RESUMO
This study investigates the incidences and predictors of hepatitis B virus (HBV) relapse after tenofovir disoproxil fumarate (TDF) therapy in hepatitis B e antigen (HBeAg)-positive and -negative patients. We retrospectively recruited 143 chronic hepatitis B (CHB) patients without cirrhosis (39 HBeAg-positive and 104 HBeAg-negative patients) who were previously treated with TDF and had post-treatment follow-up for at least 6 months (median: 55, IQR 36-85 weeks). All the patients fulfilled the stopping criteria of APASL 2012. The virological and clinical relapse rates at 104 weeks in HBeAg-positive patients were 66.6% and 59.1%, while they were 72.3% and 55.9%, respectively, in HBeAg-negative patients. Cox regression analysis revealed that the higher end-of-treatment HBsAg levels were an independent factor of virological relapse in HBeAg-positive and HBeAg-negative patients. The end-of-treatment HBsAg levels of 200 (area under the receiver operating characteristic (AUROC): 0.624) and 80 IU/mL (AUROC: 0.959) were the optimal values for predicting HBV relapse in HBeAg-positive and HBeAg-negative patients, respectively. The virological relapse rate at 78 weeks was 14.3% and 19.6% in HBeAg-positive and HBeAg-negative patients who achieved HBsAg ≤200 IU/mL and HBsAg ≤80 IU/mL, respectively. Two patients experienced hepatic decompensation upon hepatitis flares, and no patient died after timely retreatment. Seven patients experienced off-therapy HBsAg loss. The cumulative rates of HBsAg loss at 104 weeks were 45.5% and 59.3% in patients with end-of-treatment HBsAg ≤80 IU/mL and ≤50 IU/mL, respectively. In conclusions, the end-of-treatment HBsAg levels were a useful marker for predicting HBV relapse in HBeAg-positive and HBeAg-negative CHB patients.
Assuntos
Antivirais/uso terapêutico , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/epidemiologia , Tenofovir/uso terapêutico , Adulto , Idoso , Feminino , Seguimentos , Antígenos de Superfície da Hepatite B/sangue , Antígenos E da Hepatite B/sangue , Hepatite B Crônica/patologia , Hepatite B Crônica/virologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Recidiva , Estudos Retrospectivos , Medição de RiscoRESUMO
We investigated the incidence and predictors of post-treatment hepatitis B virus (HBV) relapse and hepatitis B surface antigen (HBsAg) loss. After cessation of nucleoside analogue (NA) treatment in hepatitis B e antigen (HBeAg)-negative patients with cirrhosis. The rates of HBsAg loss and hepatocellular carcinoma (HCC) development in HBeAg-negative patients with cirrhosis who continued NA treatment were compared with those who discontinued treatment. Patients with compensated cirrhosis who had discontinued NA treatment for at least 12 months (discontinuing group; n=73) and patients who continued entecavir treatment for at least 4 years (continuing group; n=158) were recruited. Serum HBsAg levels were analysed at the end of treatment (discontinuing group) or at 2.5-3 years of treatment (continuing group). In the discontinuing group, the 6-year cumulative incidence of post-treatment virological relapse and HBsAg loss were 56.3% and 46.7%, respectively. The end-of-treatment HBsAg level of 300 IU/mL was a cut-off value for subsequent post-treatment HBsAg loss and sustained response. In the continuing group, HBsAg loss occurred in five of 158 patients. Cox regression analysis showed that HBsAg levels in the discontinuing group were independent predictors for HBsAg loss in all patients and 104 propensity score (PS)-matched patients. There was no significant difference in HCC development between the groups in all patients and 104 PS-matched patients. Two patients experienced post-treatment alanine aminotransferase flare with hepatic decompensation, and neither of them died after retreatment. In conclusion, HBeAg-negative patients with cirrhosis who discontinued NA treatment might have a higher rate of HBsAg loss and their risk of developing HCC did not increase compared with those who continued entecavir treatment.
