RESUMO
OBJECTIVE: To explore the technical details and short-term effects of radiofrequency obliteration of varicose veins of lower extremities guided by combined venography and ultrasound. METHODS: Thirty-seven patients with varicose veins of lower extremities were treated with radiofrequency obliteration using Olympus Celon RFiTT® under combined guidance of venography and ultrasound. The indications included varicose veins of lower extremities and reflux of the great saphenous vein confirmed by ultrasound. The contraindications included deep vein thrombosis, cardiac pacemaker, severe cardio- and cerebrovascular diseases or coagulation disorders. Under ultrasound guidance, the saphenous vein around knee level was punctured using a 21G needle, and a 7F sheath was introduced. Through the sheath a venography was made, and an Olympus Celon ProCurve radiofrequency catheter was inserted and advanced to the great saphenous vein under road map, and the catheter tip was positioned at the point 2 cm below the sapheno-femoral junction. The swelling anesthesia was made under ultrasound guidance. Then the radiofrequency obliteration was performed with pressing of the treatment section. The venography was repeated to ensure optimal outcomes. If necessary the radiofrequency obliteration could be repeated once to twice. After that the superficial varicose veins were stripping by small incisions under local anesthesia. After operation, medical decompression stocking was utilized immediately and sustained for three months. The clinical data, intraoperative radiation dose, exposure time and short-term effects were retrospectively analyzed. RESULTS: After the operation, all the patients walked out of the operating room by themselves. The success rate of operation was 100%. The intraoperative radiation dose was 1.78-10.12 mGy (mean 6.56 mGy), and the exposure time was 61-448 s (mean 161 s). By 3 months follow-up, the symptoms were alleviated in all the 37 patients, and the occlusion rate was 100%. No complications such as skin burns, ecchymosis and deep venous thrombosis were found. CONCLUSION: The short-term effects of radiofrequency obliteration using Olympus Celon RFiTT® system in a manner of twice fixed point followed by once reciprocating radiofrequency were satisfactory. Radiofrequency obliteration of great saphenous veins guided by venography and ultrasound has not only the advantages of minimal trauma and rapid recovery, but also the advantages of accurate location, exact effect and avoidance of complications.
Assuntos
Ablação por Cateter , Varizes , Humanos , Extremidade Inferior/diagnóstico por imagem , Flebografia , Estudos Retrospectivos , Resultado do Tratamento , Ultrassonografia , Varizes/diagnóstico por imagem , Varizes/cirurgiaRESUMO
During chronic inflammation, interleukin (IL)-22 expression is up-regulated in both CD4 and CD8 T cells, exerting a protective role in infections. However, in autoimmunity, IL-22 appears to have either a protective or a pathogenic role in a variety of murine models of autoimmunity and, by extrapolation, in humans. It is not clear whether IL-22 itself mediates inflammation or is a by-product of inflammation. We have taken advantage of the dominant negative form of transforming growth factor beta receptor type II (dnTGF-ßRII) mice that develop both inflammatory bowel disease and autoimmune cholangitis and studied the role and the biological function of IL-22 by generating IL-22(-/-) dnTGF-ßRII mice. Our data suggest that the influence of IL-22 on autoimmunity is determined in part by the local microenvironment. In particular, IL-22 deficiency exacerbates tissue injury in inflammatory bowel disease, but has no influence on either the hepatocytes or cholangiocytes in the same model. These data take on particular significance in the previously defined effects of IL-17A, IL-12p40 and IL-23p19 deficiency and emphasize that, in colitis, there is a dominant role of IL-23/T helper type 17 (Th17) signalling. Furthermore, the levels of IL-22 are IL-23-dependent. The use of cytokine therapy in patients with autoimmune disease has significant potential, but must take into account the overlapping and often promiscuous effects that can theoretically exacerbate inflammation.
Assuntos
Doenças Autoimunes/imunologia , Colangite/imunologia , Doenças Inflamatórias Intestinais/prevenção & controle , Interleucinas/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/deficiência , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Doenças Inflamatórias Intestinais/imunologia , Interleucina-17/análise , Interleucina-23/metabolismo , Interleucinas/deficiência , Interleucinas/imunologia , Cirrose Hepática Biliar/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Fatores de Crescimento Transformadores beta/genética , Interleucina 22RESUMO
The diagnosis of primary sclerosing cholangitis (PSC) is difficult due to the lack of sensitive and specific biomarkers, as is the early diagnosis of cholangiocarcinoma (CC), a complication of PSC. The aim of this study was to identify specific serum miRNAs as diagnostic biomarkers for PSC and CC. The levels of 667 miRNAs were evaluated in 90 human serum samples (30 PSC, 30 CC and 30 control subjects) to identify disease-associated candidate miRNAs (discovery phase). The deregulated miRNAs were validated in an independent cohort of 140 samples [40 PSC, 40 CC, 20 primary biliary cirrhosis (PBC) and 40 controls]. Receiver operating characteristic (ROC) curves were established and only miRNAs with an area under the curve (AUC) > 0·70 were considered useful as biomarkers. In the discovery phase we identified the following: 21 miRNAs expressed differentially in PSC, 33 in CC and 26 in both in comparison to control subjects as well as 24 miRNAs expressed differentially between PSC and CC. After the validation phase, miR-200c was found to be expressed differentially in PSC versus controls, whereas miR-483-5p and miR-194 showed deregulated expression in CC compared with controls. We also demonstrate a difference in the expression of miR-222 and miR-483-5p in CC versus PSC. Combination of these specific miRNAs further improved the specificity and accuracy of diagnosis. This study provides a basis for the use of miRNAs as biomarkers for the diagnosis of PSC and CC.
