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High-flow nasal oxygen can be administered at induction of anaesthesia for the purposes of pre-oxygenation and apnoeic oxygenation. This intervention is claimed to enhance carbon dioxide elimination during apnoea, but the extent to which this occurs remains poorly quantified. The optimal nasal oxygen flow rate for gas exchange is also unknown. In this study, 114 patients received pre-oxygenation with high-flow nasal oxygen at 50 l.min-1. At the onset of apnoea, patients were allocated randomly to receive one of three nasal oxygen flow rates: 0 l.min-1; 70 l.min-1; or 120 l.min-1. After 4 minutes of apnoea, all oxygen delivery was ceased, tracheal intubation was performed, and oxygen delivery was recommenced when SpO2 was 92%. Mean (SD) PaCO2 rise during the first minute of apnoea was 1.39 (0.39) kPa, 1.41 (0.29) kPa, and 1.26 (0.38) kPa in the 0 l.min-1, 70 l.min-1 and 120 l.min-1 groups, respectively; p = 0.16. During the second, third and fourth minutes of apnoea, mean (SD) rates of rise in PaCO2 were 0.34 (0.08) kPa.min-1, 0.36 (0.06) kPa.min-1 and 0.37 (0.07) kPa.min-1 in the 0 l.min-1, 70 l.min-1 and 120 l.min-1 groups, respectively; p = 0.17. After 4 minutes of apnoea, median (IQR [range]) arterial oxygen partial pressures in the 0 l.min-1, 70 l.min-1 and 120 l.min-1 groups were 24.5 (18.6-31.4 [12.3-48.3]) kPa; 36.6 (28.1-43.8 [9.8-56.9]) kPa; and 37.6 (26.5-45.4 [11.0-56.6]) kPa, respectively; p < 0.001. Median (IQR [range]) times to desaturate to 92% after the onset of apnoea in the 0 l.min-1, 70 l.min-1 and 120 l.min-1 groups, were 412 (347-509 [190-796]) s; 533 (467-641 [192-958]) s; and 531 (462-681 [326-1007]) s, respectively; p < 0.001. In conclusion, the rate of carbon dioxide accumulation in arterial blood did not differ significantly between apnoeic patients who received high-flow nasal oxygen and those who did not.
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Apneia , Oxigenoterapia , Oxigênio , Troca Gasosa Pulmonar , Humanos , Apneia/terapia , Apneia/fisiopatologia , Apneia/metabolismo , Masculino , Feminino , Pessoa de Meia-Idade , Oxigenoterapia/métodos , Troca Gasosa Pulmonar/fisiologia , Oxigênio/sangue , Oxigênio/metabolismo , Oxigênio/administração & dosagem , Dióxido de Carbono/sangue , Dióxido de Carbono/metabolismo , Adulto , Idoso , Administração IntranasalRESUMO
The performance of a moving bed biofilm reactor (MBBR) depends largely on the type of biofilm carrier used. However, how different carriers affect the nitrification process, particularly when treating anaerobic digestion effluents, is not completely understood. This study aimed to evaluate the nitrification performance of two distinct biocarriers in MBBRs over a 140-d operation period, with a gradually decreasing hydraulic retention time (HRT) from 20 to 10 d. Reactor 1 (R1) was filled with fiber balls, whereas a Mutag Biochip was used for reactor 2 (R2). At an HRT of 20 d, the ammonia removal efficiency of both reactors was >95%. However, as the HRT was reduced, the ammonia removal efficiency of R1 gradually declined, ultimately dropping to 65% at a 10-d HRT. In contrast, the ammonia removal efficiency of R2 consistently exceeding 99% throughout the long-term operation. R1 exhibited partial nitrification, whereas R2 exhibited complete nitrification. Analysis of microbial communities showed that the abundance and diversity of bacterial communities, particularly nitrifying bacteria such as Hyphomicrobium sp. And Nitrosomonas sp., in R2 was higher than that in R1. In conclusion, the choice of biocarrier significantly impact the abundance and diversity of microbial communities in MBBR systems. Therefore, these factors should be closely monitored to ensure the efficient treatment of high-strength ammonia wastewater.
