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BACKGROUND AND AIM: Nonattendance of outpatient colonoscopy leads to inefficient use of health-care resources. We aimed to study the effectiveness of using Short Message Service (SMS) reminder prior in patients scheduled for outpatient colonoscopy on their nonattendance rate. METHODS: Patients who scheduled for an outpatient colonoscopy and had access of SMS were recruited from three clinics in Hong Kong. Patients were randomized to SMS group and standard care (SC) group. All patients were given a written appointment slip on the booking date. In addition, patients in the SMS group received an SMS reminder 7-10 days before their colonoscopy appointment. Patients' demographics, attendance, colonoscopy completion, and bowel preparation quality were recorded. Logistic regression was performed to identify predictors of nonattendance. RESULTS: From November 2013 to October 2019, a total of 2225 eligible patients were recruited. A total of 1079 patients were allocated to the SMS group and 1146 to the SC group. The nonattendance rate of patients in the SMS group was significantly lower than that in the SC group (8.9% vs 11.9%, P = 0.022). There were no significant differences in their baseline characteristics and colonoscopy completion rate and bowel preparation quality. A trend towards a higher rate of adequate bowel preparation was observed in the SMS group when compared with the SC group (69.9% vs 65.8%, P = 0.053). Independent predictors for nonattendance included younger age, underprivilege, and existing diabetes. CONCLUSIONS: An SMS reminder for outpatient colonoscopy is effective in reducing the nonattendance rate and may potentially improve the bowel preparation quality.
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Citas y Horarios , Colonoscopía/estadística & datos numéricos , Pacientes no Presentados/estadística & datos numéricos , Pacientes Ambulatorios/estadística & datos numéricos , Cooperación del Paciente/estadística & datos numéricos , Sistemas Recordatorios/estadística & datos numéricos , Envío de Mensajes de Texto , Factores de Edad , Femenino , Disparidades en Atención de Salud , Hong Kong/epidemiología , Humanos , Modelos Logísticos , MasculinoRESUMEN
INTRODUCTION: Authorities publish recommendations on the hepatitis B virus (HBV) viral load threshold to initiate antiviral treatment but the timing of quantification during pregnancy is not well defined. HBV DNA levels in pregnancy women at 28-30 weeks predict the risk of immunoprophylaxis failure. This study compared and evaluated the correlation between HBV DNA levels before 22 and 28-30 weeks' gestation. Clinical predictive factors for HBV DNA >6, 7 and 8 log10 IU/mL were studied. MATERIAL AND METHODS: A retrospective analysis of HBV DNA levels of women <22 and 28-30 weeks of gestation was carried out in 352 pregnant HBV carriers. HBV DNA was examined using the COBAS TaqMan HBV Monitor Test coupled with the COBAS Ampliprep extraction system (Both Roche Diagnostics, Branchburg, NJ, USA). RESULTS: A strong positive correlation was found between the viral loads of women <22 weeks (mean 16.7 weeks) and 28-30 weeks of gestation, which was independent of the viral load level and gestational age of quantification (r = 0.942, P < 0.001). Univariate analysis showed that positive hepatitis B e antigen (HBeAg), maternal age <35 years old and body mass index ≤21 kg/m2 were associated with a higher mean viral load at 28-30 weeks of gestation (P < 0.05). These factors were also associated with a higher chance of viral load >6, 7 and 8 log10 IU/mL at 28-30 weeks (P < 0.05). In multiple regression analysis, only the viral load of <22 weeks and positive HBeAg remained predictive of a higher mean viral load at 28-30 weeks of gestation (P < 0.05). The receiver operating characteristic curve showed that the HBV DNA of <22 weeks was an excellent predictor for different viral load cut-offs at 28-30 weeks. The area under curve was 0.986, 0.998 and 0.994 for viral load 6, 7 and 8 log10 IU/mL, respectively. CONCLUSIONS: HBV DNA quantification should be performed before 22 weeks of gestation. Viral load cut-offs similar to those at 28 weeks can be used to determine immunoprophylaxis failure at earlier gestation. Maternal positive HBeAg status was associated with a higher chance of viral load >6, 7 or 8 log10 IU/mL.