Assuntos
Biomarcadores Tumorais/genética , Colangiocarcinoma/diagnóstico , Colangite Esclerosante/diagnóstico , Regulação Neoplásica da Expressão Gênica , Cirrose Hepática Biliar/diagnóstico , Adulto , Idoso , Área Sob a Curva , Biomarcadores Tumorais/sangue , Estudos de Casos e Controles , Colangiocarcinoma/sangue , Colangiocarcinoma/genética , Colangiocarcinoma/patologia , Colangite Esclerosante/sangue , Colangite Esclerosante/genética , Colangite Esclerosante/patologia , Diagnóstico Diferencial , Feminino , Perfilação da Expressão Gênica , Humanos , Cirrose Hepática Biliar/sangue , Cirrose Hepática Biliar/genética , Cirrose Hepática Biliar/patologia , Masculino , MicroRNAs/sangue , MicroRNAs/genética , Pessoa de Meia-Idade , Curva ROCRESUMO
Cytotoxic T lymphocyte antigen 4 (CTLA-4) immunoglobulin (Ig) is an important regulator of T cell activation and a fusion protein directed at CD80 and CD86; it blocks co-stimulatory signalling and T cell activation. We have taken advantage of a murine model of human primary biliary cirrhosis (PBC), mice expressing a transforming growth factor (TGF)-ß receptor II dominant negative (dnTGF-ßRII) transgene to address the potential therapeutic efficacy of CTLA-4 Ig. To mimic patients with PBC at different stages or duration of disease, we treated mice with either CTLA-4 Ig or control IgG three times weekly from 3 to 12 or 24 weeks of age, or from 12 to 24 weeks of age. CTLA-4 Ig treatment from 3 weeks of age significantly reduced liver inflammation to 12 weeks of age. Treatment initiated at 12 weeks of age also ameliorated the autoimmune cholangitis at 24 weeks of age. However, in mice treated at 3 weeks of age, suppression of liver inflammation was not sustained and colitis was aggravated when treatment was extended to 24 weeks of age. Our data indicate that, in dnTGF-ßRII mice, CTLA-4 Ig treatment has short-term beneficial effects on autoimmune cholangitis, but the effect varies according to duration of treatment and the time in which therapy was initiated. Further dissection of the events that lead to the reduction in therapeutic effectiveness of CTLA-4 Ig will be critical to determining whether such efforts can be applied to human PBC.
Assuntos
Doenças Autoimunes/imunologia , Antígeno CTLA-4/imunologia , Colangite/imunologia , Imunoglobulinas/imunologia , Animais , Autoanticorpos/sangue , Autoanticorpos/imunologia , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/patologia , Autoimunidade/efeitos dos fármacos , Colangite/tratamento farmacológico , Colangite/patologia , Modelos Animais de Doenças , Imunoglobulina G/imunologia , Imunoglobulinas/administração & dosagem , Imunoglobulinas/farmacologia , Fígado/efeitos dos fármacos , Fígado/imunologia , Fígado/patologia , Ativação Linfocitária/imunologia , Camundongos , Camundongos Transgênicos , Mitocôndrias/imunologia , Proteínas Serina-Treonina Quinases/genética , Receptor do Fator de Crescimento Transformador beta Tipo II , Receptores de Fatores de Crescimento Transformadores beta/genética , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Fatores de TempoRESUMO
Several epidemiological studies have demonstrated that patients with primary biliary cirrhosis (PBC) have a higher incidence of urinary tract infections (UTI) and there is significant homology of the immunodominant mitochondrial autoantigen, the E2 component of the pyruvate dehydrogenase complex (PDC-E2), between mammals and bacteria. Previous work has demonstrated that non-obese diabetic (NOD).B6 Idd10/Idd18 infected with Novosphingobium aromaticivorans developed liver lesions similar to human PBC. It was postulated that the biliary disease was dependent upon the presence of the unique N. aro glycosphingolipids in activating natural killer T (NK T) cells. To address this issue, we infected NOD.B6 Idd10/Idd18 mice with either Escherichia coli, N. aro or use of a phosphate-buffered saline (PBS) vehicle control and serially followed animals for the appearance of liver pathology and anti-mitochondrial autoantibodies (AMA). Of striking importance, the biliary disease of E. coli-infected mice was more severe than N. Aro-infected mice and the titre of AMA was higher in E. coli-infected mice. Furthermore, the immunopathology did not correlate with the ability of bacterial extracts to produce antigen-dependent activation of NK T cells. Our data suggest that the unique glycosphingolipids of N. aro are not required for the development of autoimmune cholangitis. Importantly, the data highlight the clinical significance of E. coli infection in a genetically susceptible host, and we suggest that the appearance of autoimmune cholangitis is dependent upon molecular mimicry. These data highlight that breach of tolerance to PDC-E2 is probably the first event in the natural history of PBC in genetically susceptible hosts.