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Microbiota , Nitrificação , Amônia , Biofilmes , Anaerobiose , Reatores Biológicos/microbiologia , Bactérias , Eliminação de Resíduos LíquidosRESUMO
The respiratory chains of nearly all aerobic organisms are terminated by proton-pumping heme-copper oxygen reductases (HCOs). Previous studies have established that C-family HCOs contain a single channel for uptake from the bacterial cytoplasm of all chemical and pumped protons, and that the entrance of the K(C)-channel is a conserved glutamate in subunit III. However, the majority of the K(C)-channel is within subunit I, and the pathway from this conserved glutamate to subunit I is not evident. In the present study, molecular dynamics simulations were used to characterize a chain of water molecules leading from the cytoplasmic solution, passing the conserved glutamate in subunit III and extending into subunit I. Formation of the water chain, which controls the delivery of protons to the K(C)-channel, was found to depend on the conformation of Y241(Vc), located in subunit I at the interface with subunit III. Mutations of Y241(Vc) (to A/F/H/S) in the Vibrio cholerae cbb3 eliminate catalytic activity, but also cause perturbations that propagate over a 28-Å distance to the active site heme b3. The data suggest a linkage between residues lining the K(C)-channel and the active site of the enzyme, possibly mediated by transmembrane helix α7, which contains both Y241(Vc) and the active site cross-linked Y255(Vc), as well as two CuB histidine ligands. Other mutations of residues within or near helix α7 also perturb the active site, indicating that this helix is involved in modulation of the active site of the enzyme.
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Proteínas de Bactérias/química , Complexo IV da Cadeia de Transporte de Elétrons/química , Vibrio cholerae/enzimologia , Domínio Catalítico , Cobre/química , Citoplasma/metabolismo , Histidina/química , Ligantes , Conformação Molecular , Simulação de Dinâmica Molecular , Mutagênese Sítio-Dirigida , Mutação , Oxigênio/química , Conformação Proteica , Prótons , Espectrofotometria Ultravioleta , Análise Espectral Raman , Água/químicaRESUMO
The C-family (cbb3) of heme-copper oxygen reductases are proton-pumping enzymes terminating the aerobic respiratory chains of many bacteria, including a number of human pathogens. The most common form of these enzymes contains one copy each of 4 subunits encoded by the ccoNOQP operon. In the cbb3 from Rhodobacter capsulatus, the enzyme is assembled in a stepwise manner, with an essential role played by an assembly protein CcoH. Importantly, it has been proposed that a transient interaction between the transmembrane domains of CcoP and CcoH is essential for assembly. Here, we test this proposal by showing that a genetically engineered form of cbb3 from Vibrio cholerae (CcoNOQP(X)) that lacks the hydrophilic domain of CcoP, where the two heme c moieties are present, is fully assembled and stable. Single-turnover kinetics of the reaction between the fully reduced CcoNOQP(X) and O2 are essentially the same as the wild type enzyme in oxidizing the 4 remaining redox-active sites. The enzyme retains approximately 10% of the steady state oxidase activity using the artificial electron donor TMPD, but has no activity using the physiological electron donor cytochrome c4, since the docking site for this cytochrome is presumably located on the absent domain of CcoP. Residue E49 in the hydrophobic domain of CcoP is the entrance of the K(C)-channel for proton input, and the E49A mutation in the truncated enzyme further reduces the steady state activity to less than 3%. Hence, the same proton channel is used by both the wild type and truncated enzymes.