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ADN Viral/análisis , Vacunas contra Hepatitis B/administración & dosificación , Virus de la Hepatitis B/genética , Hepatitis B/tratamiento farmacológico , Complicaciones Infecciosas del Embarazo/virología , Carga Viral , Adulto , Femenino , Hong Kong , Hospitales Públicos , Humanos , Recién Nacido , Transmisión Vertical de Enfermedad Infecciosa/prevención & control , Embarazo , Segundo Trimestre del Embarazo , Estudios Prospectivos , Estudios Retrospectivos , Factores de RiesgoRESUMEN
BACKGROUND: Recurrent pyogenic cholangitis (RPC) is a known risk factor for intrahepatic cholangiocarcinoma (ICC), whether it represents a poor prognostic factor remains controversial. The aim of this study was to investigate the post-hepatectomy oncological outcomes of patients with ICC and coexisting RPC. METHOD: A retrospective analysis with propensity score matching (PSM) was performed for comparison between ICC patient with and without RPC. RESULTS: There were 143 patients with ICC with a median follow-up of 21 months. RPC was diagnosed in 18% of patients. The time from RPC diagnosis to ICC diagnosis was 137(47-481) months. The 3-year disease-free (DFS) and overall survival for the whole population was 34% and 43% respectively. Preoperative child score, elevated carcinoembryonic antigen, presence of microvascular invasion, multiple tumours, presence of postoperative complications and RPC were independent factors for DFS and OS. After PSM, 60 ICC patients who did not have RPC were compared with 20 ICC patients with RPC. Patients with RPC had significantly worse median DFS (10 vs 23 months, P = 0.020) and OS (15 vs 45 months, P = 0.004) when compared to the patients without RPC. CONCLUSION: RPC represents a poor prognostic factor affecting outcomes after hepatectomy for patients with ICC.
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Neoplasias de los Conductos Biliares/cirugía , Colangiocarcinoma/cirugía , Colangitis/complicaciones , Hepatectomía , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de los Conductos Biliares/complicaciones , Neoplasias de los Conductos Biliares/diagnóstico por imagen , Colangiocarcinoma/complicaciones , Colangiocarcinoma/diagnóstico por imagen , Colangitis/diagnóstico , Supervivencia sin Enfermedad , Femenino , Hepatectomía/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/etiología , Puntaje de Propensión , Recurrencia , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Factores de TiempoRESUMEN
An integrative approach, involving marketing and management issues on the business side, and product design and prototyping on the technical side, is proposed for the development of chemical-based products. For the former, objective-time chart, RAT2IO modules and workflow diagrams are used for project management. For the latter, the integration of experiments, modeling and synthesis expedites product conceptualization and prototyping. Tasks for which chemical engineers are expected to play a key or a supporting role are discussed. An industrial application - the development of a skin-care cream is described alongside the procedure in order to illustrate the myriad issues in product development. In addition to the traditional engineering problems such as process and equipment design, product characterization, performance evaluation, and stability tests are also included as an integral part of this approach.
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Danggui Buxue Tang (DBT) is an ancient herbal mixture containing Astragali Radix and Angelicae Sinensis Radix, and which are commonly consumed for "qi-invigorating" (i.e., stimulating vital energy/energy metabolism) as traditional Chinese medicine (TCM). The pharmacological activities of DBT in anti-oxidation, estrogenic, hematopoietic, and immunogenic have been reported; however, the role of DBT in cellular energy metabolism has not been determined. Here, we employed an extracellular flux analyzer to evaluate the mitochondrial respiration of cultured H9C2 cardiomyoblasts in present of DBT. The herbal extract of DBT was qualified chemically for the major ingredients, i.e. astragaloside, calycosin, formononetin, Z-ligustilide, and ferulic acid. The anti-oxidant activities of DBT, as well as its major ingredients, were determined by Folin-Ciocalteu assay, 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay, and protective effect in tert-butyl hydroperoxide (tBHP)-treated cultured cardiomyoblasts. In addition, a real-time oxygen consumption rate (OCR) in herbal extract-treated cultured cardiomyoblasts was revealed by using a Seahorse extracellular flux analyzer. In addition, the transcript expressions of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PCG-1α) and other genes relating to mitochondria biogenesis were determined in cardiomyoblasts under different herbal treatments. DBT possessed the strongest anti-oxidant activity and protective effects on the oxidatively stressed cardiomyoblasts. By revealing the OCR in mitochondria, the health state of cultured cardiomyoblasts under DBT was improved via increase of basal respiration, proton leak, non-mitochondria, and adenosine triphosphate (ATP) production. Furthermore, the transcriptional activities of genes responsible for mitochondrial biogenesis and DNA replication were stimulated by application of DBT in cultures.