Assuntos
Autoantígenos/imunologia , Colangite/imunologia , Di-Hidrolipoil-Lisina-Resíduo Acetiltransferase/imunologia , Infecções por Escherichia coli/imunologia , Mitocôndrias/imunologia , Proteínas Mitocondriais/imunologia , Sphingomonadaceae/imunologia , Animais , Anticorpos/imunologia , Autoanticorpos/sangue , Autoanticorpos/imunologia , Doenças Autoimunes/imunologia , Doenças Autoimunes/microbiologia , Colangite/microbiologia , Escherichia coli/imunologia , Feminino , Glicoesfingolipídeos/metabolismo , Fígado/microbiologia , Abscesso Hepático/microbiologia , Cirrose Hepática Biliar/imunologia , Camundongos , Camundongos Endogâmicos NOD , Células T Matadoras Naturais/imunologiaRESUMO
Treatment of primary biliary cirrhosis (PBC) has lagged behind that of other autoimmune diseases. In this study we have addressed the potential utility of immunotherapy using regulatory T cells (Treg ) to treat murine autoimmune cholangitis. In particular, we have taken advantage of our ability to produce portal inflammation and bile duct cell loss by transfer of CD8(+) T cells from the dominant negative form of transforming growth factor beta receptor type II (dnTGF-ßRII) mice to recombination-activating gene (Rag)1(-/-) recipients. We then used this robust established adoptive transfer system and co-transferred CD8(+) T cells from dnTGF-ßRII mice with either C57BL/6 or dnTGF-ßRII forkhead box protein 3 (FoxP3(+) ) T cells. Recipient mice were monitored for histology, including portal inflammation and intralobular biliary cell damage, and also included a study of the phenotypical changes in recipient lymphoid populations and local and systemic cytokine production. Importantly, we report herein that adoptive transfer of Treg from C57BL/6 but not dnTGF-ßRII mice significantly reduced the pathology of autoimmune cholangitis, including decreased portal inflammation and bile duct damage as well as down-regulation of the secondary inflammatory response. Further, to define the mechanism of action that explains the differential ability of C57BL/6 Treg versusâ dnTGF-ßRII Treg on the ability to down-regulate autoimmune cholangitis, we noted significant differential expression of glycoprotein A repetitions predominant (GARP), CD73, CD101 and CD103 and a functionally significant increase in interleukin (IL)-10 in Treg from C57BL/6 compared to dnTGF-ßRII mice. Our data reflect the therapeutic potential of wild-type CD4(+) FoxP3(+) Treg in reducing the excessive T cell responses of autoimmune cholangitis, which has significance for the potential immunotherapy of PBC.
Assuntos
Doenças Autoimunes/imunologia , Doenças Autoimunes/terapia , Colangite/imunologia , Colangite/terapia , Imunoterapia Adotiva , Linfócitos T Reguladores/imunologia , Animais , Doenças Autoimunes/patologia , Colangite/patologia , Citocinas/biossíntese , Modelos Animais de Doenças , Fatores de Transcrição Forkhead/metabolismo , Imunofenotipagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fenótipo , Baço/citologia , Baço/imunologia , Baço/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/metabolismoRESUMO
The effects of γ-irradiation on potassium dihydrogen phosphate crystals containing arsenic impurities are investigated with different optical diagnostics, including UV-VIS absorption spectroscopy, photo-thermal common-path interferometer and photoluminescence spectroscopy. The optical absorption spectra indicate that a new broad absorption band near 260 nm appears after γ-irradiation. It is found that the intensity of absorption band increases with the increasing irradiation dose and arsenic impurity concentration. The simulation of radiation defects show that this absorption is assigned to the formation of AsO44⻠centers due to arsenic ions substituting for phosphorus ions. Laser-induced damage threshold test is conducted by using 355 nm nanosecond laser pulses. The correlations between arsenic impurity concentration and laser induced damage threshold are presented. The results indicate that the damage performance of the material decreases with the increasing arsenic impurity concentration. Possible mechanisms of the irradiation-induced defects formation under γ-irradiation of KDP crystals are discussed.