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OBJECTIVE: We explored the inhibitory effect of sulphoraphane (SFN), a potent inducer of Phase 2 enzymes, on cytokine-induced prostaglandin E(2) (PGE2) and nitric oxide (NO) production and cartilage degradation in articular chondrocytes. The regulatory mechanism of SFN on nuclear factor (NF)-κB was investigated. METHODS: Chondrocytes were obtained from patients with knee OA. Chondrocytes were stimulated with IL-1ß or TNF-α with or without pre-incubation with SFN. Production of PGE2 and NO was evaluated by the Griess reaction and an ELISA. The expression of microsomal PGE synthase (mPGES), cyclo-oxygenase (COX)-2 and inducible NO synthase (iNOS) was evaluated by real-time RT-PCR and western blot analysis. The regulation of NF-κB activity was explored using luciferase and chromatin immunoprecipitation assays as well as a western blot for phosphorylated IκB kinase (IKK), IκB and the degradation of IκB. Proteoglycan and type II collagen degradation products released from explant cultures were analysed using the dimethylmethylene blue assay and an ELISA for C-terminal telopeptides of type II collagen. RESULTS: SFN inhibited the production of PGE2 and NO induced by IL-1ß and TNF-α. At a concentration as low as 5 µM, SFN completely inhibited mPGES, COX-2 and iNOS at the mRNA and protein levels, and proteoglycan and type II collagen degradation product release in explant culture. Various signalling pathways required for the NF-κB activation were affected by SFN. CONCLUSION: SFN inhibited a broad range of catabolic mechanisms in articular chondrocytes. SFN may be a safe and effective candidate drug for the inhibition of cartilage degradation in arthritic diseases.
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Condrócitos/efeitos dos fármacos , Condrócitos/enzimologia , Dinoprostona/metabolismo , Óxido Nítrico/metabolismo , Nitrilas/farmacologia , Osteoartrite do Joelho/tratamento farmacológico , Sulfóxidos/farmacologia , Idoso , Cartilagem Articular/citologia , Células Cultivadas , Condrócitos/citologia , Colágeno Tipo II/metabolismo , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/biossíntese , Dinoprostona/imunologia , Matriz Extracelular/imunologia , Matriz Extracelular/metabolismo , Feminino , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Humanos , Interleucina-1beta/farmacologia , Oxirredutases Intramoleculares/antagonistas & inibidores , Oxirredutases Intramoleculares/genética , Oxirredutases Intramoleculares/metabolismo , Masculino , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Óxido Nítrico/biossíntese , Óxido Nítrico/imunologia , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Osteoartrite do Joelho/imunologia , Osteoartrite do Joelho/metabolismo , Prostaglandina-E Sintases , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
BACKGROUND AND AIMS: Metabolically obese normal weight (MONW) subjects are a subgroup of individuals who have a normal weight and body mass index (BMI), but exhibit obesity-related abnormalities. The objective of this study was to analyze the prevalence of metabolic syndrome (MetS) and characteristics of diet patterns in MONW Koreans. METHODS AND RESULTS: We analyzed the data of 3050 adults > 20 years of age with a normal BMI (18.5~24.9 kg/m(2)) obtained from the Korea National Health and Nutrition Examination Survey III. Anthropometric measurements and information on health behaviors were obtained. The diagnostic criteria for MetS were defined by the International Diabetes Federation consensus. Dietary intake was assessed by the 24-h recall method. The weighted prevalence of MONW was 14.3%. The risk of MONW correlated inversely with the frequency of snacking and positively with the type of snack, particularly those with high carbohydrates. A high carbohydrate diet (≥73.9% of energy intake) compared to a low carbohydrate diet (<59.9% of energy intake) was positively associated with the risk of MONW (OR = 2.54; 95% CI: 1.41, 4.56), whereas a high protein diet (≥17.1% of energy intake) compared to a low protein diet (<12.2% of energy intake) reduced the risk of MONW (OR = 0.60; 95% CI: 0.39, 0.92) in females, but not in males. CONCLUSIONS: This study suggests that a reduced intake of carbohydrates and carbohydrate snacks were associated with a lower prevalence of MONW in females.