Assuntos
Antivirais/uso terapêutico , Carcinoma Hepatocelular/epidemiologia , Guanina/análogos & derivados , Antígenos de Superfície da Hepatite B/sangue , Hepatite B Crônica/tratamento farmacológico , Cirrose Hepática/tratamento farmacológico , Neoplasias Hepáticas/epidemiologia , Adulto , Idoso , Feminino , Guanina/uso terapêutico , Hepatite B Crônica/complicações , Humanos , Cirrose Hepática/complicações , Masculino , Pessoa de Meia-Idade , Recidiva , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Autophagy is a programmed cell survival mechanism that has a key role in both physiologic and pathologic conditions. The relationship between autophagy and cancer is complex because autophagy can act as either a tumour suppressor or as a tumour promoter. The role of autophagy in oral squamous cell carcinoma (OSCC) is controversial. Several studies have claimed that either a high or low expression of autophagy-related proteins was associated with poor prognosis of OSCCs. The aims of the study were to compare autophagy in OSCCs, verrucous hyperplasias, and normal oral mucosas, and to inspect the prognostic role of autophagy in OSCCs. METHODS: We used the autophagosome marker, LC3B, and autophagy flux marker, p62/SQSTM1 (p62), by using immunohistochemistry, and examined p62 mRNA by RNA in situ hybridization, to evaluate autophagy in 195 OSCCs, 47 verrucous hyperplasias, and 37 normal oral mucosas. The prognostic roles of LC3B and p62 protein expressions in OSCCs were investigated. RESULTS: We discovered that the normal oral mucosa exhibited limited LC3B punctae and weak cytoplasmic p62 staining, whereas the OSCCs exhibited a marked increase in LC3B punctae and cytoplasmic p62 expression. The expression pattern of LC3B and cytoplasmic p62 of the verrucous hyperplasias were between normal oral mucosas and OSCCs. The normal oral mucosas, verrucous hyperplasias, and OSCCs presented no differences in nuclear p62 expression and the p62 mRNA level. p62 mRNA expression was elevated in a minority of cases. High p62 mRNA expression was associated with high p62 protein expression in the cytoplasm. Increased LC3B punctae, high cytoplasmic p62, and low nuclear p62 expressions in OSCCs were associated with aggressive clinicopathologic features and unfavourable prognosis. In addition, low nuclear p62 expression was an independent prognostic factor for overall and disease-specific survival rates. Furthermore, we disclosed that high cytoplasmic p62 expression accompanied with either a low or high LC3B expression, which indicated autophagy impairment under basal or activated autophagic activity, was associated with aggressive behaviour in advanced OSCCs. CONCLUSIONS: We suggested that autophagy was altered during cancer initiation and progression. Autophagy impairment contributed to cancer progression in advanced OSCCs.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Carcinoma de Células Escamosas/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Neoplasias Bucais/metabolismo , Adulto , Autofagia/fisiologia , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/patologia , Núcleo Celular/metabolismo , Sobrevivência Celular , Citoplasma/metabolismo , Feminino , Humanos , Hiperplasia/metabolismo , Hiperplasia/patologia , Masculino , Pessoa de Meia-Idade , Mucosa Bucal/metabolismo , Mucosa Bucal/patologia , Neoplasias Bucais/patologia , Prognóstico , Estudos Retrospectivos , Proteína Sequestossoma-1 , Taxa de SobrevidaRESUMO
BACKGROUND: Tryptophan metabolites have been suggested to play a role in immune modulation, wherein those have recently been shown to be endogenous ligands of aryl hydrocarbon receptor (AhR; a unique cellular chemical sensor). However, the involvement of tryptophan metabolites and AhR in modulating mast cell function remains to be fully defined. We therefore investigated that the functional impacts of tryptophan metabolites on human and mouse mast cell responses in vitro and their functional importance in vivo. METHODS: Three tryptophan metabolites, kynurenine (KYN), kynurenic acid (KA) and quinolinic acid (QA), were examined in terms of their effect on IgE-mediated responses in mouse bone marrow-derived mast cells (BMMCs) and in human peripheral blood-derived cultured mast cells (HCMCs) and on in vivo anaphylactic responses. For evaluation of AhR involvement, we examined the responses of mast cells from AhR-null or AhR-wild-type mice with the use of a known AhR antagonist, CH223191. RESULTS: Kynurenine, but not KA and QA, enhanced IgE-mediated responses, including degranulation, LTC4 release, and IL-13 production in BMMCs through the activation of PLCγ1, Akt, MAPK p38, and the increase of intracellular calcium. KYN also enhanced cutaneous anaphylaxis in vivo. These enhancing effects of KYN were not observed in AhR-deficient BMMCs and could be inhibited by CH223191 in BMMCs. Further, KYN had similar enhancing effects on HCMCs, which were inhibited by CH223191. CONCLUSION: The AhR-KYN axis is potentially important in modulating mast cell responses and represents an example of AhR's critical involvement in the regulation of allergic responses.
Assuntos
Cinurenina/farmacologia , Mastócitos/imunologia , Mastócitos/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Triptofano/metabolismo , Animais , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/imunologia , Células da Medula Óssea/metabolismo , Células Cultivadas , Humanos , Imunoglobulina E/imunologia , Cinurenina/administração & dosagem , Mastócitos/efeitos dos fármacos , Camundongos , Transdução de Sinais/efeitos dos fármacosRESUMO
We report a rare case of melanotic oncocytic metaplasia of the nasopharynx in a 63-year-old man, presenting as several black nodules up to several millimeters at the nasopharynx. It is a benign mimicker of malignant melanoma.