Assuntos
Arsênio/análise , Vidro/química , Lasers , Óptica e Fotônica , Fosfatos/efeitos da radiação , Compostos de Potássio/efeitos da radiação , Arsênio/efeitos da radiação , Cristalização/métodos , Relação Dose-Resposta à Radiação , Desenho de Equipamento , Raios gama , Vidro/efeitos da radiação , Teste de Materiais , Fosfatos/análise , Compostos de Potássio/análise , Doses de Radiação , Reprodutibilidade dos Testes , Espectroscopia de Infravermelho com Transformada de FourierRESUMO
Congenital infiltrating lipomatosis of the face (CILF) is a rare congenital disease of the head and neck region. In this study, the cases of 20 patients diagnosed with CILF were reviewed retrospectively to analyse the characteristics of the disease. The symptoms, signs, and clinical progression were investigated. Radiological changes were analysed according to the distribution of the trigeminal nerve. The pathological features of the fatty facial lesions, jaw hyperplasia, and lingual lesions were further identified. All 20 patients demonstrated hemifacial hypertrophy at birth. None had a family history of the disease. Significant radiological features of CILF (prevalence ≥90%) included thickened buccal subcutaneous fat, palatal submucosal fat, and temporal subcutaneous fat, maxillary tuberosity heteroplasia, and fatty infiltration of the masseteric intermuscular space. With regard to the trigeminal nerve, the frontal branch region (CNV1) was rarely affected, while the maxillary (CNV2) and mandibular (CNV3) branch regions showed considerable changes. Pathologically, CILF was observed to be characterized by the infiltration of mature adipose tissue into the adjacent buccal soft tissue, osteal remodelling surrounded by sheets of mature lipocytes and supporting fibrovascular stroma, and lingual hamartoma. In summary, CILF exhibits distinct characteristics that are related to the regions controlled by the maxillary and mandibular branches of the trigeminal nerve, suggesting that CILF may be associated with early neural development.
Assuntos
Lipomatose , Humanos , Feminino , Masculino , Estudos Retrospectivos , Lipomatose/diagnóstico por imagem , Lipomatose/patologia , Lipomatose/congênito , Criança , Adolescente , Face/patologia , Face/anormalidades , Face/diagnóstico por imagem , Pré-Escolar , Tomografia Computadorizada por Raios X , Adulto , LactenteRESUMO
The phagocytic clearance of apoptotic cells is critical for tissue homeostasis; a number of non-professional phagocytic cells, including epithelial cells, can both take up and process apoptotic bodies, including the release of anti-inflammatory mediators. These observations are particularly important in the case of human intrahepatic biliary cells (HiBEC), because such cells are themselves a target of destruction in primary biliary cirrhosis, the human autoimmune disease. To address the apoptotic ability of HiBECs, we have focused on their ability to phagocytize apoptotic blebs from autologous HiBECs. In this study we report that HiBEC cells demonstrate phagocytic function from autologous HiBEC peers accompanied by up-regulation of the chemokines CCL2 [monocyte chemotactic protein-1 (MCP-1)] and CXCL8 [interleukin (IL)-8]. In particular, HiBEC cells express the phagocytosis-related receptor phosphatidylserine receptors (PSR), implying that HiBECs function through the 'eat-me' signal phosphatidylserine expressed by apoptotic cells. Indeed, although HiBEC cells acquire antigen-presenting cell (APC) function, they do not change the expression of classic APC function surface markers after engulfment of blebs, both with and without the presence of Toll-like receptor (TLR) stimulation. These results are important not only for understanding of the normal physiological function of HiBECs, but also explain the inflammatory potential and reduced clearance of HiBEC cells following the inflammatory cascade in primary biliary cirrhosis.
Assuntos
Apoptose , Ductos Biliares Intra-Hepáticos/imunologia , Células Epiteliais/imunologia , Macrófagos/imunologia , Fagocitose , Animais , Ácidos e Sais Biliares/farmacologia , Ductos Biliares Intra-Hepáticos/citologia , Células Cultivadas , Quimiocina CCL2/genética , Quimiocina CCL2/imunologia , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Expressão Gênica , Humanos , Interleucina-8/genética , Interleucina-8/imunologia , Lipopolissacarídeos/farmacologia , Cirrose Hepática Biliar/imunologia , Cirrose Hepática Biliar/patologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Camundongos , Fosfatidilserinas/imunologia , Fosfatidilserinas/metabolismo , Poli I-C/farmacologia , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/imunologia , Transdução de Sinais , Receptores Toll-Like/genética , Receptores Toll-Like/imunologia , Regulação para CimaRESUMO
