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BACKGROUND: Renal dysfunction remains an issue in tenofovir disoproxil fumarate (TDF) for chronic hepatitis B (CHB) patients. AIM: To evaluate renal safety of TDF according to the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. METHODS: We retrospectively recruited CHB patients who received either TDF or entecavir (ETV) monotherapy from January 2008 to August 2015. After excluding confounding conditions, 253 patients who received TDF were randomly matched 1:2 with 506 patients who received ETV through the propensity scores, which consisted of age, gender, cirrhosis, chronic kidney disease (CKD) and estimated glomerular filtration rate (eGFR). Renal function deterioration was defined as a drop in GFR category accompanied with a ≥25% eGFR decline. Cumulative incidences of and hazard ratios (HRs) for renal dysfunction were analysed. RESULTS: The mean eGFR decline was significantly greater in the TDF group over 48 months (TDF vs ETV: 15.73 mL/min/1.73 m2 , 95% confidence interval [CI]: 13.76-17.70 vs 5.96 mL/min/1.73 m2 , 95% CI: 4.72-7.19; P < 0.001). The cumulative incidence of renal function deterioration was significantly higher in the TDF group (TDF vs ETV: 11.1%, 95% CI: 7.4-14.8 vs 1.7%, 95% CI: 1.0-2.4; P < 0.001). After adjusting for age, pre-existing CKD and diabetes, TDF was independently associated with an increased risk of renal function deterioration (HR 5.36, 95% CI: 2.16-13.35; P < 0.001). Pre-existing CKD (HR 6.71, 95% CI: 2.25-17.65), proteinuria (HR 3.39, 95% CI: 1.23-9.39), and haematuria (HR 4.25, 95% CI: 1.32-13.68) were also independent factors of renal dysfunction. CONCLUSION: By following the KDIGO guidelines, we confirmed that TDF was associated with a higher risk of renal dysfunction as compared to ETV.
Assuntos
Antivirais/efeitos adversos , Guanina/análogos & derivados , Hepatite B Crônica/tratamento farmacológico , Tenofovir/efeitos adversos , Adulto , Antivirais/uso terapêutico , Feminino , Taxa de Filtração Glomerular , Guanina/administração & dosagem , Guanina/efeitos adversos , Humanos , Incidência , Rim/patologia , Cirrose Hepática/epidemiologia , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/epidemiologia , Estudos Retrospectivos , Tenofovir/uso terapêuticoRESUMO
OBJECTIVE: To investigate the association of different antipsychotic treatments with hospitalization due to self-harm among patients with schizophrenia. METHOD: This retrospective cohort study was based on Taiwan's universal health insurance database. Patients aged 15-45 years with a newly diagnosed schizophrenic disorder in 2001-2012 were included. The study outcome was the first hospitalization due to self-harm or undetermined injury after the diagnosis of schizophrenic disorders. The exposure status of antipsychotics was modeled as a time-dependent variable. The analyses were stratified by antipsychotic dosage based on defined daily dose (DDD). RESULTS: Among 70 380 patients with a follow-up of 500 355 person-years, 2272 self-harm hospitalization episodes were identified. Compared with none or former use, current use of several second-generation antipsychotics with a dose of one DDD or above, including amisulpride, aripiprazole, clozapine, risperidone, and sulpiride, was associated with decreased risk of self-harm hospitalization, with clozapine showing the strongest effect (adjusted rate ratio = 0.26, 95% confidence interval 0.15-0.47). CONCLUSION: The protective effect on self-harm may vary across different antipsychotics. Further studies are needed to replicate the findings.