Assuntos
Melaninas/análise , Melanócitos/química , Melanócitos/patologia , Doenças Nasofaríngeas/diagnóstico , Nasofaringe/química , Nasofaringe/patologia , Biópsia , Diagnóstico Diferencial , Endoscopia , Humanos , Imuno-Histoquímica , Masculino , Metaplasia , Pessoa de Meia-Idade , Doenças Nasofaríngeas/metabolismo , Doenças Nasofaríngeas/patologia , Valor Preditivo dos TestesRESUMO
BACKGROUND: Interferon (IFN)-based therapies could eradicate hepatitis C (HCV) and reduce the risk of hepatocellular carcinoma (HCC). However, HCC could still happen after sustained virological response (SVR). We aimed to develop a simple scoring system to predict the risk of HCC development among HCV patients after antiviral therapies. METHODS: From 1999 to 2009, 1879 patients with biopsy-proven HCV infection treated with IFN-based therapies were analyzed. RESULTS: Multivariable analysis showed old age (adjusted HR (aHR)=1.73, 95% CI=1.13-2.65 for aged 60-69 and aHR=2.20, 95% CI=1.43-3.37 for aged ≥ 70), Male gender (aHR=1.74, 95% CI=1.26-2.41), platelet count <150 × 10(9)/l (HR=1.91, 95% CI=1.27-2.86), α-fetoprotein ≥ 20 ng ml(-1) (HR=2.23, 95% CI=1.58-3.14), high fibrotic stage (HR=3.32, 95% CI=2.10-5.22), HCV genotype 1b (HR=1.53, 95% CI=1.10-2.14), and non SVR (HR=2.40, 95% CI=1.70-3.38) were independent risk factors for HCC. Regression coefficients were used to build up a risk score and the accuracy was evaluated by using the area under the receiver operating characteristic curve (AUC). Three groups as low-, intermediate-, and high-risk are classified based on the risk scores. One hundred sixty patients (12.78%) in the derivation and 82 patients (13.08%) in the validation cohort developed HCC with AUC of 79.4%, sensitivity of 84.38%, and specificity of 60.66%. In the validation cohort, the 5-year HCC incidence was 1.81%, 12.92%, and 29.95% in low-, intermediate-, and high-risk groups, with hazard ratios 4.49 in intermediate- and 16.14 in high-risk group respectively. The risk reduction of HCC is greatest in patients with SVR, with a 5-year and 10-year risk reduction of 28.91% and 27.99% respectively. CONCLUSION: The risk scoring system is accurate in predicting HCC development for HCV patients after antiviral therapies.
Assuntos
Antivirais/uso terapêutico , Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/virologia , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/epidemiologia , Interferons/uso terapêutico , Neoplasias Hepáticas/virologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Hepatite C Crônica/complicações , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Risco , Fatores de Risco , Taiwan/epidemiologiaRESUMO
Recent studies have indicated that amino acid (aa) substitutions in the core region and NS5A interferon sensitivity-determining region (ISDR) of hepatitis C virus (HCV) as well as genetic polymorphisms in the interleukin-28B (IL-28B) locus affect the outcome of interferon (IFN)-based therapies. We aimed to investigate the role of these factors on response to peginterferon plus ribavirin in a prospective study of response-guided therapy. The aa sequences in core region and ISDR and rs12979860 genotypes were analysed in 115 HCV-1 patients. The treatment was 24 weeks for patients achieving a rapid virological response (RVR), 48 weeks for those with an early virological response (EVR) and early terminated in those without an EVR. A sustained virological response (SVR) was achieved in 82% of 34 RVR patients, 45% of 74 EVR patients and 0% of seven non-EVR patients. Logistic regression analysis showed that ISDR mutation (≥2) [odds ratio(OR): 6.024], double core 70/91 mutations (OR: 0.136), and platelet counts≥15×10(4) /µL (OR: 3.119) were independent pretreatment factors associated with SVR. Apart from rs12979860 CC genotype, low viral load and ISDR mutation (≥2) were significant factors predictive of RVR. Combination of rs12979860 genotype and baseline viral characteristics (viral load and core/ISDR mutations) could predict RVR and SVR with positive predictive value of 100% and 91%, and negative predictive value of 80% and 54%, respectively. In conclusion, pretreatment screening rs12979860 genotype and aa substitutions in the core region and ISDR could help identifying patients who are good candidates for peginterferon plus ribavirin therapy.