While there have been significant advances in our understanding of the autoimmune responses and the molecular nature of the target autoantigens in primary biliary cirrhosis (PBC), unfortunately these data have yet to be translated into new therapeutic agents. We have taken advantage of a unique murine model of autoimmune cholangitis in which mice expressing a dominant negative form of transforming growth factor ß receptor II (dnTGFßRII), under the control of the CD4 promoter, develop an intense autoimmune cholangitis associated with serological features similar to human PBC. CD40-CD40 ligand (CD40L) is a major receptor-ligand pair that provides key signals between cells of the adaptive immune system, prompting us to determine the therapeutic potential of treating autoimmune cholangitis with anti-CD40L antibody (anti-CD40L; MR-1). Four-week-old dnTGFßRII mice were injected intraperitoneally with either anti-CD40L or control immunoglobulin (Ig)G at days 0, 2, 4 and 7 and then weekly until 12 or 24 weeks of age and monitored for the progress of serological and histological features of PBC, including rigorous definition of liver cellular infiltrates and cytokine production. Administration of anti-CD40L reduced liver inflammation significantly to 12 weeks of age. In addition, anti-CD40L initially lowered the levels of anti-mitochondrial autoantibodies (AMA), but these reductions were not sustained. These data indicate that anti-CD40L delays autoimmune cholangitis, but the effect wanes over time. Further dissection of the mechanisms involved, and defining the events that lead to the reduction in therapeutic effectiveness will be critical to determining whether such efforts can be applied to PBC.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Doenças Autoimunes/terapia , Ligante de CD40/imunologia , Colangite/terapia , Mitocôndrias/imunologia , Animais , Anticorpos Monoclonais/imunologia , Autoantígenos/imunologia , Doenças Autoimunes/imunologia , Autoimunidade/imunologia , Antígenos CD4/genética , Antígenos CD40/imunologia , Antígenos CD40/metabolismo , Ligante de CD40/metabolismo , Colangite/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Genótipo , Fígado/citologia , Fígado/metabolismo , Cirrose Hepática Biliar/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Regiões Promotoras Genéticas/genética , Receptores de Fatores de Crescimento Transformadores beta/imunologiaRESUMO
Although the hallmark of primary biliary cirrhosis (PBC) is the presence of anti-mitochondrial antibodies (AMA), a significant number of patients have anti-nuclear antibodies (ANA) directed primarily against two nuclear proteins, gp210 and sp100. In PBC, there are considerable data on the specificity of these anti-nuclear antibodies as well as suggestive evidence that antibodies to gp210 predict a poor outcome. However, a further understanding of the significance of these autoantibodies has been hampered by limitations in accessing human subjects in a preclinical or early asymptomatic stage. To overcome this limitation, we have taken advantage of transgenic mice with abrogated transforming growth factor-ß signalling in T cells (dnTGF-ßRII) that develop histological features of PBC as well as the same AMA specificity. We studied these mice for serum ANA, including specific autoantibodies against gp210 and sp100. We further examined sera from dnTGF-ßRII mice with concurrent deletions of the genes encoding interleukin (IL)-12p35, IL-12p40, IL-23p19, IL-17, IL-6, interferon (IFN)-γ or tumour necrosis factor (TNF)-α. Sera from all the dnTGF-ßRII mouse lines contained antibodies against gp210 and sp100. Of significance, mice with germline deletions of the genes encoding IL-12p40, IL-23p19, IL-17, IL-6 and TNF-α had significantly lower titres of anti-gp210 antibodies. These results provide a platform to dissect the mechanisms of gp210 and sp100 autoantibody production in dnTGF-ßRII mice as well as to study the possible role of ANA in the pathophysiology of PBC.
Assuntos
Anticorpos Antinucleares/biossíntese , Citocinas/metabolismo , Cirrose Hepática Biliar/imunologia , Animais , Antígenos Nucleares , Autoantígenos , Células Cultivadas , Citocinas/genética , Citocinas/imunologia , Modelos Animais de Doenças , Epitopos/imunologia , Humanos , Camundongos , Camundongos Transgênicos , Complexo de Proteínas Formadoras de Poros Nucleares/imunologia , Deleção de Sequência/genéticaRESUMO
A void in understanding primary biliary cirrhosis (PBC) is the absence of appropriate animal models. Our laboratory has studied a murine model of autoimmune cholangitis induced following immunization with 2-octynoic acid (2OA), an antigen identified following extensive quantitative structural activity relationship (QSAR) analysis, using human autoantibodies and three-dimensional analysis of the mitochondrial autoantigen, the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2). Mice immunized with 2OA coupled to bovine serum albumin (BSA) develop anti-mitochondrial antibodies (AMAs) of the identical specificity as humans with PBC, and in addition develop inflammatory portal cell infiltrates in liver. However, the natural history of disease is less severe than in humans and does not include fibrosis. Data from human and autoimmune murine models suggest that environmental and/or infectious agents can exacerbate autoimmune reactions, and a model of PBC has been described in which polyinosinic-polycytidylic acid (poly I:C), a viral RNA mimetic and Toll-like receptor 3 (TLR-3) agonist induces low-titre AMAs and in mild portal infiltrates. We took advantage of our established model to determine whether immunization with 2OA-BSA coupled with poly I:C alters the disease process. Indeed, the addition of poly I:C produces a profound exacerbation of autoimmune cholangitis, including a significant increase in CD8(+) infiltrating T cells, as well as a marked increase of proinflammatory cytokines. In addition, mice have evidence of fibrosis. These findings lend support to the concept that besides breakdown of self-tolerance, there is a requirement of a second 'hit' during the breakdown process that leads to disease which more faithfully mimics human PBC.