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INTRODUCTION: According to global data for 2002, one quarter of new cases of primary bronchopulmonary cancer were non-smokers. We undertook this study with the aim of describing the epidemiological characteristics of non-smokers with primary bronchopulmonary cancer in the Dakar region of Senegal. METHODS: A multicenter descriptive study that included all non-smokers who presented with primary bronchopulmonary cancer between January 1st 2014 and December 31st 2015. The data were captured on an Excel file and then transferred to Epi InfoTM 7 software for analysis. RESULTS: The rate of diagnosis for primary bronchopulmonary cancers was 72.1 %. The prevalence of non-smokers was 33.3 %. The sex ratio was 1.27. The average age was 54.6 years. More than a third of the sample were housewives. Carpenters and craftsmen exposed to metals predominated. Exposure to cooking oils was reported in one case. Three patients presented sequelae of pulmonary tuberculosis. Adenocarcinoma was the most common histological type and predominated in young subjects. CONCLUSION: The proportion of primary bronchopulmonary cancers diagnosed among non-smokers is increasing in Dakar. An analytical study of suspected risk factors would be helpful for prevention.
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Neoplasias Pulmonares/epidemiología , No Fumadores/estadística & datos numéricos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Exposición a Riesgos Ambientales/efectos adversos , Exposición a Riesgos Ambientales/estadística & datos numéricos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Estudios Retrospectivos , Factores de Riesgo , Senegal/epidemiología , Adulto JovenRESUMEN
INTRODUCTION: Tobacco smoke alters lung defense mechanisms against infections and so increases the risk of mycobacterium tuberculosis infection. OBJECTIVE: To determine the particular clinical features of tuberculosis in smokers and identify risk factors. METHODS AND PATIENTS: We conducted a prospective, cross-sectional study over a period of nine months in Dakar, Senegal. The Chi-square test and multiple logistic regression were used to identify differences between smokers and non-smokers and to identify factors associated with clinical outcomes. RESULTS: We included 165 patients with active pulmonary tuberculosis (59 smokers versus 106 never-smokers). The average age of smokers was 43.8±12.7 versus 32.1±13.1 years (P<0.0001). Smokers were overwhelmingly male (98.3% versus 1.8%, P<0.0001). The average delay to consultation was longer among smokers (90 days [30-120] versus 60 days [30-90] ; P<0.0001). In multivariate analysis, alcohol abuse, increasing age, male sex, and an unknown retroviral status were independent risk factors for pulmonary tuberculosis. Haemoptysis was observed more frequently in smokers (49.1% versus 31.1%, P=0.017). With regards to chest X-ray features, smokers presented with more advanced, bilateral and cavitating lung lesions. CONCLUSION: Diagnostic delay and haemoptysis are important characteristics of the pulmonary tuberculosis in tobacco smokers.
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Fumar/epidemiología , Tuberculosis Pulmonar/diagnóstico , Tuberculosis Pulmonar/epidemiología , Adolescente , Adulto , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mycobacterium tuberculosis/aislamiento & purificación , Radiografía Torácica , Factores de Riesgo , Senegal/epidemiología , Fumadores/estadística & datos numéricos , Esputo/microbiología , Tuberculosis Pulmonar/microbiología , Adulto JovenRESUMEN
INTRODUCTION: The Drug Reaction with Eosinophilia and Systemic Symptom (DRESS) is a severe drug-induced reaction. CASE REPORT: We report the case of a 35-year-old man treated by RHEZ for a first episode of a smear positive pulmonary tuberculosis and who developed a DRESS syndrome due to pyrazinamide after twenty days of treatment, associated with a viral reactivation to Human Herpes Virus 6 (HHV6). He had a skin eruption, liver involvement and hypereosinophilia. He fully recovered after drug withdrawal, associated with local and general corticosteroids. He died two weeks after discharge. CONCLUSIONS: Discovery of DRESS syndrome during tuberculosis treatment is an uncommon complication and requires a searching for the responsible drug. That should be difficult because tuberculosis drugs are often given as fixed-dose combination. Physicians have to bear in mind the potential role of pyrazinamide.