Assuntos
Antivirais/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Interferons/uso terapêutico , Interleucinas/genética , Polimorfismo Genético , Ribavirina/uso terapêutico , Proteínas não Estruturais Virais/genética , Idoso , Quimioterapia Combinada/métodos , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Resultado do Tratamento , Carga ViralRESUMO
BACKGROUND: Exposure to environmental endocrine-disrupting chemicals (EDCs) is associated with allergy, chronic inflammation, and immunodeficiency. Phthalates, the common EDCs used in plastic industry, may act as adjuvants to disrupt immune system and enhance allergy. Plasmacytoid DCs (pDCs) are predominant cells secreting type I interferon (IFN) against infection and are professional antigen-presenting cells in regulating adaptive immunity. However, the effects of phthalates on the function of pDCs are unknown. METHODS: Circulating pDCs were isolated from healthy subjects, were pretreated with diethylhexyl phthalate (DEHP) and butyl benzyl phthalate (BBP), and were stimulated with Toll-like receptor (TLR)-9 agonist CpG. IFN-α/IFN-ß levels, surface markers, and T-cell stimulatory function were investigated using ELISA, flow cytometry, and pDC/T-cell coculture assay. Mechanisms were investigated using receptor antagonists, pathway inhibitors, Western blotting, and chromatin immunoprecipitation. RESULTS: Diethylhexyl phthalate and butyl benzyl phthalate suppressed CpG-induced IFN-α/IFN-ß expression in pDCs, and the effect was reversed by aryl hydrocarbon receptor (AHR) antagonist. Diethylhexyl phthalate suppressed CpG-activated mitogen-activated protein kinase (MAPK)-MEK1/2-ERK-ELK1 and NFκB signaling pathways. Diethylhexyl phthalate suppressed CpG-induced interferon regulatory factor (IRF)-7 expression by suppressing histone H3K4 trimethylation at IRF7 gene promoter region through inhibiting translocation of H3K4-specific trimethyltransferase WDR5 from cytoplasm into nucleus. Butyl benzyl phthalate or diethylhexyl phthalate-treated pDCs suppressed IFN-γ but enhanced IL-13 production by CD4+ T cells. CONCLUSION: Phthalates may interfere with immunity against infection and promote the deviation of Th2 response to increase allergy by acting on human pDCs via suppressing IFN-α/IFN-ß expression and modulating the ability to stimulate T-cell responses.
Assuntos
Células Dendríticas/efeitos dos fármacos , Epigenômica , Interferon Tipo I/efeitos dos fármacos , Interferon Tipo I/genética , Ácidos Ftálicos/farmacologia , Western Blotting , Sobrevivência Celular , Células Cultivadas , Células Dendríticas/citologia , Células Dendríticas/imunologia , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Humanos , Interferon Tipo I/metabolismo , Interferon-alfa/análise , Interferon-alfa/imunologia , Interferon-alfa/metabolismo , Interferon beta/análise , Interferon beta/metabolismo , Interferon gama/imunologia , Interferon gama/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Estudos de Amostragem , Sensibilidade e Especificidade , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Receptor Toll-Like 9/genética , Receptor Toll-Like 9/imunologia , Receptor Toll-Like 9/metabolismoRESUMO
BACKGROUND: Exposure to environmental hormones, such as alkylphenols, has been suggested to be associated with the development of asthma, but the mechanism of action remains unclear. OBJECTIVE: This study examined the effect of 4-nonylphenol (NP), one of the most important alkylphenols, on conventional dendritic cells (cDCs) and adaptive T-cell responses. It also explored the role of aryl hydrocarbon receptor (AhR) in NP's effect. METHODS: NP-conditioned bone marrow-derived DCs (BM-DCs) and splenic CD11c(+) cDCs were assessed regarding function in a murine model under conditions relevant to route and level of exposure in humans. RESULTS: Our results showed that splenic cDCs from NP-exposed mice have potent Th2-skewing ability and secrete increased levels of IL-6 and TNF-α, but not IL-10 and IL-12, at baseline and after stimulation with LPS. Further, bone marrow-derived DCs were cultured in the presence of NP and showed similar cytokine pattern and influenced the antigen-specific T cells secreting significantly less IFN-γ. Importantly, NP-exposed mice developed more severe OVA-induced allergic lung inflammation compared with control group. Interestingly, in a congenic strain of mice carrying low-affinity, ligand-binding mutant AhR (AhR(d) ), NP's effect on DC functions and lung inflammation was not observed in vitro and in vivo. CONCLUSION: These results suggested that NP may disturb physiologic function of DCs through, in part, AhR-dependent mechanisms, supporting the importance of NP exposure on the regulation of DC functions and allergic inflammation.
