonly used. Novel therapeutic approaches such as the use of anti-tumour necrosis factor alpha (TNF-alpha) inhibitors and drug-eluting arterial stents show promise for improving the prognosis in severe disease. In addition, strict management of traditional cardiovascular risk factors such as dyslipidaemia, hypertension and lifestyle factors is mandatory to minimize secondary cardiovascular complications, which are the major cause of death in this disease.


Assuntos
Arterite de Takayasu/diagnóstico , Angiografia/métodos , Glucocorticoides/uso terapêutico , Humanos , Imunossupressores/uso terapêutico , Angiografia por Ressonância Magnética/métodos , Tomografia por Emissão de Pósitrons/métodos , Arterite de Takayasu/terapia , Ultrassonografia Doppler/métodos
12.
Clin Exp Immunol ; 146(1): 133-45, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16968408

RESUMO

Abnormal clearance by the mononuclear phagocytic system of immune complexes (IC) is important in the pathogenesis of systemic lupus erythematosus (SLE). We have developed an in vitro model to investigate the cellular mechanisms involved in the transfer of soluble IC from erythrocytes to human macrophages under physiological flow conditions. In this assay, erythrocytes bearing fluorescently labelled IC are perfused over monolayers of human monocytes or monocyte-derived macrophages in a parallel-plate flow chamber, and transfer quantified using confocal microscopy and flow cytometry. Using aggregated human IgG as a model IC, we have been able to demonstrate transfer of IC from erythrocytes to macrophages. Blocking studies with specific neutralizing antibodies have shown that both complement and Fcgamma receptors are required for IC transfer. Blockade of CR4 (alpha(x)beta(2) integrin), FcgammaRIIa or FcgammaRIII reduced transfer, while anti-CR3 (alpha(m)beta(2) integrin) had no effect. Blockade of CR3, FcgammaRIIa or FcgammaRIII also reduced the number of adhesive interactions between fluorescently labelled IC-bearing erythrocytes and macrophage monolayers. Taken together with the transfer data, this suggests differing roles for these receptors in the human IC transfer reaction that includes an adhesive function which facilitates IC processing by mononuclear phagocytes. Finally, a functional effect of the FcgammaRIIa R131/H131 polymorphism, important in susceptibility to SLE, has also been demonstrated using this model. Uptake of IgG(2) but not IgG(1)-containing soluble IC was reduced by macrophages from individuals homozygous for the R131 allelic variant of the receptor.


Assuntos
Complexo Antígeno-Anticorpo/imunologia , Eritrócitos/imunologia , Macrófagos/imunologia , Receptores de Complemento/imunologia , Receptores de IgG/imunologia , Antígenos CD/genética , Adesão Celular/imunologia , Células Cultivadas , Humanos , Imunoglobulina G/imunologia , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia , Modelos Imunológicos , Polimorfismo Genético , Receptores de IgG/genética
13.
Circ Res ; 94(1): 119-26, 2004 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-14656926

RESUMO

The recently described hemoglobin scavenger receptor CD163 mediates the endocytosis of hemoglobin:haptoglobin (Hb:Hp) complexes and thereby counters Hb-induced oxidative tissue damage after hemolysis. Although CD163 has been indirectly associated with antiinflammatory and atheroprotective activity, no ligand-receptor-effector pathway has yet been described for this receptor. To understand the significance of CD163 and more clearly define downstream pathways linked to inflammatory resolution, we studied the expression and function of CD163 in human monocytes/macrophages using both in vitro and in vivo models. Differentiation of human blood monocytes into macrophages either by in vitro culture or in resolving cantharidin-induced skin blisters led to an equivalent increase (>15x) in CD163 expression. Elevated CD163 levels were also noted on circulating monocytes in cardiac surgical patients during the resolution phase of the systemic inflammatory response to cardiopulmonary bypass surgery. In each case, binding of Hb:Hp to CD163-bearing cells elicited potent interleukin-10 secretion, and this was inhibited by the anti-CD163 antibody RM3/1. Release of interleukin-10, in turn, induced heme oxygenase-1 stress protein synthesis via an autocrine mechanism. Such induction of heme oxygenase-1 was observed in vivo 24 to 48 hours after the onset of cardiopulmonary bypass surgery. These results identify novel antiinflammatory and cytoprotective effector pathways in human monocytes/macrophages related to Hb scavenging and metabolism, which may have relevance in atheroprotection, wound healing, and patient recovery postoperatively.