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Antipsicóticos/farmacologia , Clozapina/farmacologia , Esquizofrenia/tratamento farmacológico , Comportamento Autodestrutivo/prevenção & controle , Adolescente , Adulto , Antipsicóticos/administração & dosagem , Clozapina/administração & dosagem , Feminino , Seguimentos , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Programas Nacionais de Saúde/estatística & dados numéricos , Risco , Esquizofrenia/epidemiologia , Comportamento Autodestrutivo/epidemiologia , Taiwan/epidemiologia , Adulto JovemRESUMO
Essentials Disabled-2 (Dab2) phosphorylation status in thrombin signaling of human platelet was investigated. Ser723 was the major Dab2 phosphorylation site in human platelets stimulated by thrombin. Dab2 S723 phosphorylation (pS723) caused the dissociation of Dab2-CIN85 protein complex. Dab2-pS723 regulated ADP release and integrin αIIbß3 activation in thrombin-treated platelets. SUMMARY: Background Disabled-2 (Dab2) is a platelet protein that is functionally involved in thrombin signaling in mice. It is unknown whether or not Dab2 undergoes phosphorylation during human platelet activation. Objectives To investigate the phosphorylation status of Dab2 and its functional consequences in thrombin-stimulated human platelets. Methods Dab2 was immunoprecipitated from resting and thrombin-stimulated platelet lysates for differential isotopic labeling. After enrichment of the phosphopeptides, the phosphorylation sites were analyzed by mass spectrometry. The corresponding phospho-specific antibody was generated. The protein kinases responsible for and the functional significance of Dab2 phosphorylation were defined by the use of signaling pathway inhibitors/activators, protein kinase assays, and various molecular approaches. Results Dab2 was phosphorylated at Ser227, Ser394, Ser401 and Ser723 in thrombin-stimulated platelets, with Ser723 phosphorylation being the most significantly increased by thrombin. Dab2 was phosphorylated by protein kinase C at Ser723 in a Gαq -dependent manner. ADP released from the stimulated platelets further activated the Gßγ -dependent pathway to sustain Ser723 phosphorylation. The Cbl-interacting protein of 85 kDa (CIN85) bound to Dab2 at a motif adjacent to Ser723 in resting platelets. The consequence of Ser723 phosphorylation was the dissociation of CIN85 from the Dab2-CIN85 complex. These molecular events led to increases in fibrinogen binding and platelet aggregation in thrombin-stimulated platelets by regulating αIIb ß3 activation and ADP release. Conclusions Dab2 Ser723 phosphorylation is a key molecular event in thrombin-stimulated inside-out signaling and platelet activation, contributing to a new function of Dab2 in thrombin signaling.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Plaquetas/efeitos dos fármacos , Ativação Plaquetária/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Trombina/farmacologia , Proteínas Supressoras de Tumor/metabolismo , Proteínas Reguladoras de Apoptose , Plaquetas/metabolismo , Fibrinogênio/metabolismo , Células HEK293 , Humanos , Fosforilação , Agregação Plaquetária/efeitos dos fármacos , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Proteína Quinase C/metabolismo , Serina , Fatores de TempoRESUMO
BACKGROUND: The aim of the study was to evaluate the comparative risk of self-harm associated with the use of different antidepressants. METHOD: A cohort study was conducted using data from Taiwan's National Health Insurance Research Database from 2001 to 2012. A total of 751 606 new antidepressant users with depressive disorders were included. The study outcome was hospitalization due to self-harm (International Classification of Diseases, Ninth Revision, Clinical Modification codes: E950-E958 and E980-E988). Cox proportional hazards models with stratification of the propensity score deciles were used to estimate the hazard ratios of self-harm hospitalization during the first year following the initiation of antidepressant treatment. RESULTS: There were 1038 hospitalization episodes due to self-harm that occurred during the follow-up of 149 796 person-years, with an overall incidence rate of 6.9 [95% confidence interval (CI) 6.5-7.4] per 1000. Compared with fluoxetine, the risk of self-harm hospitalization was higher for maprotiline [adjusted hazard ratio (aHR) = 3.00, 95% CI 1.40-6.45], milnacipran (aHR = 2.34, 95% CI 1.24-4.43) and mirtazapine (aHR = 1.40, 95% CI 1.06-1.86), lower for bupropion (aHR = 0.51, 95% CI 0.30-0.86), and similar level of risk was found for other selective serotonin reuptake inhibitors (citalopram, escitalopram, fluvoxamine, paroxetine and sertraline). CONCLUSIONS: The risk of self-harm may vary across different antidepressant drugs. It would be of importance to conduct further research to investigate the influence of antidepressant use on self-harm behaviors.