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Dieta , Síndrome Metabólica/epidemiologia , Obesidade/epidemiologia , Adulto , Idoso , Povo Asiático , Composição Corporal , Índice de Massa Corporal , Peso Corporal , Estudos Transversais , Carboidratos da Dieta/administração & dosagem , Ingestão de Energia , Feminino , Comportamentos Relacionados com a Saúde , Humanos , Estilo de Vida , Modelos Logísticos , Masculino , Síndrome Metabólica/fisiopatologia , Pessoa de Meia-Idade , Inquéritos Nutricionais , Obesidade/metabolismo , Obesidade/fisiopatologia , Prevalência , República da Coreia/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Inquéritos e QuestionáriosRESUMO
OBJECTIVES: Using an ecological conceptual model, this study examined the social context, structural, and behavioral factors within an immigrant community that contribute to increased access and use of oral health services by Latino children. The predictors of health service use at the level of the individual, the family, the provider, and the health service system were studied for their effects on the initiation of care, continuity of care, and frequency of planned visits. METHODS: In-depth face-to-face interviews were conducted with 320 Latino mothers regarding their use of oral health services for 4-8-year-old children [Mexican (n = 221), Puerto Rican (n = 69), and Central and South American (n = 30)]. Outcome measures of dental care utilization were early age at initiation of care, continuity of care, and frequency of planned dental visits. RESULTS: Regular planned dental visits were significantly related to the structural variables of household income and provider availability. The initiation of dental care was related to the mother's beliefs about the value of early preventive dental care. Mothers were more likely to continue care if they believed that the purpose was to keep the child's teeth healthy and had satisfactory communication with the dentist. CONCLUSIONS: Identifying the structural and behavioral factors that increase the likelihood of the use of oral health services can provide the basis for developing effective interventions specific to Latino children at the neighborhood level. The study findings can be also used for designing culturally appropriate oral health promotion programs and provider coordination of care.
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Serviços de Saúde Bucal/estatística & dados numéricos , Acessibilidade aos Serviços de Saúde , Hispânico ou Latino/estatística & dados numéricos , Modelos Psicológicos , Aceitação pelo Paciente de Cuidados de Saúde , Fatores Etários , Atitude Frente a Saúde , Chicago , Criança , Serviços de Saúde da Criança/estatística & dados numéricos , Pré-Escolar , Continuidade da Assistência ao Paciente , Disparidades em Assistência à Saúde , Humanos , Renda , Seguro Odontológico , Entrevistas como Assunto , Análise Multinível , Análise de Regressão , Fatores Socioeconômicos , Inquéritos e QuestionáriosRESUMO
This study evaluated the effects of surgically implanted passive integrated transponder (PIT) tags on growth rate, survival and tag retention of yellow shortfin eels Anguilla australis with an initial mean mass of 101 g. There were no significant differences in body mass, total length, specific growth rate and survival between tagged and untagged A. australis in a 108 day laboratory trial. This tagging method was very reliable, with a tag retention of >95%.
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Anguilla/crescimento & desenvolvimento , Anguilla/fisiologia , Sistemas de Identificação Animal/instrumentação , Animais , Aquicultura , Tamanho Corporal , Peso CorporalRESUMO
mTOR plays a key role in tumor cell cycle control, proliferation, and survival. RAD001 (everolimus) is a novel macrolide that inhibits mTOR and thus downstream signaling pathways. 31 post-menopausal women with early breast cancer were given 5 mg RAD001 once daily for 14 days prior to surgery. Biopsies were taken at diagnosis and at surgery (post 14 days of treatment) and assessed for immunohistochemical changes in proliferation (Ki67), apoptosis (active caspase-3), p-AKT (s473), p-S6 (s235/236 and s240/244), p-mTOR (s2448), ER, and PR. Five patients did not complete the 2-week treatment period due to adverse events. All adverse events were grade 1 or 2 (NCIC-CTC scale). RAD001 treatment significantly decreased proliferation (geometric mean reduction 74% from baseline (p = 0.019)), particularly in HER-2 positive tumors. High Ki67 pre-treatment correlated with reduction in Ki67, an increase in apoptosis, a reduction in p-AKT (cytoplasmic) and reduction in p-mTOR following treatment. Nuclear expression of p-AKT was significantly reduced with treatment. Tumors that had a reduction in Ki67 with treatment exhibited a significant reduction in cytoplasmic p-AKT. p-S6 staining was significantly reduced independently of Ki67 (p < 0.001 for two sites of phosphorylation). RAD001 5 mg/daily is safe and tolerable in postmenopausal early breast cancer patients and inhibits the mTOR pathway and its downstream effectors, significantly reducing tumor cell proliferation. Tumors with high Ki67, high p-AKT, and HER-2 positivity may be more responsive to mTOR inhibition with RAD001. This is the first study to report results of RAD001 5 mg as a single agent in early breast cancer.