Assuntos
Doenças Autoimunes/imunologia , Colangite/imunologia , Di-Hidrolipoil-Lisina-Resíduo Acetiltransferase/efeitos adversos , Modelos Animais de Doenças , Ácidos Graxos Monoinsaturados/efeitos adversos , Cirrose Hepática Biliar/imunologia , Fígado/imunologia , Proteínas Mitocondriais/efeitos adversos , Poli I-C/efeitos adversos , Receptor 3 Toll-Like/imunologia , Animais , Autoanticorpos/sangue , Autoanticorpos/imunologia , Autoantígenos/efeitos adversos , Autoantígenos/química , Autoantígenos/imunologia , Doenças Autoimunes/induzido quimicamente , Doenças Autoimunes/patologia , Bovinos , Colangite/induzido quimicamente , Colangite/patologia , Citocinas/biossíntese , Citocinas/imunologia , Di-Hidrolipoil-Lisina-Resíduo Acetiltransferase/química , Di-Hidrolipoil-Lisina-Resíduo Acetiltransferase/imunologia , Ácidos Graxos Monoinsaturados/química , Ácidos Graxos Monoinsaturados/imunologia , Feminino , Humanos , Imunização , Fígado/efeitos dos fármacos , Fígado/patologia , Cirrose Hepática Biliar/induzido quimicamente , Cirrose Hepática Biliar/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/imunologia , Proteínas Mitocondriais/química , Proteínas Mitocondriais/imunologia , Poli I-C/química , Poli I-C/imunologia , Albumina Sérica/química , Receptor 3 Toll-Like/agonistas , Receptor 3 Toll-Like/metabolismoRESUMO
OBJECTIVE: To uncover the potential function of LINC00628 in influencing the progression of colorectal cancer (CRC) and its underlying mechanism. PATIENTS AND METHODS: Relative levels of LINC00628 and p57 in CRC tissues and cell lines were determined by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). Regulatory effects of LINC00628 and p57 on proliferation, cell cycle, and apoptosis of SW480 and SW620 cells were assessed. Subcellular distribution of LINC00628 in CRC cells was analyzed. Moreover, the interaction between LINC00628 and enhancer of zeste homolog 2 (EZH2) was evaluated by the RNA Binding Protein Immunoprecipitation (RIP) assay. RESULTS: LINC00628 was downregulated in CRC tissues and cell lines. CRC patients expressing a low level of LINC00628 suffered worse prognosis. The. knockdown of LINC00628 enhanced proliferative ability, prolonged S phase in cell cycle progression, and inhibited apoptosis in SW480 and SW620 cells. LINC00628 was mainly distributed in the nucleus. The RIP assay demonstrated that LINC00628 could bind to EZH2 to upregulate the p57 level. Rescue experiments verified that the overexpression of p57 could reverse regulatory effects of downregulated LINC00628 on proliferative and apoptotic abilities of CRC. CONCLUSIONS: LINC00628 is downregulated in CRC. It aggravates the progression of CRC by binding to EZH2 to further inhibit the p57 level.
Assuntos
Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Inibidor de Quinase Dependente de Ciclina p57/antagonistas & inibidores , RNA Longo não Codificante , Apoptose/genética , Linhagem Celular , Proliferação de Células/genética , Inibidor de Quinase Dependente de Ciclina p57/genética , Progressão da Doença , Regulação para Baixo , Proteína Potenciadora do Homólogo 2 de Zeste/genética , HumanosRESUMO
The effects of stacking periodicity on the electronic and optical properties of GaAs/AlAs superlattice have been explored by density functional theory calculations. Among the (GaAs)m/(AlAs)m, (GaAs)1/(AlAs)m and (GaAs)m/(AlAs)1 (m = 1 to 5) superlattices, the band gaps of (GaAs)m/(AlAs)1 superlattices decrease significantly as the layer of GaAs increases, and the cut-off wavelengths are found to locate in the near infrared region. For (GaAs)m/(AlAs)1 SLs, the conduction bands shift toward Fermi level, resulting in the smaller band gap, while conduction bands of (GaAs)1/(AlAs)n SLs slightly shift to higher energy, which lead to comparable band gaps. The layer number of GaAs shows negligible effects on the reflectivity spectra of superlattice structures, while the absorption coefficient shows a red-shift with the increasing layer of GaAs, which is beneficial for the application of GaAs/AlAs superlattice in the field of near infrared detector. These results demonstrate that controlling the number of GaAs layers is a good method to engineer the optoelectronic properties of GaAs/AlAs superlattice.
RESUMO
Objective: To evaluate the effect of oral nutritional supplementation (ONS) on the nutritional status and quality of life in patients with colorectal cancer and postoperative adjuvant chemotherapy. Methods: This study was registered in the Chinese Clinical Trial Registry (ChiCTR-TRC-13003798). A multi-center randomized controlled trial was conducted. Colorectal cancer patients who underwent radical surgery and postoperative adjuvant chemotherapy, and had nutritional risk (nutrition risk screening 2002 score ≥3) when discharge from hospital in six hospitals (Beijing Hospital, Peking University Third Hospital, Guangzhou Nanfang Hospital, Shanghai Xinhua Hospital, Shanghai Ruijin Hospital, and Shanghai The Sixth People's Hospital) from June 2013 to August 2015 were prospectively enrolled. These patients were randomly divided into the ONS group and control group. Patients in the ONS group received dietary guidance and oral nutritional supplements (2092 kJ/day, whole protein enteral nutrition) for 90 days after discharge from hospital, while patients in the control group only received dietary guidance. Anthropometric measurements (body weight, body mass index [BMI], upper arm circumference, gripping power of the dominant hand, triceps skin fold), nutrition-related laboratory tests (hemoglobin, albumin, prealbumin, total cholesterol, triglyceride), gastrointestinal function scores and quality of life (evaluated by EuroQol five dimensions questionnaire) were collected and compared at baseline (at discharge), and at 30-day, 60-day and 90-day after discharge. Results: A total of 90 patients were included into this multi-center study, of whom 5 patients dropped out, 43 patients were assigned to the ONS group and 42 patients to the control group. Compared with baseline, the body weight of patients in the ONS group increased by (1.523±0.525) kg at 60-day and (1.967±0.661) kg at 90-day, which were significantly higher than those of patients in the control group [60-day: (-0.325±0.518) kg, P=0.015; 90-day: (-0.224±0.705) kg, P=0.027, respectively]. A similar pattern was observed for BMI, the ONS group increased by (0.552±0.203) kg/m(2) at 60-day and (0.765±0.205) kg/m(2) at 90-day, which were significantly higher than those of patients in control group [60-day: (-0.067±0.202) kg/m(2), P=0.034; 90-day: (0.022±0.210) kg/m(2), P=0.013]. No significant differences of other anthropometric measurements and nutrition-related laboratory tests were found between the two groups (all P>0.05). Furthermore, there were no significant differences of improvement in gastrointestinal function and quality of life between two groups (all P>0.05). Conclusion: Oral nutritional supplements can improve the body weight and BMI of colorectal cancer patients with nutritional risk receiving postoperative adjuvant chemotherapy, though it does not improve the quality of life.