Assuntos
Antígenos CD/fisiologia , Antígenos de Diferenciação Mielomonocítica/fisiologia , Ponte Cardiopulmonar , Heme Oxigenase (Desciclizante)/biossíntese , Interleucina-10/biossíntese , Macrófagos/imunologia , Monócitos/imunologia , Receptores de Superfície Celular/fisiologia , Idoso , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Comunicação Autócrina , Vesícula/imunologia , Células Cultivadas , Ponte de Artéria Coronária , Feminino , Haptoglobinas/metabolismo , Heme Oxigenase-1 , Hemoglobinas/metabolismo , Humanos , Inflamação/enzimologia , Inflamação/metabolismo , Macrófagos/enzimologia , Masculino , Proteínas de Membrana , Pessoa de Meia-Idade , Monócitos/enzimologia , Receptores de Superfície Celular/metabolismo
14.
Transpl Infect Dis ; 4(4): 218-22, 2002 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-12535266

RESUMO

Renal transplant recipients are at increased risk of malignancy and infection. We present the case of a 72-year-old-man with recurrent bladder carcinoma, abdominal aortic aneurysm repair, and end-stage renal failure due to renovascular disease. He received a cadaveric renal allograft into his left iliac fossa, was given cyclosporin A, azathioprine, and prednisolone triple therapy immunosuppression, and had no rejection episodes. He presented four years post-transplantation with a two-year history of intermittent sweats and fevers. Previous episodes had been investigated with no firm diagnosis made. This time he had right iliac fossa pain of three weeks' duration. Examination revealed a tender mass. Investigations showed unchanged graft function, but elevated inflammatory indices. Ultrasonography and computed tomography detailed an infiltrating mass associated with the sigmoid colon, which colonoscopy failed to visualise. At laparotomy a 6-cm tumor was removed, with adherent sigmoid colon and bladder dome. Macroscopically the mass was an abscess, and microscopy found acute and chronic inflammatory giant cells and fibrillary masses suggestive of actinomycosis, with no malignancy. The patient recovered uneventfully on antibiotics. At six months' follow-up, examination, inflammatory markers, and radiographic imaging showed no evidence of recurrence. Twelve months later the patient died of rupture of his proximal abdominal aorta. There was no evidence of recurrence at postmortem examination. We conclude with a brief review of actinomycosis in transplant recipients.


Assuntos
Abdome/microbiologia , Actinomicose/diagnóstico , Transplante de Rim/efeitos adversos , Abscesso Abdominal , Actinomyces/crescimento & desenvolvimento , Actinomicose/tratamento farmacológico , Actinomicose/etiologia , Actinomicose/microbiologia , Idoso , Antifúngicos/uso terapêutico , Cefaclor/farmacologia , Cefaclor/uso terapêutico , Humanos , Imunossupressores/uso terapêutico , Masculino , Infecções Oportunistas/diagnóstico , Infecções Oportunistas/tratamento farmacológico , Infecções Oportunistas/microbiologia
15.
Otolaryngol Head Neck Surg ; 125(1): 49-53, 2001 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-11458214

RESUMO

OBJECTIVE: Endoscopic resection has been proposed for sinonasal inverted papilloma (IP). Our objective was to determine the efficacy of aggressive endoscopic resection of IP. METHODS: Retrospective analysis was performed on patients undergoing endoscopic resection of IP at the University of Virginia between 1990 and 1996. Total ethmoidectomies, wide maxillary antrostomies, frontal recess explorations, sphenoidotomies, and turbinate resection were performed as required. Once all visible papilloma was removed, residual mucosa was removed by using a diamond burr to polish bone at the site of origin. RESULTS: Twenty-one patients were treated with endoscopic resection of IP. Only 1 of 21 patients had an adjunctive external procedure (an osteoplastic flap without obliteration). Average follow-up was 41.9 months after initial aggressive endoscopic resection at the ureterovesical angle. Recurrences occurred in 19% (4/21) of patients. One of the 4 had two recurrences. Recurrences occurred in 16 months or less, except for one noted at 35 months and another at 56 months. CONCLUSIONS: Aggressive endoscopic resection of IP by experienced rhinologists is an acceptable treatment.