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Antineoplásicos/uso terapêutico , Neoplasias da Mama , Sirolimo/análogos & derivados , Serina-Treonina Quinases TOR/antagonistas & inibidores , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Everolimo , Feminino , Humanos , Antígeno Ki-67/metabolismo , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor ErbB-2/metabolismo , Proteínas Quinases S6 Ribossômicas/metabolismo , Sirolimo/efeitos adversos , Sirolimo/uso terapêuticoRESUMO
Background: Juvenile cystic adenomyosis (JCA) represents a rare form of focal adenomyosis in young women. Objectives: To determine safety and effectiveness of minimally invasive surgery (MIS for JCA). Materials and Methods: Three patients aged 16-30 years old presented with chronic pelvic pain [2016 - 2019]. Hormonal treatment failed in two cases. Cystic lesions in the myometrium (n=2), and the broad ligament (n=1) was detected on transvaginal 2D ultrasound (TV 2D US) and/or magnetic resonance imaging (MRI). The cyst was separate from the endometrium in all the cases, within the myometrium in two patients and in the right broad ligament in one case. The cystic lesions were confirmed on laparoscopy; and laparoscopic excision of the cysts with adequate repair of the myometrial beds were performed in all cases with fertility preservation. Robotic assistance was chosen in one case in an attempt to avoid injury of the fallopian tube based on the cyst location during a previous laparoscopy. The endometrial cavity was entered in one case. Main outcome measures: Absence of intraoperative complications and relief of presenting symptoms postoperatively. Results: Pathology report confirmed the diagnosis of JCA is all cases. There were no intraoperative complications. All three patients reported relief of their symptoms 6 to 8 months after surgery. No recurrence of the JCA was reported using TV 2D US in all cases. Conclusions: MIS could be the treatment of choice for patients with JCA. The technique described in our study is safe, effective, and easy to master in experienced hands. What is new?: Value of MIS in treatment of patients with JCA.
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This study aimed to fully recover ammonia contained at a high concentration in anaerobic digestate of piggery wastewater (ADPW) by forming struvite. As magnesium and phosphorus sources, ferronickel slag (FNS) and K2HPO4 were used, respectively. By leaching 200â gâ L-1 of FNS with 3.0â M H2SO4, 10,309â mgâ L-1 of magnesium ions were extracted, and this acid-leachate of FNS (FNSL) also contained 5965â mgâ L-1 of total iron. In order to simultaneously remove both high concentrations of organic matters in ADPW and iron in FNSL which were known to hinder struvite formation, the mixture of ADPW and FNSL was added with H2O2 at the H2O2/Fe molar ratio of 0.75 and pH 4.0. After Fenton reaction, removal efficiencies of COD and total iron reached 77.36% and 99.89%, respectively. Then COD and an iron-reduced mixture of ADPW and FNSL were added with K2HPO4 satisfying Mg:N:P molar ratio of 1.2:1:1.15 at pH 9.5 to produce struvite for 1â h. From 1â L of ADPW (2.21â g NH3-N), 0.65â L of FNSL (4.65â g Mg2+), and 5.63â g of PO4 3-P, 46.7â g of precipitates were obtained. Overall removal efficiencies of magnesium, NH3-N, and phosphorus were 98.59%, 94.25%, and 99.97%, respectively. Obtained precipitates were analysed by using XRD, XRF, SEM-EDX and found to be struvite with impurities of potassium and metals. Additionally, the economic feasibility of FNS was assessed by estimating chemical costs of various magnesium sources.