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Antituberculosos/efectos adversos , Síndrome de Hipersensibilidad a Medicamentos/diagnóstico , Pirazinamida/efectos adversos , Tuberculosis Pulmonar/tratamiento farmacológico , Corticoesteroides/uso terapéutico , Adulto , Coinfección/tratamiento farmacológico , Herpesvirus Humano 6/aislamiento & purificación , Humanos , Masculino , Infecciones por Roseolovirus/complicaciones , Infecciones por Roseolovirus/tratamiento farmacológico , Tuberculosis Pulmonar/complicacionesRESUMEN
We report the case of a 31-year-old immunocompetent woman residing in Senegal, with localized microscopy-proved pulmonary tuberculosis, complicated by macrophage activation syndrome and associated with viral hepatitis B, identified due to hepatic cytolysis and a bicytopenia.
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Antituberculosos/administración & dosificación , Hepatopatías/etiología , Hepatopatías/patología , Síndrome de Activación Macrofágica/etiología , Tuberculosis Pulmonar/complicaciones , Tuberculosis Pulmonar/tratamiento farmacológico , Adulto , Quimioterapia Combinada , Femenino , Humanos , Senegal , Factores de TiempoRESUMEN
The rising prevalence of asthma is an alarming health concern. The morbidity and mortality associated with asthma not only disrupts the quality of life, but it also escalates health care costs. Asthma is a chronic inflammatory disease of the respiratory tract. An exaggerated production of the arachidonic acid-derived eicosanoids, leukotrienes, has been implicated as the chemical trigger for inflammation. n-3 fatty acid supplementation has been shown to suppress the synthesis of the n-6 series of leukotrienes by competing and inhibiting the metabolism of arachidonic acid. The results from epidemiological studies suggested that fish consumption was beneficially associated with lung function and prevalence of asthma. The data generated from clinical trials, however, indicated that n-3 fatty acid supplementation did not consistently improve severity of symptoms, lung functions, airway responsiveness, and medication use in asthmatic patients. Future research should focus on the effects of long-term supplementation using weight-based dosages on specific biochemical markers and clinical outcomes. Leading organizations have not included nutrition as part of the management guidelines for asthma. Meanwhile, regular fish consumption at least three times per week should be highly encouraged as part of a well-balanced diet and to meet the adequate intake levels established for n-3 fatty acids.
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Asma/dietoterapia , Grasas Insaturadas en la Dieta/administración & dosificación , Ácidos Grasos Omega-3/administración & dosificación , Animales , Ácido Araquidónico/metabolismo , Asma/etiología , Grasas Insaturadas en la Dieta/metabolismo , Ácido Eicosapentaenoico/metabolismo , Ácidos Grasos Omega-3/uso terapéutico , Aceites de Pescado/administración & dosificación , Aceites de Pescado/uso terapéutico , Peces , Humanos , Inmunoglobulina E/biosíntesis , Leucotrienos/efectos adversos , Leucotrienos/metabolismo , Resultado del TratamientoRESUMEN
This is a retrospective analysis of 659 patients with cervical squamous cell carcinoma with a minimum follow-up of 2 years at Keio University Hospital between May 1974 and March 1990. All patients were treated with external radiation (50 Gy) and high-dose rate (HDR) intracavitary brachytherapy (20-34 Gy). The 5-year survival rates in each stage gradually decreased with the advance of the stage (I, 84%; II, 71%; III, 47%; and IVa, 12%). When 366 patients with stage III were classified into three groups according to tumor size, i.e. small (S, 102 patients), medium (M, 145) and large (L, 119), a survival gradient of small > medium > large was demonstrated and the differences between them were significant. At follow-up visits conducted between 1 and 2 months after completion of treatment, 135 patients (20%) had physical indications of residual disease. The larger the tumor size, the more likely was residual disease by 2 months. The patients with residual disease had a significantly higher rate of the pelvic failure than those without it. There was no significant correlation between radiation doses by RALS and pelvic failure rates, except in the stage III-L group. In the stage III-L group, intracavitary doses of 24 Gy or less to point A could be correlated with the higher pelvic failure rate and the lower survival rate, in contrast to doses of 27 Gy or more. The incidence of major rectosigmoid complications was 11.8% with doses of 24 Gy or less to point A, 8.1% with 27 Gy and 19.2% with doses of 30 Gy or more.(ABSTRACT TRUNCATED AT 250 WORDS)