Assuntos
Endoscopia/métodos , Recidiva Local de Neoplasia/epidemiologia , Neoplasias Nasais/cirurgia , Papiloma Invertido/cirurgia , Seios Paranasais/cirurgia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Feminino , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Mucosa Nasal/patologia , Recidiva Local de Neoplasia/patologia , Neoplasias Nasais/diagnóstico , Papiloma Invertido/diagnóstico , Seios Paranasais/patologia , Estudos Retrospectivos , Medição de Risco , Tomografia Computadorizada por Raios X , Resultado do Tratamento
16.
Arthritis Rheum ; 44(1): 138-50, 2001 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-11212152

RESUMO

OBJECTIVE: Decay-accelerating factor (DAF) is a widely expressed, multifunctional cell surface protein involved in complement regulation and cell signaling. Previous studies have demonstrated that endothelial cell (EC) DAF is up-regulated by tumor necrosis factor alpha and inhibits complement binding. Because vascular endothelial growth factor (VEGF) is cytoprotective to endothelium and is expressed at sites of chronic inflammation, we hypothesized that VEGF may induce DAF expression during inflammatory angiogenesis. METHODS: Human umbilical vein and dermal microvascular EC were isolated using routine procedures, and the regulation and function of DAF, as well as other complement-regulatory proteins (membrane cofactor protein and CD59), were analyzed following stimulation with VEGF. RESULTS: Incubation of large- or small-vessel EC with VEGF led to increased expression of DAF, with maximal expression after 48-72 hours of stimulation. This effect depended on the activation of protein kinase C (PKC) and required increased steady-state messenger RNA levels and de novo protein synthesis. Although VEGF-induced EC proliferation was inhibited by both p38 and p42/44 mitogen-activated protein kinase (MAPK) antagonists, DAF up-regulation in response to VEGF was only sensitive to inhibition of p38 MAPK. VEGF-stimulated EC showed a 60% reduction in C3 deposition following complement activation, and this resulted in a marked reduction in complement-mediated EC lysis. These protective effects were abolished by anti-DAF monoclonal antibody 1H4. CONCLUSION: This study confirms the importance of PKC for the regulation of DAF expression by EC and reveals VEGF to be a physiologic agonist for this pathway. The up-regulation of DAF expression by VEGF may represent an important mechanism for the protection of EC from complement-mediated injury during angiogenesis in inflammatory rheumatic diseases.


Assuntos
Antígenos CD55/biossíntese , Fatores de Crescimento Endotelial/farmacologia , Endotélio Vascular/citologia , Linfocinas/farmacologia , Antígenos CD55/genética , Sobrevivência Celular/efeitos dos fármacos , Proteínas do Sistema Complemento/farmacologia , Citoproteção/efeitos dos fármacos , Citoproteção/fisiologia , Endotélio Vascular/química , Humanos , Masculino , Microcirculação/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/fisiologia , Neovascularização Patológica/prevenção & controle , Proteína Quinase C/antagonistas & inibidores , RNA Mensageiro/metabolismo , Pele/irrigação sanguínea , Pele/citologia , Veias Umbilicais , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio Vascular , Proteínas Quinases p38 Ativadas por Mitógeno
17.
Laryngoscope ; 110(12): 1994-9, 2000 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-11129007