Assuntos
Asma/induzido quimicamente , Poluentes Ambientais/toxicidade , Fenóis/toxicidade , Imunidade Adaptativa/efeitos dos fármacos , Animais , Asma/imunologia , Asma/metabolismo , Biomarcadores/metabolismo , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/metabolismo , Citocinas/metabolismo , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Receptores de Hidrocarboneto Arílico/metabolismoRESUMO
BACKGROUND/AIMS: The independent and interactive effects of hepatitis B virus (HBV) and hepatitis C virus (HCV) factors on the development of hepatocellular carcinoma (HCC) in chronic HBV/HCV dually-infected patients remain unclear. METHODS: In a cross-sectional and case-controlled study, the HBV and HCV loads and genotypes and the sequences of pre-S and precore/core promoter regions were determined in 146 HCC patients and 167 chronic carriers with HBV/HCV dual infection. RESULTS: Age (odds ratio (OR) 1.1), male sex (OR 2.3), pre-S deletion (OR 5.0), A1762T/G1764A mutant (OR 2.5), HCV genotype-1 (OR 2.4) and platelet count <15 × 10(4)/µl (OR 1.9) were independently associated with HCC by stepwise logistic regression analysis. Patients with combined HBV mutations (pre-S deletion and A1762T/G1764A mutant) and HCV genotype-1 had a 39-fold increased risk of developing HCC compared to those with A1762T/G1764A and pre-S wild-type strains and HCV genotype non-1. In the nested case-control study, patients with HCC had a higher HBV DNA level (p < 0.001), a higher frequency of pre-S deletion (p < 0.001) and A1762T/G1764A mutant (p = 0.005), a lower HCV RNA level (p = 0.012) and a higher prevalence of HCV genotype-1 (p = 0.002) than those without. CONCLUSIONS: Pre-S deletion, A1762T/G1764A mutation and HCV genotype-1 are important in hepatocarcinogenesis in chronic HBV/HCV dual infection.
Assuntos
Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/virologia , Coinfecção/virologia , Vírus da Hepatite B/genética , Hepatite B Crônica/virologia , Hepatite C Crônica/virologia , Adulto , Idoso , Estudos de Casos e Controles , Coinfecção/complicações , Feminino , Genótipo , Antígenos de Superfície da Hepatite B/genética , Vírus da Hepatite B/classificação , Hepatite B Crônica/complicações , Hepatite C Crônica/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Mutação Puntual , Fatores de Risco , Deleção de Sequência , Carga ViralRESUMO
AIM: To evaluate the incidence and associated factors of postoperative intense pain and haemodynamic changes during radiofrequency ablation of hepatocellular carcinoma. MATERIALS AND METHODS: A total of 123 consecutive hepatocellular carcinoma patients who underwent radiofrequency ablation were prospectively recruited. Patient factors, tumour characteristics, procedural factors, intraoperative haemodynamic changes, complications, postoperative events, laboratory values before and after ablation, and postoperative pain were evaluated. Postoperative pain was scored using a visual analogue scale after the procedure. RESULTS: The mean age of the patients was 65.6 ± 9.6 years. In multiple logistic regression analysis, patients who underwent general anaesthesia [odds ratio (95% CI): 2.68 (1.23-5.81); p = 0.013] and had more postoperative nausea and vomiting episodes [3.10 (1.11-8.63); p = 0.036] were associated with intense pain. These findings remain robust after propensity score matching. For mean difference values between before and after RFA, higher in change in aspartate transaminase (p = 0.026), alanine transaminase (p = 0.016) and white blood cell count (p = 0.015), and lower in change in haemoglobin (p = 0.009) were also correlated with intense pain. There was no significant difference in haemodynamic changes between the general anaesthesia and local anaesthesia group during ablation. CONCLUSION: General anaesthesia, postoperative nausea and vomiting, and laboratory factors were associated with postoperative intense pain in patients who underwent radiofrequency ablation. Counselling and modification of analgesics should be considered in patients with related factors for intense pain.
Assuntos
Carcinoma Hepatocelular/cirurgia , Ablação por Cateter/efeitos adversos , Neoplasias Hepáticas/terapia , Dor Pós-Operatória/etiologia , Idoso , Anestesia Geral/efeitos adversos , Feminino , Humanos , Masculino , Medição da Dor , Pontuação de Propensão , Estudos ProspectivosRESUMO
This study is the first to analyse the soluble factors secreted by the bronchial epithelium after exposure to isophorone diisocyanate (IPDI) that are responsible for increasing migration and proliferation of primary normal human bronchial smooth muscle cells (BSMCs). We treated immortalised, nontumorigenic human bronchial epithelial cells (cell line BEAS-2B) and primary normal human bronchial epithelial cells (HBEC) with IPDI, and then collected the conditioned culture media (IPDI-BEAS-2B-CM and IPDI-HBEC-CM, respectively), which was added to BSMCs. Exposure of BEAS-2B cells and HBECs to IPDI increased interleukin (IL)-8 production. Culture of BSMCs with IPDI-BEAS-2B-CM and IPDI-HBEC-CM increased BSMC proliferation and migration, which are major features in asthma-related airway remodelling. Induction of BSMC proliferation and migration by IPDI-BEAS-2B-CM and IPDI-HBEC-CM was associated with increased focal adhesion kinase (FAK), Src, extracellular signal-regulated kinase (ERK)1/2 and AKT activation. Blocking FAK with a specific inhibitor significantly decreased BSMC migration and proliferation by inhibiting ERK1/2 activation. FAK and ERK1/2 inhibitor also decreased IPDI-BEAS-2B-CM-, IPDI-HBEC-CM- and recombinant human IL-8-mediated BSMC proliferation and migration, whereas blocking Rnd3 using small interfering RNA failed to affect BSMC proliferation, suggesting that Rnd3 was only involved in the regulation of BSMC migration. Our study suggests that inhibition of IL-8 or IL-8-mediated FAK/ERK/Rnd3 signalling is an attractive therapeutic target for IPDI-mediated asthma.