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Magnésio , Águas Residuárias , Anaerobiose , Precipitação Química , Peróxido de Hidrogênio , Ferro , Níquel , Fosfatos , Fósforo , EstruvitaRESUMO
BACKGROUND: The insulin-responsive glucose transporter 4 (GLUT4) plays prominent role in insulin-mediated facilitated glucose uptake into most of the cell types, majorly muscle, liver and adipose tissue. Impaired expression of GLUT4 has been linked to insulin resistance and diabetes. In adipocytes, excess lipids that are generated from liver and by de novo lipogenesis utilizing blood sugar, are stored. There are various nuclear factors, co-factors and signaling mechanisms that directly and indirectly regulate glucose transporter activity in adipocytes. Molecular mechanism behind the regulation of GLUT4 in adipocytes has not elucidated well. OBJECTIVE: Therefore, the present study focuses to explore the role of Liver X receptor- alpha (LXRα) on GLUT4 expression and the possible co-factors involved during in vitro adipogenesis and is assessed by modulating the activity of LXRα with specific agonist and antagonist ligands in 3T3L1 differentiated cells. RESULTS: The results demonstrate that SR 9238 (300nM), a strong inhibitor of LXRα, decreased the rate of adipogenesis through reduced lipid droplet formation in adipocytes without affecting the cell morphology. The FMOC-l-Leucine (FLL), a known partial ligand of PPARγ, enhanced the expression of LXRα. Thus, it can be concluded that LXRα has a significant role in adipocyte differentiation and FLL interaction promoted the transcription of LXRα, thereby promotes GLUT4 expression. The results in this study identified the role of LXRα in regulating the expression of GLUT4 through SRC1. CONCLUSION: The study is of much relevance in treatment of diabetes and also opens the possibility of identifying new drug molecules that target LXRα.
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Adipócitos/metabolismo , Diabetes Mellitus/patologia , Transportador de Glucose Tipo 4/metabolismo , Receptores X do Fígado/metabolismo , Células 3T3 , Adipogenia , Animais , Diferenciação Celular , Diabetes Mellitus/metabolismo , Glucose/metabolismo , Camundongos , PPAR gama/metabolismoRESUMO
INTRODUCTION: Changes in proliferation as measured by Ki67 occur within 14 days of starting treatment with an aromatase inhibitor and these changes have been shown to be predictors of long term outcome. This study aimed to compare changes in proliferation following 14 days of treatment with anastrozole and letrozole. METHODS: Two hundred and six women with 209 estrogen receptor (ER) positive operable breast cancers (three bilateral) were randomly allocated to receive either 14 days treatment with 2.5 mg of letrozole or 1 mg of anastrozole prior to surgery. Changes in expression of estrogen (ER) and progesterone receptors (PgR) as assessed by ALLRED scores and proliferation as assessed by Ki67 were analysed. The HER2 status of each tumour was also assessed using a combination of the Hercept test and FISH. RESULTS: Both letrozole and anastrozole reduced ER expression (ALLRED score) by a mean of 0.32 (0.20-0.44), P<0.001 and PgR fell by a mean of 2.54 (2.20-2.89) P<0.0001. Letrozole reduced proliferation from a geometric mean of 6.37% to 0.81%, P<0.0001 and anastrozole reduced proliferation from 5.81% to 0.77%, P<0.0001. There was no differences between drugs in the fall in ER, PgR or proliferation. Both letrozole and anastrozole produced significant falls in proliferation in both HER2 positive and HER2 negative cancers, all P<0.001. DISCUSSION: 14 days of both letrozole and anastrozole reduces proliferation, ER and PgR expression. No significant difference between these two drugs was identified.
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Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Receptor alfa de Estrogênio/biossíntese , Nitrilas/uso terapêutico , Triazóis/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anastrozol , Antineoplásicos Hormonais/uso terapêutico , Inibidores da Aromatase/uso terapêutico , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Antígeno Ki-67/biossíntese , Letrozol , Pessoa de Meia-Idade , Pós-Menopausa , Receptores de Progesterona/biossíntese , Resultado do TratamentoRESUMO
Early clinical trials of anticancer agents may be enriched by robust biomarkers of activity. Surrogate measures used in trials of cytotoxic agents, such as tumor size regression, may not be informative when investigating targeted agents that act principally to inhibit invasion or proliferation. This study aimed to determine the validity of invasion-related biomarkers of activity for AZD0530, a potent Src inhibitor currently in clinical development. Focal adhesion kinase (FAK) and paxillin are downstream phosphorylation substrates of Src and mediate tumor cell adhesion and invasiveness. These were therefore selected as biologically relevant markers of Src inhibition. Early breast cancer was chosen as a model as multiple samples can be collected during standard treatment and there is an intervening period in which experimental intervention can be applied. Tumor tissue was collected from diagnostic core biopsies and subsequent surgical tumor excision samples in 29 women with early breast cancer attending a single center. Protein levels were assessed quantitatively by Luminex and qualitatively by immunohistochemistry. AZD0530 inhibited tumor growth in a manner independent of dose and inhibited phosphorylation of FAK and paxillin in a dose-dependent manner in a Calu-6 xenograft model. In the clinical study, agreement of within-visit and also of between-visit measurements was high and the estimated number of patients required to detect a drug effect would be low enough to allow use of these markers as endpoints in future dose selection studies.