RESUMO

OBJECTIVES/HYPOTHESIS: Cartilage-perichondrium grafting of the tympanic membrane has been used in an effort to reduce recurrence or progression of middle ear disease. The rigidity of cartilage has obvious benefit in preventing tympanic membrane retraction, but concern has been raised regarding its sound conduction properties Few studies in the literature address hearing results after cartilage tympanoplasty. The purpose of this study was to investigate the hearing results after primary cartilage tympanoplasty and compare them with results after primary tympanoplasty with temporalis fascia. STUDY DESIGN: A retrospective review of all ear surgeries using cartilage between 1994 and 1999 was performed. METHODS: Only primary cases in which the ossicular chain was intact and no mastoid surgery was performed were included. Indications for surgery included tympanic membrane perforation, retraction, and cholesteatoma Pre- and postoperative speech reception thresholds and air-bone gaps at 500 Hz, 1,000 Hz, 2,000 Hz, and 4,000 Hz were compared. RESULTS: Eleven patients comprised the cartilage study group, and there were 11 age- and temporally matched control subjects. The mean improvement in speech reception threshold for both the study group and the control group was 10 dB. The majority of patients in both groups had ABG closure to within 10 dB at all frequencies examined. There were no statistically significant differences in speech reception threshold improvement or air-bone gap closures between the two groups. CONCLUSIONS: These results demonstrate that hearing results after cartilage tympanoplasty are comparable to those after temporalis fascia tympanoplasty. Therefore, when indicated, a cartilage-perichondrium graft can be used for prevention of disease recurrence or progression without fear of impairing hearing.


Assuntos
Cartilagem/transplante , Audição , Timpanoplastia , Adolescente , Adulto , Audiometria , Condução Óssea , Criança , Humanos , Pessoa de Meia-Idade , Período Pós-Operatório , Estudos Retrospectivos , Resultado do Tratamento
18.
Blood ; 96(8): 2784-92, 2000 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-11023512

RESUMO

There is increasing evidence for functional crosstalk between inflammatory and thrombotic pathways in inflammatory vascular diseases such as atherosclerosis and vasculitis. Thus, complement activation on the endothelial cell (EC) surface during inflammation may generate thrombin via the synthesis of tissue factor. We explored the hypothesis that thrombin induces EC expression of the complement-regulatory proteins decay-accelerating factor (DAF), membrane cofactor protein (MCP), and CD59 and that this maintains vascular integrity during coagulation associated with complement activation. Thrombin increased DAF expression on the surface of ECs by 4-fold in a dose- and time-dependent manner as measured by flow cytometry. DAF up-regulation was first detectable at 6 hours and maximal 24 hours poststimulation, whereas no up-regulation of CD59 or MCP was seen. Thrombin-induced expression required increased DAF messenger RNA and de novo protein synthesis. The response depended on activation of protease-activated receptor 1 (PAR1) and was inhibited by pharmacologic antagonists of protein kinase C (PKC), p38 and p42/44 mitogen-activated protein kinase, and nuclear factor-kappa B. The increased DAF expression was functionally relevant because it significantly reduced C3 deposition and complement-mediated EC lysis. Thus, thrombin-generated at inflammatory sites in response to complement activation-is a physiologic agonist for the PKC-dependent pathway of DAF regulation, thereby providing a negative feedback loop protecting against thrombosis in inflammation. (Blood. 2000;96:2784-2792)


Assuntos
Antígenos CD55/biossíntese , Proteínas do Sistema Complemento/imunologia , Endotélio Vascular/efeitos dos fármacos , Proteína Quinase C/fisiologia , Receptores de Trombina/efeitos dos fármacos , Trombina/farmacologia , Antígenos CD55/genética , Células Cultivadas , Ativação do Complemento , Fatores de Crescimento Endotelial/farmacologia , Endotélio Vascular/citologia , Endotélio Vascular/patologia , Inibidores Enzimáticos/farmacologia , Retroalimentação , Flavonoides/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Imidazóis/farmacologia , Indóis/análise , Indóis/farmacologia , Inflamação/sangue , Inflamação/fisiopatologia , Linfocinas/farmacologia , MAP Quinase Quinase 1 , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Maleimidas/farmacologia , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 1 Ativada por Mitógeno/fisiologia , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Quinases de Proteína Quinase Ativadas por Mitógeno/fisiologia , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/fisiologia , NF-kappa B/antagonistas & inibidores , NF-kappa B/fisiologia , Oligopeptídeos/farmacologia , Fragmentos de Peptídeos/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/fisiologia , Piridinas/farmacologia , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Receptor PAR-1 , Receptores de Trombina/fisiologia , Proteínas Recombinantes/farmacologia , Trombose/prevenção & controle , Veias Umbilicais , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio Vascular , Proteínas Quinases p38 Ativadas por Mitógeno
19.
J Leukoc Biol ; 68(2): 233-42, 2000 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-10947068