Assuntos
Interleucina-8/biossíntese , Interleucina-8/metabolismo , Isocianatos/farmacologia , Músculo Liso/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Brônquios/efeitos dos fármacos , Brônquios/metabolismo , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Inibidores Enzimáticos/farmacologia , Proteína-Tirosina Quinases de Adesão Focal/antagonistas & inibidores , Proteína-Tirosina Quinases de Adesão Focal/biossíntese , Humanos , Proteína Quinase 1 Ativada por Mitógeno/biossíntese , Proteína Quinase 3 Ativada por Mitógeno/biossíntese , Proteínas Proto-Oncogênicas c-akt/biossíntese , RNA Interferente Pequeno/farmacologia , Proteínas rho de Ligação ao GTP/antagonistas & inibidores , Proteínas rho de Ligação ao GTP/biossíntese , Quinases da Família src/biossínteseRESUMO
Noroviruses are an important aetiological agent of acute gastroenteritis. They are responsible for large outbreaks of disease in the community, hospitals and long-term-care facilities. The clinical manifestations of norovirus outbreaks in psychiatric units are rarely described. The disease burden and impact highlight the importance of timely notification and investigation of these outbreaks. We analysed the characteristics of four norovirus outbreaks which occurred during a 3-year period in an in-patient psychiatric care unit. A total of 184 patients were affected which included 172 hospitalized patients, seven healthcare workers (HCWs) and five psychiatric nursing-home residents. The mean incidence rate of norovirus gastroenteritis (NVG) in hospitalized patients during these outbreaks was 12·7%. These outbreaks were characterized by higher incidence in middle-aged male patients, predominant sickness of diarrhoea, short duration of illness, peaks in late winter and early spring, and higher susceptibility in acute psychiatric patients. HCWs had longer duration of illness than psychiatric patients. More than 10% of affected patients experienced ≥ 2 infections. Infection control measures were instituted and a comprehensive, responsive standard operating procedure for NVG and outbreak management was developed. After implementation of these measures, no further outbreaks of NVG occurred during the study period.
Assuntos
Infecções por Caliciviridae/epidemiologia , Surtos de Doenças , Gastroenterite/epidemiologia , Gastroenterite/virologia , Norovirus , Adolescente , Adulto , Distribuição por Idade , Idoso , Infecção Hospitalar/prevenção & controle , Feminino , Hospitais Psiquiátricos , Humanos , Incidência , Controle de Infecções/métodos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Estações do Ano , Fatores de Tempo , Adulto JovemRESUMO
In the present work we use Raman microscopy to investigate the size effect of spin-phonon coupling in antiferromagnetic Cr2O3 nanoparticles. The peculiarities of the dependency of the phonon wave number on temperature (with a relatively weak peak at 293 cm(-1)) can be attributed to the spin-phonon coupling. The variation with temperature of the spin-phonon mode develops when the antiferromagnetic state is near the ordering temperature of the Cr spins. The observations can be reasonably well interpreted by describing the order parameter. A shift in frequency is caused by a strong spin-phonon interaction in Cr2O3. The obtained s-ph coefficients are found to be consistent with the strain, where raising the strain results in weakening of the s-ph coupling.