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Benzodioxóis/farmacologia , Neoplasias da Mama/tratamento farmacológico , Quinase 1 de Adesão Focal/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Paxilina/metabolismo , Proteínas Tirosina Quinases/antagonistas & inibidores , Quinazolinas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proteína Tirosina Quinase CSK , Estudos de Viabilidade , Feminino , Humanos , Técnicas Imunoenzimáticas , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Fosforilação/efeitos dos fármacos , Ratos , Ratos Nus , Células Tumorais Cultivadas , Quinases da Família srcRESUMO
A proportion of breast cancers are attributable to BRCA1 or BRCA2 mutations. Technological advances has meant that mutation testing in newly diagnosed cancer patients can be used to inform treatment plans. Although oncologists increasingly deliver treatment-focused genetic testing (TFGT) as part of mainstream ovarian cancer care, we know little about non-genetics specialists' views about offering genetic testing to newly diagnosed breast cancer patients. This study sought to determine genetics and non-genetics specialists' views of a proposal to mainstream BRCA1 and 2 testing in newly diagnosed breast cancer patients. Qualitative interview study. Nineteen healthcare professionals currently responsible for offering TFGT in a standard (triage + referral) pathway (breast surgeons + clinical genetics team) and oncologists preparing to offer TFGT to breast cancer patients in a mainstreamed pathway participated in in-depth interviews. Genetics and non-genetics professionals' perceptions of mainstreaming are influenced by their views of: their clinical roles and responsibilities, the impact of TFGT on their workload and the patient pathway and the perceived relevance of genetic testing for patient care in the short-term. Perceived barriers to mainstreaming may be overcome by: more effective communication between specialities, clearer guidelines/patient pathways and the recruitment of mainstreaming champions.
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Atitude do Pessoal de Saúde , Neoplasias da Mama/genética , Genes BRCA1 , Genes BRCA2 , Testes Genéticos , Neoplasias da Mama/terapia , Tomada de Decisão Clínica , Feminino , Genética Médica , Humanos , Mutação , Oncologistas , Papel do Médico , Pesquisa Qualitativa , Encaminhamento e Consulta , Cirurgiões , TriagemRESUMO
Fulvestrant (Faslodex) is a pure anti-oestrogen that reduces markers of hormone sensitivity and proliferation in postmenopausal women with oestrogen-receptor (ER)-positive breast cancer. This randomised trial compared the effects on the tumours of a single dose of 750mg fulvestrant to those of daily tamoxifen (20mg) taken 14-16 days prior to surgery in 60 premenopausal women with ER-positive primary breast cancer. There were statistically significant falls in the expression of ER and Ki67 levels compared to the baseline with both drugs. Both drugs caused a decrease in PgR expression from baseline but this was only statistically significant with fulvestrant. No statistically significant differences were seen between the two treatment groups. Fulvestrant caused an increase in circulating levels of oestradiol, irrespective of the stage of the menstrual cycle at which patients commenced treatment. No major changes were seen in LH, FSH and progesterone levels with either drug. The most common adverse events with fulvestrant were headaches, hot flushes, nausea and disturbance of menses. Contrary to previous studies with fulvestrant 250mg, these findings suggest that at a dose of 750mg fulvestrant is effective at reducing the effects of oestrogen on ER-positive breast cancer in premenopausal women.