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Antidepressivos/farmacologia , Transtorno Depressivo/tratamento farmacológico , Hospitalização/estatística & dados numéricos , Comportamento Autodestrutivo/prevenção & controle , Adolescente , Adulto , Idoso , Criança , Estudos de Coortes , Transtorno Depressivo/complicações , Transtorno Depressivo/epidemiologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Risco , Comportamento Autodestrutivo/epidemiologia , Comportamento Autodestrutivo/etiologia , Taiwan/epidemiologia , Adulto JovemRESUMO
BACKGROUND: Neutrophil gelatinase-associated lipocalin (NGAL) is a biomarker for the early prediction of renal damage and the progression of chronic kidney disease (CKD) in humans and dogs. HYPOTHESIS: Neutrophil gelatinase-associated lipocalin also may play a role in the progression of CKD in cats. ANIMALS: Eighty CKD and 18 control cats. METHODS: Cats were categorized into different stages according to the International Renal Interest Society (IRIS) staging system. Urine and plasma samples were collected and tested for NGAL concentrations using an in-house sandwich ELISA system and urinary NGAL (uNGAL)-to-creatinine ratio (UNCR) was determined. Cats in which serum creatinine concentration increased by >0.5 mg/dL from baseline within 30 days were defined as exhibiting progression. RESULTS: The urinary NGAL and UNCR of CKD cats were significantly higher than those of healthy cats (P < .05) and were highly correlated with serum creatinine concentration. The area under the receiver operating characteristic curve (AUROC) for uNGAL, when predicting the progression of CKD, was 0.71 and the best cutoff value was 2.06 ng/mL with a sensitivity of 76.9% and a specificity of 75%. The AUROC for UNCR when predicting the progression of CKD was 0.79 and the best cutoff value was 4.08 × 10-6 with a sensitivity of 76.9% and specificity of 79.2%. Cats with UNCR values higher than their cutoffs experienced significantly faster deterioration with a median of 19 days. CONCLUSIONS: Both urinary NGAL and UNCR are useful markers for the prediction of CKD progression in cats.
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Biomarcadores/sangue , Doenças do Gato/diagnóstico , Lipocalina-2/sangue , Insuficiência Renal Crônica/veterinária , Animais , Análise Química do Sangue/veterinária , Estudos de Casos e Controles , Doenças do Gato/sangue , Gatos , Feminino , Masculino , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/diagnóstico , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: Although there is evidence that exposure to tobacco smoke is harmful to children's respiratory health, the effects of tobacco smoke exposure on the regulation of immunoglobulin E (IgE)-mediated immune responses to specific allergens remain unclear. This study aimed to investigate the relationship between objectively assessed tobacco smoke exposure and specific IgE profiles for a broad spectrum of allergens in a population setting. METHODS: Children aged 5-18 years (N = 1315) were assessed using serum cotinine measurement and microarray-based multiplexed detection of specific IgE against 40 allergens. RESULTS: Serum cotinine levels were positively associated with sensitization to foods (adjusted odds ratio [AOR] = 4.95; 95% CI: 1.59-15.34), cockroaches (AOR = 3.77; 95% CI: 1.49-9.51), and pollen (AOR = 2.84; 95% CI: 1.20-6.73) while the association was borderline significant for animals (AOR = 2.53; 95% CI: 0.92-6.93). No associations were found for sensitization against mites, mold, and latex. When considering the degree of allergic sensitization, serum cotinine levels were positively correlated to the number of sensitization to cockroaches (P = 0.004), pollen (P = 0.006), and foods (P < 0.001), with statistically significant positive dose-response relationships (all P < 0.01). Similar results were observed when summing up specific IgE concentrations for the aforementioned allergen categories. CONCLUSIONS: The association between tobacco smoke exposure and IgE sensitization to environmental allergens varies for different allergens among children. This study demonstrates that elevated serum cotinine levels are significantly associated with IgE sensitization to cockroaches, grass pollen, and certain foods, with potential dose-dependent relationships.