RESUMO
Plasmacytoid dendritic cells (pDCs) are critical in controlling adaptive immunity, but the mechanisms governing cytokine expression remain incompletely defined. Analogues of prostaglandin (PG)I(2), such as iloprost, can modulate functions of myeloid dendritic cells, but their involvement in the regulation of human pDCs remains unknown. To this end, the regulatory role of PGI(2) analogues on cytokine expression in pDCs was investigated. Circulating pDCs were magnetically sorted with BDCA-4 cell isolation kits from human peripheral blood mononuclear cells and treated with varying concentrations of iloprost with or without the addition of Toll-like receptor agonists, or an I prostanoid (IP) receptor antagonist, CAY10449. The levels of tumour necrosis factor (TNF)-alpha, interferon (IFN)-alpha and interleukin (IL)-10 were measured by ELISA. Iloprost induced IL-10 expression, but suppressed CpG oligodeoxynucleotide- (or imiquimod-) induced TNF-alpha and IFN-alpha production in pDCs. This effect was reversed by the addition of CAY10449. Forskolin, a cyclic adenosine monophosphate activator, conferred a similar modulating effect to that noted in iloprost-treated pDCs, although a higher concentration of forskolin was required to exert the same effect. Iloprost enhanced interleukin-10 and suppressed Toll-like receptor-mediated tumour necrosis factor-alpha and interferon-alpha production of human plasmacytoid dendritic cells via the I prostanoid receptor and, in part, the cyclic adenosine monophosphate pathway.
Assuntos
Citocinas/biossíntese , Células Dendríticas/citologia , Epoprostenol/análogos & derivados , Regulação da Expressão Gênica , Benzofenonas/farmacologia , Colforsina/farmacologia , AMP Cíclico/metabolismo , Ensaio de Imunoadsorção Enzimática , Humanos , Iloprosta/farmacologia , Imidazóis/farmacologia , Interferon-alfa/metabolismo , Interleucina-10/metabolismo , Oligonucleotídeos/química , Inibidores da Agregação Plaquetária/farmacologia , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismoRESUMO
SETTING: Many hospitals use the fully-automated BACTEC 960 Mycobacteria Growth Indicator Tube (MGIT) system and acid-fast staining to detect acid-fast bacilli (AFB) in clinical specimens; however, labour-intensive biochemical methods are used for further mycobacterial species identification. OBJECTIVE: To develop a user-friendly algorithm for mycobacterial species identification from AFB smear-positive BACTEC tubes. DESIGN: AFB smear-positive BACTEC tubes were collected and mycobacteria were isolated and identified by biochemical methods. The tubes were subgrouped by rpoB duplex polymerase chain reaction restriction enzyme analysis (rpoB DPRA). The results were combined with key phenotypic characters of mycobacteria isolated from the tubes to develop a species identification algorithm with 16S rDNA sequencing of the isolate being used as the gold standard method. RESULTS: By rpoB DPRA, 441 AFB smear-positive BACTEC tubes were correctly subgrouped into 100 tubes containing Mycobacterium tuberculosis complex, 335 tubes containing non-tuberculous mycobacteria and six tubes containing both. A species identification algorithm was developed by combining the rpoB DPRA results of the tubes with growth rate, photoreactivity and two biochemical results of mycobacteria recovered from the tubes. CONCLUSION: This user-friendly algorithm can be used for mycobacterial species identification from AFB smear-positive BACTEC tubes.
Assuntos
Técnicas Bacteriológicas , Mycobacterium tuberculosis/isolamento & purificação , Reação em Cadeia da Polimerase/métodos , Mapeamento por Restrição/métodos , Algoritmos , Técnicas Bacteriológicas/métodos , Enzimas de Restrição do DNA , DNA Bacteriano/análise , Mycobacterium tuberculosis/genética , Fenótipo , TaiwanRESUMO
SETTING: Many hospitals in Taiwan use the fully automated BACTEC Mycobacterial Growth Indicator Tube (MGIT) 960 system to identify mycobacteria in clinical specimens, while the labour-intensive BD ProbeTec ET (CTB) system or biochemical methods are used to identify Mycobacterium tuberculosis complex (MTC) in mycobacterially positive BACTEC cultures. OBJECTIVE: To evaluate whether the Capilia TB assay can be used to replace the BD ProbeTec ET (CTB) system or biochemical methods for identifying MTC in BACTEC cultures. DESIGN: Mycobacterially positive BACTEC cultures were collected and MTC in the cultures was identified using biochemical methods. MTC was identified using serpentine cording in smears, the Capilia TB assay or the BD ProbeTec ET (CTB) system, and the results were compared. RESULTS: Using 233 mycobacterially positive BACTEC cultures, the sensitivity and specificity of identification of the Capilia TB assay were respectively 96.9% and 98.6%, while those of the BD ProbeTec ET (CTB) system were respectively 99.4% and 97.3%. Combining the Capilia TB assay with serpentine cording in smears led to 100% specificity for intersected results and 100% sensitivity for combined results. CONCLUSION: The Capilia TB assay can be used to identify MTC in BACTEC cultures. By combining the assay with serpentine cording in smears, false-positives and -negatives may be reduced.