Assuntos
Neoplasias Colorretais/terapia , Proteínas Alimentares/administração & dosagem , Nutrição Enteral/métodos , Administração Oral , Antineoplásicos/administração & dosagem , Quimioterapia Adjuvante , China , Suplementos Nutricionais , Procedimentos Cirúrgicos do Sistema Digestório , Humanos , Estado Nutricional , Período Pós-Operatório , Estudos Prospectivos , Qualidade de VidaRESUMO
We have demonstrated spontaneous development of autoimmune cholangitis, similar to human primary biliary cirrhosis, in mice expressing a dominant negative form of the transforming growth factor-beta receptor (dnTGF-betaRII) restricted to T cells. The autoimmune cholangitis appears to be mediated by autoreactive CD8(+) T lymphocytes that home to the portal tracts and biliary system. Because the liver pathology is primarily secondary to CD8(+) T cells, we have determined herein whether administration of beta-glucosylceramide (GC), a naturally occurring plant glycosphingolipid, alters the natural history of disease in this model. We chose GC because previous work has demonstrated its ability to alter CD8(+) T cell responses and to down-regulate tissue inflammation. Accordingly, dnTGF-betaRII mice were treated with either GC or control for a period of 18 weeks beginning at 6 weeks of age. Importantly, in mice that received GC, there was a significant decrease in the frequency and absolute number of autoreactive liver-infiltrating CD8(+) T cells, accompanied by a significant decrease in activated CD44(high) CD8(+) T cell populations. Further, there was a significant reduction in portal inflammation in GC-treated mice. Interestingly, there were no changes in anti-mitochondrial antibodies, CD4(+) T cells, CD19(+) B cells or natural killer (NK) T cell populations, indicating further that the beneficial effects of GC on liver inflammation were targeted specifically to liver-infiltrating CD8(+) T cells. These data suggest that further work on GC in models of CD8(+) T-mediated inflammation are needed and point to a new therapeutic venue for potentially treating and/or modulating autoimmune disease.
Assuntos
Doenças Autoimunes/tratamento farmacológico , Linfócitos T CD8-Positivos/imunologia , Colangite/tratamento farmacológico , Glucosilceramidas/uso terapêutico , Fígado/imunologia , Animais , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Colangite/imunologia , Colangite/patologia , Citometria de Fluxo , Fígado/efeitos dos fármacos , Fígado/patologia , Cirrose Hepática Biliar , Camundongos , Camundongos Transgênicos , Modelos Animais , Proteínas Serina-Treonina Quinases/genética , Receptor do Fator de Crescimento Transformador beta Tipo II , Receptores de Fatores de Crescimento Transformadores beta/genéticaRESUMO
Our laboratory has suggested that loss of tolerance to pyruvate dehydrogenase (PDC-E2) leads to an anti-mitochondrial antibody response and autoimmune cholangitis, similar to human primary biliary cirrhosis (PBC). We have suggested that this loss of tolerance can be induced either via chemical xenobiotic immunization or exposure to select bacteria. Our work has also highlighted the importance of genetic susceptibility. Using the non-obese diabetic (NOD) congenic strain 1101 (hereafter referred to as NOD.1101 mice), which has chromosome 3 regions from B6 introgressed onto a NOD background, we exposed animals to 2-octynoic acid (2OA) coupled to bovine serum albumin (BSA). 2OA has been demonstrated previously by a quantitative structural activity relationship to react as well as or better than lipoic acid to anti-mitochondrial antibodies. We demonstrate herein that NOD.1101 mice immunized with 2OA-BSA, but not with BSA alone, develop high titre anti-mitochondrial antibodies and histological features, including portal infiltrates enriched in CD8(+) cells and liver granulomas, similar to human PBC. We believe this model will allow the rigorous dissection of early immunogenetic cause of biliary damage.