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Exposição Ambiental/efeitos adversos , Hipersensibilidade/epidemiologia , Hipersensibilidade/etiologia , Imunoglobulina E/imunologia , Nicotiana/efeitos adversos , Fumaça/efeitos adversos , Adolescente , Alérgenos/imunologia , Animais , Criança , Pré-Escolar , Cotinina/sangue , Feminino , Humanos , Imunização , Imunoglobulina E/sangue , Masculino , Razão de Chances , Vigilância da População , Fatores de RiscoRESUMO
Taiwan had been declared rabies-free in humans and domestic animals for five decades until July 2013, when surprisingly, three Formosan ferret badgers (FB) were diagnosed with rabies. Since then, a variety of wild carnivores and other wildlife species have been found dead, neurologically ill, or exhibiting aggressive behaviors around the island. To determine the affected animal species, geographic areas, and environments, animal bodies were examined for rabies by direct fluorescent antibody test (FAT). The viral genomes from the brains of selected rabid animals were sequenced for the phylogeny of rabies viruses (RABV). Out of a total of 1016 wild carnivores, 276/831 (33.2%) Formosan FBs were FAT positive, with occasional biting incidents in 1 dog and suspected spillover in 1 house shrew. All other animals tested, including dogs, cats, bats, mice, house shrews, and squirrels, were rabies-negative. The rabies was badger-associated and confined to nine counties/cities in sylvatic environments. Phylogeny of nucleoprotein and glycoprotein genes from 59 Formosan FB-associated RABV revealed them to be clustered in two distinct groups, TWI and TWII, consistent with the geographic segregation into western and eastern Taiwan provided by the Central Mountain Range and into northern rabies-free and central-southern rabies-affected regions by a river bisecting western Taiwan. The unique features of geographic and genetic segregation, sylvatic enzooticity, and FB-association of RABV suggest a logical strategy for the control of rabies in this nation.
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Mustelidae , Filogenia , Vírus da Raiva/genética , Raiva/veterinária , Animais , Animais Selvagens , Antígenos Virais , Doenças do Gato/epidemiologia , Doenças do Gato/virologia , Gatos , Doenças do Cão/epidemiologia , Doenças do Cão/virologia , Cães , Raiva/epidemiologia , Raiva/virologia , Especificidade da Espécie , Taiwan/epidemiologiaRESUMO
Taiwan had been considered rabies free since 1961. In 2013, Taiwan confirmed the detection of rabies virus in wild Taiwan ferret-badgers. Up to December 2014, there have been 423 rabies-confirmed ferret-badgers and three cases of spillover infection into non-reservoir hosts. Genetic analysis indicates that TFBV is distinct from all other known rabies virus variants. To date, ferret-badger rabies is known to occur only in China and Taiwan. The temporal dynamics of rabid ferret-badgers in Taiwan suggests that the epizootic appears to have subsided to enzootic levels as of December 2014. According to the current epidemiologic data, there is only one TFBV strain in Taiwan. TFBV is still sequestered to the mountainous regions. Humans are at risk mainly through exposure to the virus from infected domestic meso-carnivores, mainly dogs and cats. Dogs and cats should be vaccinated to establish an immunological barrier to stop the spread of the disease from mountainous regions to domestic meso-carnivores.
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Reservatórios de Doenças/veterinária , Mustelidae/virologia , Administração em Saúde Pública , Vírus da Raiva/isolamento & purificação , Raiva/veterinária , Animais , Doenças do Gato/prevenção & controle , Gatos , Surtos de Doenças/veterinária , Doenças do Cão/prevenção & controle , Cães , Humanos , Vigilância da População , Prevalência , Raiva/epidemiologia , Raiva/prevenção & controle , Vacina Antirrábica/imunologia , Taiwan/epidemiologiaRESUMO
Epigenetic modifying enzymes have a crucial role in the pathogenesis of acute myeloid leukemia (AML). Methylation of lysine 9 on histone H3 by the methyltransferase G9a and SUV39H1 is associated with inhibition of tumor suppressor genes. We studied the effect of G9a and SUV39H1 inhibitors on viability and differentiation of AML cells and tested the cytotoxicity induced by combination of G9a and SUV39H1 inhibitors and various epigenetic drugs. The SUV39H1 inhibitor (chaetocin) and the G9a inhibitor (UNC0638) caused cell death in AML cells at high concentrations. However, only chaetocin-induced CD11b expression and differentiation of AML cells at non-cytotoxic concentration. HL-60 and KG-1a cells were more sensitive to chaetocin than U937 cells. Long-term incubation of chaetocin led to downregulation of SUV39H1 and reduction of H3K9 tri-methylation in HL-60 and KG-1a cells. Combination of chaetocin with suberoylanilide hydroxamic acid (SAHA, a histone deacetylase inhibitor) or JQ (a BET (bromodomain extra terminal) bromodomain inhibitor) showed synergistic cytotoxicity. Conversely, no synergism was found by combining chaetocin and UNC0638. More importantly, chaetocin-induced differentiation and combined cytotoxicity were also found in the primary cells of AML patients. Collectively, the SUV39H1 inhibitor chaetocin alone or in combination with other epigenetic drugs may be effective for the treatment of AML.