Assuntos
Imunoensaio/métodos , Mycobacterium tuberculosis/classificação , Técnicas de Amplificação de Ácido Nucleico/métodos , Antígenos de Bactérias/análise , Antígenos de Bactérias/isolamento & purificação , Proteínas de Bactérias/análise , Proteínas de Bactérias/isolamento & purificação , Cromatografia/métodos , Humanos , Mycobacterium tuberculosis/imunologia , Kit de Reagentes para Diagnóstico , Sensibilidade e Especificidade , Tuberculose Pulmonar/diagnósticoRESUMO
BACKGROUND: It has been proposed that the volatile anesthetic isoflurane induces neuroprotection and that the endogenous opioid peptide dynorphin induces neurocytotoxicity in cells. The levels of dynorphin are often significantly elevated in neuropathophysiological conditions, and dynorphin can directly induce toxicity. However, the neuroprotective effects of isoflurane on dynorphin-induced cytotoxicity are still unclear. METHODS: In order to determine the effect of isoflurane on dynorphin-induced cytotoxicity in neuronal cells, we have designed a device wherein cultured human neuroblastoma SH-SY5Y cells can be exposed to isoflurane. Fully differentiated SH-SY5Y cells were obtained by treating the cells with retinoic acid for 6 days. We examined SH-SY5Y cell survival, apoptosis, and antiapoptotic protein expression by cell viability, terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling stain, and Western blot analysis, respectively. RESULTS: After 16 h of dynorphin (10 microM) treatment, the SH-SY5Y cells showed significant cytotoxicity, apoptosis, and downregulation of the antiapoptotic Bcl-2 protein expression. These effects of dynorphin were significantly inhibited by isoflurane exposure for 32 h [pretreatment for 16 h and posttreatment (after dynorphin treatment) for 16 h]. CONCLUSION: Thus, our results suggest that isoflurane exerts neuroprotective effects in the case of dynorphin-induced pathophysiological disruption.
Assuntos
Diferenciação Celular , Regulação para Baixo/efeitos dos fármacos , Dinorfinas/toxicidade , Isoflurano/farmacologia , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , HumanosRESUMO
Municipal solid waste incinerator (MSWI) fly ash has been examined for possible use as landfill interim cover. For this aim, three anaerobic bioreactors, 1.2m high and 0.2m in diameter, were used to assess the co-digestion or co-disposal performance of MSW and MSWI fly ash. Two bioreactors contained ratios of 10 and 20 g fly ash per liter of MSW (or 0.2 and 0.4 g g(-1) VS, that is, 0.2 and 0.4 g fly ash per gram volatile solids (VS) of MSW). The remaining bioreactor was used as control, without fly ash addition. The results showed that gas production rate was enhanced by the appropriate addition of MSWI fly ash, with a rate of approximately 6.5l day(-1)kg(-1)VS at peak production in the ash-added bioreactors, compared to approximately 4l day(-1)kg(-1)VS in control. Conductivity, alkali metals and VS in leachate were higher in the fly ash-added bioreactors compared to control. The results show that MSW decomposition was maintained throughout at near-neutral pH and might be improved by release of alkali and trace metals from fly ash. Heavy metals exerted no inhibitory effect on MSW digestion in all three bioreactors. These phenomena indicate that proper amounts of MSWI fly ash, co-disposed or co-digested with MSW, could facilitate bacterial activity, digestion efficiency and gas production rates.
Assuntos
Anaerobiose , Reatores Biológicos , Carbono , Material Particulado , Cinza de Carvão , Concentração de Íons de HidrogênioRESUMO
This study used finite element (FE) analysis with the load-controlled method (LCM) and the displacement-controlled method (DCM) to examine motion differences at the implant level and adjacent levels between fusion and non-fusion implants. A validated three-dimensional intact (INT) L1-L5 FE model was used. At the L3-L4 level, the INT model was modified to surgery models, including the artificial disc replacement (ADR) of ProDisc II, and the anterior lumbar interbody fusion (ALIF) cage with pedicle screw fixation. The LCM imposed 10 Nm moments of four physiological motions and a 150 N preload at the top of L1. The DCM process was in accordance with the hybrid testing protocol. The average percentage changes in the range of motion (ROM) for whole non-operated levels were used to predict adjacent level effects (ALE%). At the implant level, the ALIF model showed similar stability with both control methods. The ADR model using the LCM had a higher ROM than the model using the DCM, especially in extension and torsion. At the adjacent levels, the ALIF model increased ALE% (at least 17 per cent) using the DCM compared with the LCM. The ADR model had an ALE% close to that of the INT model, using the LCM (average within 6 per cent), while the ALE% decreased when using the DCM. The study suggests that both control methods can be adopted to predict the fusion model at the implant level, and similar stabilization characteristics can be found. The LCM will emphasize the effects of the non-fusion implants. The DCM was more clinically relevant in evaluating the fusion model at the adjacent levels. In conclusion, both the LCM and the DCM should be considered in numerical simulations to obtain more realistic data in spinal implant biomechanics.