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Braquiterapia/efectos adversos , Carcinoma de Células Escamosas/radioterapia , Neoplasias del Cuello Uterino/radioterapia , Análisis Actuarial , Carcinoma de Células Escamosas/patología , Relación Dosis-Respuesta en la Radiación , Femenino , Estudios de Seguimiento , Humanos , Estadificación de Neoplasias , Pronóstico , Radioterapia de Alta Energía/efectos adversos , Estudios Retrospectivos , Análisis de Supervivencia , Insuficiencia del Tratamiento , Neoplasias del Cuello Uterino/patologíaRESUMEN
The experimental and pharmacological characteristics of various formulations of an anticancer agent (epirubicin, EPI) and lipiodol were evaluated in vitro and in vivo. Three forms of EPI-lipiodol, i.e., an oil-in-water type of emulsion (O/W type), a water-in-oil type of emulsion (W/O type), and a suspension (S type), were prepared and investigated for their stability. An O/W-type emulsion using a stock solution of Iopamidol as the solvent for EPI was the most stable form in the stationary state in vitro. In 16 patients with malignant liver tumors (14 hepatocellular carcinomas and 2 liver metastases), the three forms of EPI-lipiodol were injected into the proper hepatic artery. The plasma EPI level was monitored periodically and analyzed pharmacokinetically. No significant difference in the pharmacokinetics of EPI was detected among the O/W, W/O, and S types.
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Quimioembolización Terapéutica , Epirrubicina/administración & dosificación , Aceite Yodado/administración & dosificación , Neoplasias Hepáticas/terapia , Anciano , Anciano de 80 o más Años , Estabilidad de Medicamentos , Epirrubicina/sangre , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
The flow chamber was used to observe the orientation and small deformation of red blood cells (RBCs) in a shear flow of low viscosity. With the aid of computer software, the percentage of RBCs oriented to the C=0 orbit (OI)(F) and the degree of deformation (DI)(F) of such RBCs were calculated by processing the photographs. It was found that these parameters were highly correlated, respectively, to the orientation index (OI)(E) and the small deformation index (DI)(E) obtained by our low viscosity Ektacytometry (LVE). Thus, our flow chamber research has provided direct evidence to validate the use of this low viscosity Ektacytometry. Although there are relative merits for the flow chamber method using low viscosity medium, the LVE is more likely to be applied in clinic for its simplicity and convenience.
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Viscosidad Sanguínea/fisiología , Deformación Eritrocítica/fisiología , Hemorreología/instrumentación , Animales , Anisotropía , Eritrocitos/citología , Eritrocitos/fisiología , Rayos Láser , Microscopía por Video , Conejos , Dispersión de Radiación , Estrés MecánicoRESUMEN
Surface charge was removed from RBC (erythrocyte) membrane to different degrees with biochemical methods, i.e., treatment of RBCs with neuraminidase, either using different doses for the same incubation time (1 hour) or using the same dose (75 milli-unit) for different incubation time. Several rheological properties of the RBCs with surface charge removal were observed, including the deformation index DI (using traditional ektacytometry) orientation index (DI)or and small deformation index (Dl)d (using new ektacytometry), the viscosity at low and high shear rates (using a cone-plate rotating viscosimeter). In addition, photographs of RBCs aggregation under a microscope and the histograms of RBC aggregate size after treatment with neuraminidase were obtained. It is found from these experiments that the decrease of the surface charge of RBCs leads to the decrease in the deformation and orientation indices as well as the increase in blood viscosity.