RESUMO

This study explored the effect on endothelial cell (EC) activation of contact with T lymphocytes, which occurs during lymphocyte emigration into inflamed tissues. Addition of T cells to umbilical vein or dermal microvascular EC monolayers stimulated expression of EC E-selectin and VCAM-1. This response required direct cell:cell contact, but not T-cell activation. The capacity of resting CD4+ T cells to activate EC was restricted to the CD45RO+ subset and could be enhanced by 6 h prestimulation of T cells with PMA and ionomycin. The EC-stimulating capacity of resting or activated T cells was independent of CD40 ligand. Furthermore, inhibition of TNF-alpha/beta and IL-1alpha/beta, together with CD40 ligand, failed to inhibit EC activation by resting T cells and only inhibited the response to PMA- and ionomycin-activated T cells by 40 +/- 18%. Our data suggest that T-cell-EC interactions can lead to EC activation through a novel contact-dependent, but CD40 ligand-independent, mechanism.


Assuntos
Antígenos CD40/fisiologia , Comunicação Celular/fisiologia , Selectina E/biossíntese , Endotélio Vascular/fisiologia , Linfócitos T/fisiologia , Molécula 1 de Adesão de Célula Vascular/biossíntese , Células Cultivadas , Endotélio Vascular/citologia , Humanos , Ativação Linfocitária , Transdução de Sinais , Linfócitos T/citologia
20.
J Thorac Cardiovasc Surg ; 120(2): 361-9, 2000 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-10917955

RESUMO

BACKGROUND: Aprotinin is a serine protease inhibitor used extensively in cardiac operations to reduce postoperative bleeding. It has also been used in trials aimed at reducing the systemic inflammatory response to cardiopulmonary bypass. It remains unclear whether the anti-inflammatory action of aprotinin is related to its general ability to suppress leukocyte activation or whether aprotinin can exercise effects during the leukocyte-endothelial cell adhesion cascade. METHODS: We used intravital microscopy to study the 3 main stages of the adhesion cascade (leukocyte rolling, firm adhesion, and extravasation) within the mesenteric microcirculation of rats. This in vivo technique allows leukocyte recruitment to be viewed directly through the transparent mesentery of anesthetized animals. RESULTS: Aprotinin, given by continuous infusion at a clinically relevant dose, exerted no effect on the rolling or firm adhesion responses toward local chemoattractant N -formyl-methyl-leucyl-phenylalanine but significantly inhibited extravasation of leukocytes (73% at 40 minutes, P =.04) into surrounding tissues. In parallel in vitro experiments, aprotinin (used at 200, 800, and 1600 kIU/mL) dose dependently inhibited neutrophil transmigration through cultured endothelial cells in response to 3 different chemoattractants: N -formyl-methyl-leucyl-phenylalanine (P <.001 at 800 and 1600 kIU/mL), interleukin 8 (P <.05 at 200 kIU/mL and P <.001 at 800 and 1600 kIU/mL), and platelet-activating factor (P <.05 at 1600 kIU/mL). CONCLUSIONS: Our studies have therefore revealed a novel anti-inflammatory mechanism of aprotinin operating at the level of leukocyte extravasation. These findings may be relevant in the prevention of systemic inflammation after cardiopulmonary bypass through the use of protease inhibitors.


Assuntos
Aprotinina/farmacologia , Adesão Celular/efeitos dos fármacos , Leucócitos/efeitos dos fármacos , Inibidores de Serina Proteinase/farmacologia , Análise de Variância , Animais , Adesão Celular/fisiologia , Relação Dose-Resposta a Droga , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiologia , Ensaio de Imunoadsorção Enzimática , Humanos , Leucócitos/fisiologia , Masculino , Microcirculação , N-Formilmetionina Leucil-Fenilalanina/farmacologia , Neutrófilos/fisiologia , Peroxidase/sangue , Ratos , Ratos Sprague-Dawley , Circulação Esplâncnica , Estatísticas não Paramétricas
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