Assuntos
Doenças Autoimunes/imunologia , Colangite/imunologia , Modelos Animais de Doenças , Animais , Autoanticorpos/sangue , Autoanticorpos/imunologia , Citocinas/sangue , Ensaio de Imunoadsorção Enzimática/métodos , Ácidos Graxos Monoinsaturados/farmacologia , Feminino , Citometria de Fluxo , Predisposição Genética para Doença , Imunização , Imunoglobulina A/sangue , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Imunofenotipagem , Cirrose Hepática Biliar/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Mitocôndrias Hepáticas/imunologia , Soroalbumina Bovina/farmacologia , Xenobióticos/farmacologiaRESUMO
Immunization with a phosphonate monoester transition-state analog of cocaine provided monoclonal antibodies capable of catalyzing the hydrolysis of the cocaine benzoyl ester group. An assay for the degradation of radiolabeled cocaine identified active enzymes. Benzoyl esterolysis yields ecgonine methyl ester and benzoic acid, fragments devoid of cocaine's stimulant activity. Passive immunization with such an artificial enzyme could provide a treatment for dependence by blunting reinforcement.
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Anticorpos Catalíticos/metabolismo , Anticorpos Monoclonais/metabolismo , Cocaína/metabolismo , Animais , Anticorpos Catalíticos/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Antígenos/imunologia , Benzoatos/metabolismo , Ácido Benzoico , Cocaína/análogos & derivados , Cocaína/imunologia , Ésteres/metabolismo , Humanos , Hibridomas/imunologia , Hidrólise , Imunização , Imunização Passiva , Camundongos , Camundongos Endogâmicos BALB C , Transtornos Relacionados ao Uso de Substâncias/tratamento farmacológicoRESUMO
Pharmacokinetics of difloxacin, a fluoroquinolone antibiotic, was determined in pigs and broilers after intravenous (i.v.), intramuscular (i.m.), or oral (p.o.) administration at a single dose of five (pigs) or 10 mg/kg (broilers). Plasma concentration profiles were analyzed by a compartmental pharmacokinetic method. Following i.v., i.m. and p.o. doses, the elimination half-lives (t(1/2beta)) were 17.14 +/- 4.14, 25.79 +/- 8.10, 16.67 +/- 4.04 (pigs) and 6.11 +/- 1.50, 5.64 +/- 0.74, 8.20 +/- 3.12 h (broilers), respectively. After single i.m. and p.o. administration, difloxacin was rapidly absorbed, with peak plasma concentrations (C(max)) of 1.77 +/- 0.66, 2.29 +/- 0.85 (pigs) and 2.51 +/- 0.36, 1.00 +/- 0.21 microg/mL (broilers) attained at t(max) of 1.29 +/- 0.26, 1.41 +/- 0.88 (pigs) and 0.86 +/- 0.4, 4.34 +/- 2.40 h (broilers), respectively. Bioavailabilities (F) were (95.3 +/- 28.9)% and (105.7 +/- 37.1)% (pigs) and (77.0 +/- 11.8)% and (54.2 +/- 12.6)% (broilers) after i.m. and p.o. doses, respectively. Apparent distribution volumes(V(d(area))) of 4.91 +/- 1.88 and 3.10 +/- 0.67 L/kg and total body clearances(Cl(B)) of 0.20 +/- 0.06 and 0.37 +/- 0.10 L/kg/h were determined in pigs and broilers, respectively. Areas under the curve (AUC), the half-lives of both absorption and distribution(t(1/2ka), t(1/2alpha)) were also determined. Based on the single-dose pharmacokinetic parameters determined, multiple dosage regimens were recommended as: a dosage of 5 mg/kg given intramuscularly every 24 h in pigs, or administered orally every 24 h at the dosage of 10 mg/kg in broilers, can maintain effective plasma concentrations with bacteria infections, in which MIC(90) are <0.25 microg/mL and <0.1 microg/mL respectively.
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Anti-Infecciosos/farmacocinética , Ciprofloxacina/análogos & derivados , Administração Oral , Animais , Anti-Infecciosos/administração & dosagem , Anti-Infecciosos/sangue , Área Sob a Curva , Disponibilidade Biológica , Galinhas , Ciprofloxacina/administração & dosagem , Ciprofloxacina/sangue , Ciprofloxacina/farmacocinética , Meia-Vida , Injeções Intramusculares , Injeções Intravenosas , Masculino , Taxa de Depuração Metabólica , Especificidade da Espécie , Suínos , Distribuição TecidualRESUMO
In this study, the low energy radiation responses of AlAs, GaAs and GaAs/AlAs superlattice are simulated and the radiation damage effects on their electronic structures are investigated. It is found that the threshold displacement energies for AlAs are generally larger than those for GaAs, i.e., the atoms in AlAs are more difficult to be displaced than those in GaAs under radiation environment. As for GaAs/AlAs superlattice, the Ga and Al atoms are more susceptible to the radiation than those in the bulk AlAs and GaAs, whereas the As atoms need comparable or much larger energies to be displaced than those in the bulk states. The created defects are generally Frenkel pairs, and a few antisite defects are also created in the superlattice structure. The created defects are found to have profound effects on the electronic properties of GaAs/AlAs superlattice, in which charge transfer, redistribution and even accumulation take place, and band gap narrowing and even metallicity are induced in some cases. This study shows that it is necessary to enhance the radiation tolerance of GaAs/AlAs superlattice to improve their performance under irradiation.