Assuntos
Antineoplásicos/farmacologia , Diferenciação Celular/efeitos dos fármacos , Metilação de DNA/efeitos dos fármacos , Leucemia Mieloide Aguda/tratamento farmacológico , Metiltransferases/antagonistas & inibidores , Proteínas Repressoras/antagonistas & inibidores , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Células Cultivadas , Sinergismo Farmacológico , Epigênese Genética , Humanos , Immunoblotting , Piperazinas/farmacologia , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
BACKGROUND AND AIM: The influenza A virus (IAV) is an important zoonotic pathogen with infections also reported in dogs. IAV infections can be detected through the presence of antibodies using the enzyme-linked immunosorbent assay (ELISA). Serum is the only standard sample source; however, there is no information on the availability of other sample sources for IAV antibody detection in dogs. Compared with serum, plasma is more widely employed in most animal hospitals. The object of this study is to investigate whether plasma collected in ethylenediaminetetraacetic acid (EDTA) tubes (EDTA plasma) or heparin tubes (heparin plasma) could be used in the ELISA protocol instead of serum for IAV antibody detection in dogs. MATERIALS AND METHODS: Totally, 82 matched EDTA plasma and serum sample pairs and 79 matched heparin plasma and serum sample pairs were employed using blocking enzyme-linked immunosorbent assay (bELISA). The agreement and correlation between the plasma (EDTA or heparin plasma) and serum were assessed using the agreement index kappa (kD) calculation and Pearson correlation coefficient, respectively. RESULTS: The agreement index kD of EDTA plasma and serum was 1.0, and that of heparin plasma and serum was 0.85. The Pearson correlation coefficient of EDTA plasma and serum was 0.87 (p<0.01), and that of heparin plasma and serum was 0.82 (p<0.01). CONCLUSION: The results proved that plasma, especially EDTA plasma, could be substituted for serum in the bELISA test. This might greatly expand the clinical applicability of IAV antibody detection in dogs.
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AIMS: To investigate the temporal relationship between non-steroidal anti-inflammatory drug use and the development of chronic kidney disease in people with Type 2 diabetes mellitus. METHODS: We conducted a retrospective cohort study and followed up a population with Type 2 diabetes who were chronic kidney disease-free (n = 48,715) using national health insurance claims data in Taiwan. Exposure status to non-steroidal anti-inflammatory drugs in 2007 was measured. A total of 6406 subjects with incident chronic kidney disease were identified from the period 2008 to 2011. Multivariable proportional hazards models were applied to determine the temporal relationship between non-steroidal anti-inflammatory drug use and the development of chronic kidney disease. RESULTS: We observed a significant temporal relationship between non-steroidal anti-inflammatory drug use and the development of chronic kidney disease in people with Type 2 diabetes. Compared with people not taking any non-steroidal anti-inflammatory drug in 2007, those who were taking such drugs for at least 90 days in 2007 had a higher risk of chronic kidney disease development (adjusted hazard ratio 1.37, 95% CI 1.26-1.49). In subgroup analyses, those people (irrespective of age, sex, various comorbidities and use of anti-hypertensive drugs, aspirin or acetaminophen) who were taking non-steroidal anti-inflammatory drugs for at least 90 days were more likely to develop chronic kidney disease than people who were not taking any non-steroidal anti-inflammatory drug. CONCLUSIONS: The results suggest that there is a positive temporal relationship between non-steroidal anti-inflammatory drug use and increased risk of chronic kidney disease in people with Type 2 diabetes. The use of non-steroidal anti-inflammatory drugs should be based on clinical evaluations of benefits and risks, and should be prescribed with caution for people with Type 2 diabetes.
Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Diabetes Mellitus Tipo 2/complicações , Insuficiência Renal Crônica/epidemiologia , Adulto , Idoso , Estudos de Coortes , Feminino , Seguimentos , Humanos , Incidência , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Taiwan/epidemiologiaRESUMO
Fourteen self-reported insomniacs (SRI) and 14 good sleepers (GS) had their cardiac neuronal activity assessed by heart rate variability (HRV) under controlled respiration at a slow frequency rate of 0.1 Hz, and a forced rate of 0.2 Hz during daytime rest. Nighttime sleep was measured by polysomnography. The SRI showed depressed high frequency power of HRV compared to the GS. An increased total power of HRV was observed among the SRI during slow, paced breathing compared with spontaneous breathing and 0.2 Hz. Sleep onset latency, number of awakenings, and awakening time during sleep were decreased and sleep efficiency was increased if SRI practiced slow, paced breathing exercises for 20 min before going to sleep. Our results indicate that there is autonomic dysfunction among insomniacs, especially in relation to vagal activity; however, this decreased vagal activity can be facilitated by practicing slow, paced breathing, thereby improving sleep quality.
Assuntos
Sistema Nervoso Autônomo/fisiopatologia , Respiração , Taxa Respiratória/fisiologia , Distúrbios do Início e da Manutenção do Sono/terapia , Sono/fisiologia , Nervo Vago/fisiopatologia , Adulto , Feminino , Frequência Cardíaca/fisiologia , Humanos , Masculino , Polissonografia , Distúrbios do Início e da Manutenção do Sono/fisiopatologia , Adulto JovemRESUMO
Transmission of hepatitis C virus (HCV) to recipients of hematopoietic stem cell transplant (HSCT) occurs frequently from HCV viremic donors and causes complications. Here, we report the outcomes of 3 cases from our 265 allogeneic HSCTs, whose donors had HCV infections. Successful prevention of HCV transmission was noted in 1 recipient by pretreatment of the donor with peginterferon/ribavirin to undetectable levels of HCV viremia before stem cell harvest. This case stressed the important role of effective antiviral therapy and HCV RNA seronegativity before cell harvest for prevention of HCV transmission in HSCT.
Assuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hepatite C/transmissão , Viremia , Adulto , Antivirais/administração & dosagem , Antivirais/uso terapêutico , Quimioterapia Combinada , Feminino , Hepacivirus/isolamento & purificação , Hepatite C/tratamento farmacológico , Hepatite C/virologia , Humanos , Interferon-alfa/administração & dosagem , Interferon-alfa/uso terapêutico , Masculino , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/uso terapêutico , RNA Viral/sangue , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/uso terapêutico , Ribavirina/administração & dosagem , Ribavirina/uso terapêutico , Doadores de Tecidos , Carga ViralRESUMO
BACKGROUND: Reelin is a large extracellular glycoprotein that is present in the peripheral blood. That Reelin interacts with the coagulation components and elicits a functional role in hemostasis has not yet been elucidated. OBJECTIVES: The hemostatic activity of Reelin is investigated and defined in this study. METHODS: The interplay of Reelin with coagulation components was elucidated by far-Western and liposome/platelet binding assays. In vivo and ex vivo hemostasis-related analyses of Reelin-deficient mice and plasma were also performed. RESULTS: Reelin interacted with the liposomes containing phosphatidylserine (PS) or phosphatidylcholine. Instead of interacting with known Reelin receptors (ApoE receptor 2, very low density lipoprotein receptor and integrin ß1), Reelin interacted with PS of the activated platelets. The interaction between Reelin and the coagulation factors of thrombin and FXa was also demonstrated with the Kd of 11.7 and 21.2 nm, respectively. Reelin-deficient mice displayed a prolonged bleeding time and an increase in rebleeding rate. Despite the fact that Reelin deficiency had no significant effect on the clotting time of prothrombin and activated partial thromboplastin time, the fibrin clot formation was abnormal and the fibrin clot structure was relatively loosened with reduced clot strength. Abnormal fibrinogen expression did not account for the hemostatic defects associated with Reelin deficiency. Instead, thrombin generation was impaired concomitant with an altered prothrombin cleavage pattern. CONCLUSIONS: By interacting with platelet phospholipids and the coagulation factors, thrombin and FXa, Reelin plays a selective role in coagulation activation, leading to thrombin generation and formation of a normal fibrin clot.