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Eritrocitos/efectos de los fármacos , Hemorreología/efectos de los fármacos , Neuraminidasa/farmacología , Animales , Viscosidad Sanguínea/efectos de los fármacos , Agregación Eritrocitaria/efectos de los fármacos , Deformación Eritrocítica/efectos de los fármacos , Membrana Eritrocítica/efectos de los fármacos , Membrana Eritrocítica/metabolismo , Conejos , Electricidad EstáticaRESUMEN
A high-dose (7 Gy) whole-body 60Co irradiation for a short period caused disturbances of hematopoietic function. A decrease in the hematocrit of the circulating blood lasted for about 15 days, thus forming an anemic animal model. We studied the influence of high-dose 60Co irradiation on hemorheologic parameters: percentage of reticulocytes, RBC deformability, sedimentation rate and plasma fibrinogen concentration in the rabbit. It was found that the plasma fibrinogen concentration increased to twice more than control level and that percentage of reticulocytes in circulation disappeared immediately after irradiation. The deformation index of RBCs in shear flow decreased from a value of 58% down to a value of 42% in the first two weeks and gradually returned to control levels about 40 days after 60Co irradiation. Our results showed that a short period of high-dose 60Co irradiation caused severe and relatively long-lasting damage of hematopoietic system in animals' body.
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Radioisótopos de Cobalto/farmacología , Hemorreología/efectos de la radiación , Animales , Sedimentación Sanguínea/efectos de la radiación , Deformación Eritrocítica/efectos de la radiación , Eritrocitos/efectos de la radiación , Femenino , Fibrinógeno/metabolismo , Fibrinógeno/efectos de la radiación , Hematócrito , Masculino , Conejos , Reticulocitos/efectos de la radiación , Irradiación Corporal TotalRESUMEN
Neuraminidase can partly remove the surface charge of RBCs through a biochemical interaction; thus it can give rise to alterations in the microstructure of membrane, the shear elastic modulus (E) and the viscosity(micron) of membrane. Changing the time of treatment and the dose of neuraminidase and using a new ektacytometry that can separate deformation index DI into orientation index (DI)or and small deformation index (DI)d for RBCs in shear flow field of low viscosity, we measured (DI)d and the half time t0.5 when the DI recovered to half of the maximum in the process of relaxation for every treated sample. (DI)d and t0.5 were put respectively into the RBC membrane shear elastic modulus formula and the membrane viscosity formula which were put forward by Wen Zong-yao and Yan Zong-yi et al[1]. The rules of the alterations of E and micron were obtained. We also measured DI and (DI)or. It was found that E and micron increased greatly but DI and (DI)or decreased when the dose of neuraminidase and the time of treatment were increased. There was a contrary correlation between them. These data demonstrated that the increase of E and micron weakened the deformability and the ability of orientation of RBCs.
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Deformación Eritrocítica , Membrana Eritrocítica/fisiología , Eritrocitos/fisiología , Animales , Células Cultivadas , Elasticidad , Membrana Eritrocítica/efectos de los fármacos , Eritrocitos/efectos de los fármacos , Neuraminidasa/farmacología , Conejos , ViscosidadRESUMEN
Phospho-aspirin (PA-2) is a novel aspirin derivative that exhibits promising anticancer properties and is considerably safer than conventional aspirin. In this study, we investigated the chemotherapeutic efficacy of PA-2 in preclinical models of estrogen receptor positive (ER+) breast cancer and elucidated its mechanism of action. PA-2 inhibited the growth of ER+ cells more potently than aspirin in vitro, and exerted a triple cytokinetic effect that includes induction of apoptosis and cell cycle arrest as well as the inhibition of cell proliferation. PA-2 is highly efficacious in vivo, as treatment of established MCF7 xenografts with PA-2 induced tumor stasis (98.2% inhibition, p<0.01). PA-2 triggered the activation of p53-dependent apoptosis via two distinct mechanisms: 1) acetylation of p53 (at K373), which disrupts its interaction with its transcription repressor MDM2, and 2) translocation of p53 to the mitochondria leading to the dissipation of mitochondrial transmembrane potential (ΔΨ(m)). Consistent with these observations, both the RNAi-mediated knockdown of p53 and forced deactylation via HDAC1 over-expression attenuated the anticancer effect of PA-2 in MCF7 cells. An upstream mediator of the signaling effects of PA-2 is RONS. PA-2 induced oxidative stress in vitro and in mice bearing MCF7 xenografts; its induction effect appears to be tumor-specific. Crucially, administration of N-acetylcysteine, a ROS scavenger, abrogated the effect of PA-2 on p53 acetylation and mitochondria translocation, thus identifying RONS as proximal molecules mediating the anticancer effect of PA-2. In summary, our findings demonstrate that PA-2 is a promising antineoplastic compound against ER+ breast cancer, warranting further evaluation as an anticancer agent.