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Moléculas de Adesão Celular Neuronais/sangue , Moléculas de Adesão Celular Neuronais/genética , Proteínas da Matriz Extracelular/sangue , Proteínas da Matriz Extracelular/genética , Hemostasia , Proteínas do Tecido Nervoso/sangue , Proteínas do Tecido Nervoso/genética , Serina Endopeptidases/sangue , Serina Endopeptidases/genética , Trombina/biossíntese , Animais , Anexina A5/química , Coagulação Sanguínea , Fatores de Coagulação Sanguínea/química , Plaquetas/citologia , Fator Xa/química , Fibrina/química , Fibrinogênio/química , Genótipo , Glicoproteínas/química , Lipídeos/química , Lipossomos/química , Camundongos , Camundongos Transgênicos , Tempo de Tromboplastina Parcial , Fosfatidilcolinas/química , Fosfatidilserinas/química , Ativação Plaquetária , Agregação Plaquetária , Ligação Proteica , Tempo de Protrombina , Proteína Reelina , Trombina/químicaRESUMO
We recently showed that Helicobacter pylori (HP)-positive gastric 'pure' diffuse large B-cell lymphoma (DLBCL) may respond to HP eradication therapy. However, whether these HP-related 'pure' DLBCL of the stomach may differ fundamentally from those unrelated to HP remains unclear. In this study, we compared the clinicopathologic features of these two groups of patients who had been uniformly treated by conventional chemotherapy. Forty-six patients were designated HP-positive and 49 were HP-negative by conventional criteria. HP-positive patients had a lower International Prognostic Index score (0-1, 65% vs 43%, P=0.029), a lower clinical stage (I-IIE1, 70% vs 39%, P=0.003), a better tumor response to chemotherapy (complete pathologic response, 76% vs 47%, P=0.004) and significantly superior 5-year event-free survival (EFS) (71.7% vs 31.8%, P<0.001) and overall survival (OS) (76.1% vs 39.8%, P<0.001). To draw a closer biologic link with HP, HP-positive tumors were further examined for CagA expression in lymphoma cells. Compared with CagA-negative cases (n=16), CagA-positive cases (n=27) were associated with high phosphorylated SHP-2 expression (P=0.016), and even better 5-year EFS (85.2% vs 46.3%, P=0.002) and OS (88.9% vs 52.9%, P=0.003). HP-related gastric 'pure' DLBCL may be a distinct tumor entity, which is less aggressive, and responds better to conventional chemotherapy.
Assuntos
Infecções por Helicobacter/fisiopatologia , Helicobacter pylori/isolamento & purificação , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/microbiologia , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/microbiologia , Antígenos de Bactérias/biossíntese , Proteínas de Bactérias/biossíntese , Intervalo Livre de Doença , Feminino , Infecções por Helicobacter/metabolismo , Infecções por Helicobacter/microbiologia , Helicobacter pylori/metabolismo , Humanos , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologiaRESUMO
This study investigated the relationship between the specific immunoglobulin E (IgE) profile for 40 allergens using a novel microarray technique (BioIC) and fraction of exhaled nitric oxide (FeNO) in a population sample of 1321 children. Significant positive associations were found between FeNO and sensitization to mites (P < 0.001), animals (P = 0.001), cockroaches (P < 0.001), and foods (P = 0.042), and furthermore, between FeNO and the number of sensitizations (all P < 0.05) or the sum of specific IgE (all P ≤ 0.01) against the aforementioned allergen categories. Specifically, sensitization to the following allergens was significantly related to higher FeNO: Dermatophagoides pteronyssinus, Dermatophagoides farina, Blomia tropicalis, cat, German cockroach, Oriental cockroach, codfish, crab, shrimp, and cheese (all P ≤ 0.01). In conclusion, IgE sensitization to mites, pets, cockroaches, seafood, and cheese, respectively, is significantly associated with elevated FeNO levels in a dose-dependent fashion in children. Our results provide new evidence that sensitization to certain food allergens may contribute to prompt inflammation in the airways.