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Antineoplásicos/química , Antineoplásicos/farmacología , Aspirina/análogos & derivados , Aspirina/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Mama/efectos de los fármacos , Acetilación/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Mama/metabolismo , Mama/patología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Proliferación Celular/efectos de los fármacos , Femenino , Humanos , Células MCF-7 , Ratones , Oxidación-Reducción/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Receptores de Estrógenos/análisis , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Successful treatment of drug addiction is hampered by high relapse rates during periods of abstinence. Neuroadaptation in the medial prefrontal cortex (mPFC) is thought to have a crucial role in vulnerability to relapse to drug seeking, but the molecular and cellular mechanisms remain largely unknown. To identify protein changes that contribute to relapse susceptibility, we investigated synaptic membrane fractions from the mPFC of rats that underwent 21 days of forced abstinence following heroin self-administration. Quantitative proteomics revealed that long-term abstinence from heroin self-administration was associated with reduced levels of extracellular matrix (ECM) proteins. After extinction of heroin self-administration, downregulation of ECM proteins was also present in the mPFC, as well as nucleus accumbens (NAc), and these adaptations were partially restored following cue-induced reinstatement of heroin seeking. In the mPFC, these ECM proteins are condensed in the perineuronal nets that exclusively surround GABAergic interneurons, indicating that ECM adaptation might alter the activity of GABAergic interneurons. In support of this, we observed an increase in the inhibitory GABAergic synaptic inputs received by the mPFC pyramidal cells after the re-exposure to heroin-conditioned cues. Recovering levels of ECM constituents by metalloproteinase inhibitor treatment (FN-439; i.c.v.) prior to a reinstatement test attenuated subsequent heroin seeking, suggesting that the reduced synaptic ECM levels during heroin abstinence enhanced sensitivity to respond to heroin-conditioned cues. We provide evidence for a novel neuroadaptive mechanism, in which heroin self-administration-induced adaptation of the ECM increased relapse vulnerability, potentially by augmenting the responsivity of mPFC GABAergic interneurons to heroin-associated stimuli.
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Matriz Extracelular/metabolismo , Dependencia de Heroína , Heroína/efectos adversos , Narcóticos/efectos adversos , Corteza Prefrontal/patología , Células Piramidales/metabolismo , Ácido gamma-Aminobutírico/metabolismo , Animales , Cromatografía Líquida de Alta Presión/métodos , Condicionamiento Operante/efectos de los fármacos , Señales (Psicología) , Esquema de Medicación , Inhibidores Enzimáticos/farmacología , Matriz Extracelular/clasificación , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Dependencia de Heroína/etiología , Dependencia de Heroína/metabolismo , Dependencia de Heroína/patología , Ácidos Hidroxámicos/farmacología , Técnicas In Vitro , Masculino , Espectrometría de Masas , Oligopéptidos/farmacología , Proteómica/métodos , Ratas , Ratas Wistar , Esquema de Refuerzo , Autoadministración/métodos , Transducción de Señal/efectos de los fármacos , Potenciales Sinápticos/efectos de los fármacosRESUMEN
Proline-rich membrane anchor (PRiMA) is a molecule to organize acetylcholinesterase (AChE) into tetrameric globular form (G(4)) that anchors onto the plasma membrane in brain and muscle. In mammal, PRiMA is encoded by a single gene with two splicing variants, PRiMA I and PRiMA II: PRiMA II is different to PRiMA I by its absence of a C-terminal cytoplasmic domain. The existence of these isoforms has not been revealed in avian specie. By using RT-PCR and bioinformatic analyses, two splicing variants of PRiMA were identified in chicken cerebrum. One variant contains very similar domains as compared to mammalian PRiMA I. The other variant, named as PRiMA II, has a very distinct cytoplasmic C-terminus of having 26 amino acids. Both forms of chicken PRiMA were able to organize the formation of G(4) AChE when that was over expressed together with AChE(T) subunit in cultured cells. The level of PRiMA mRNA, mainly PRiMA I, was higher in slow-twitch muscle than that of in fast-twitch muscle of chicken. This finding suggests that the muscle fiber type-specific expression of G(4) AChE in chicken could be a result of the different expression pattern of PRiMA in fast- and slow-twitch muscles.