Assuntos
Expiração , Imunoglobulina E/imunologia , Óxido Nítrico/metabolismo , Adolescente , Alérgenos/classificação , Alérgenos/imunologia , Animais , Criança , Feminino , Humanos , Hipersensibilidade/epidemiologia , Hipersensibilidade/imunologia , Hipersensibilidade/metabolismo , Imunoglobulina E/sangue , Masculino , Estudos ProspectivosRESUMO
Basaloid squamous cell carcinoma (BSCC) of the uterine cervix is a rare malignancy of the female genital tract with a poorer clinical outcome than SCC of the uterine cervix. We report a case of BSCC of the uterine cervix developing rapidly in a young adult Taiwanese. A 35-year-old woman, Para 2, visited the emergency room with severe dizziness, palpitations and sudden excessive vaginal bleeding with hemoglobin of 3.6 g/dl. She had been well and healthy but intermittent vaginal spotting developed for around 6 months previously and was treated as abnormal uterine bleeding by ob-gyn practitioners. She had a repeat cesarean operation 16 months prior to this episode and the last Pap smear showed reactive change 12 months ago at our hospital. On examination, she had an ulcerated, necrotic, and punched-out lesion of 5 cm of the cervix. A cervical biopsy revealed poorly differentiated typical BSCC. Abdominal/pelvic computerized tomography and whole body positron emission tomography confirmed FIGO staging IB2. She responded well to concurrent chemoradiotherapy. Follow-up for the patient is ongoing. This is a rapid developing BSCC of the uterine cervix, although we cannot actually ascertain when it started and how rapidly it progressed.
Assuntos
Carcinoma de Células Escamosas/patologia , Neoplasias do Colo do Útero/patologia , Adulto , Carcinoma de Células Escamosas/terapia , Quimiorradioterapia , Progressão da Doença , Feminino , Humanos , Taiwan , Neoplasias do Colo do Útero/terapiaAssuntos
Leiomioma/patologia , Leiomiossarcoma/patologia , Neoplasias Uterinas/patologia , Vagina/patologia , Neoplasias Vaginais/patologia , Antimetabólitos Antineoplásicos/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Docetaxel , Feminino , Humanos , Leiomioma/tratamento farmacológico , Leiomioma/cirurgia , Leiomiossarcoma/tratamento farmacológico , Leiomiossarcoma/cirurgia , Pessoa de Meia-Idade , Taxoides/administração & dosagem , Neoplasias Uterinas/tratamento farmacológico , Neoplasias Uterinas/cirurgia , Neoplasias Vaginais/tratamento farmacológico , Neoplasias Vaginais/cirurgia , GencitabinaRESUMO
We previously reported that CagA can be translocated into B cells in Helicobacter pylori (HP) coculture media, and the translocation appears biologically significant as activation of the relevant cellular pathways was noticed. In this study, we further explore if CagA can be detected in malignant B cells of HP-positive gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Expression of CagA was evaluated by immunohistochemistry. CagA expression was further confirmed by western blot analysis. The association between CagA expression in malignant B cells and tumor response to HP eradication therapy (HPE) was evaluated in 64 stage IE gastric MALT lymphoma patients. We detected CagA expression in 31 (48.4%) of 64 patients: 26 (68.4%) of the 38 HP-dependent cases and 5 (19.2%) of the 26 HP-independent cases (P<0.001). Patients with CagA expression responded to HPE quicker than those without (median time to complete remission, 3.0 vs 6.5 months, P=0.025). Our results indicated that CagA can be translocated into malignant B cells of MALT lymphoma, and the translocation is clinically and biologically significant.