Assuntos
Antineoplásicos Hormonais/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Estradiol/análogos & derivados , Neoplasias Hormônio-Dependentes/tratamento farmacológico , Receptores de Estrogênio/metabolismo , Tamoxifeno/administração & dosagem , Adulto , Antineoplásicos Hormonais/efeitos adversos , Antineoplásicos Hormonais/sangue , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Estradiol/administração & dosagem , Estradiol/efeitos adversos , Estradiol/sangue , Feminino , Fulvestranto , Humanos , Injeções Intramusculares , Antígeno Ki-67/metabolismo , Pessoa de Meia-Idade , Neoplasias Hormônio-Dependentes/metabolismo , Pré-Menopausa/efeitos dos fármacos , Pré-Menopausa/metabolismo , Receptores de Progesterona/metabolismo , Tamoxifeno/efeitos adversos , Tamoxifeno/sangue , Resultado do TratamentoRESUMO
BACKGROUND AND AIM: The aim of the present study was to investigate the clinical effectiveness, safety, and outcome associated with the use of covered expandable Nitinol stents (Taewoong Medical, Seoul, Korea) for the treatment of malignant gastroduodenal obstructions. METHODS: Between March 2001 and October 2004, covered expandable Nitinol stents were placed in 68 consecutive patients under endoscopic and fluoroscopic guidance for the following reasons: gastric carcinoma (n = 49), recurrent carcinoma after partial gastrectomy (n = 7), or another malignant neoplasm involving the duodenum (n = 12). RESULTS: Technical success was achieved in 60 of the 68 patients (88.2%). After stent placement, mean dysphagia score improved from a mean of 3.5 to 1.2 (P < 0.001). The mean period of primary stent patency was 107.2 days. During follow up (mean 4.4 months; range, 1-15 months), major complications (migration [6], bleeding [3], perforation [1], ingrowth [1], overgrowth [7], fistula [1]) occurred in 19 patients (27.9%), and stent migration occurred in six (8.8%) (proximal migration into the stomach [n = 3], or distal migration [n = 3]). Recurrent dysphagia (mainly due to tumor ingrowth/overgrowth) occurred in eight patients (11.8%). CONCLUSION: Covered expandable Nitinol stents appear to offer an effective and feasible palliative therapy in patients with a malignant gastroduodenal obstruction.
Assuntos
Ligas , Obstrução Duodenal/terapia , Duodenoscopia , Obstrução da Saída Gástrica/terapia , Neoplasias Gastrointestinais/complicações , Gastroscopia , Cuidados Paliativos , Stents , Idoso , Obstrução Duodenal/etiologia , Obstrução Duodenal/patologia , Duodenoscopia/efeitos adversos , Feminino , Obstrução da Saída Gástrica/etiologia , Obstrução da Saída Gástrica/patologia , Neoplasias Gastrointestinais/terapia , Gastroscopia/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Desenho de Prótese , Estudos Retrospectivos , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Injuries from air weapons can be serious and potentially fatal. It has been estimated that up to four million such weapons exist in UK households. CASE REPORT: We present the case of an 8-year-old boy who sustained a penetrating neck wound from an air gun. Use of the flexible laryngoscope in the resuscitation room allowed localization of the gun pellet in the airway. CONCLUSIONS: This approach, combined with careful clinical assessment led to immediate removal by direct laryngoscopy, thus avoiding the morbidity of unnecessary surgical exploration.
Assuntos
Corpos Estranhos/diagnóstico , Lesões do Pescoço/diagnóstico , Prega Vocal , Ferimentos por Arma de Fogo/diagnóstico , Criança , Cuidados Críticos , Corpos Estranhos/cirurgia , Humanos , Intubação Intratraqueal , Edema Laríngeo/terapia , Laringoscopia , Masculino , Lesões do Pescoço/cirurgia , Cuidados Pós-Operatórios , Complicações Pós-Operatórias/terapia , Sons Respiratórios/etiologia , Enfisema Subcutâneo/diagnóstico , Enfisema Subcutâneo/terapia , Ferimentos por Arma de Fogo/cirurgiaRESUMO
The hemecopper oxidases (HCuOs) are terminal components of the respiratory chain, catalyzing oxygen reduction coupled to the generation of a proton motive force. The C-family HCuOs, found in many pathogenic bacteria under low oxygen tension, utilize a single proton uptake pathway to deliver protons both for O2 reduction and for proton pumping. This pathway, called the KC-pathway, starts at Glu-49P in the accessory subunit CcoP, and connects into the catalytic subunit CcoN via the polar residues Tyr-(Y)-227, Asn (N)-293, Ser (S)-244, Tyr (Y)-321 and internal water molecules, and continues to the active site. However, although the residues are known to be functionally important, little is known about the mechanism and dynamics of proton transfer in the KC-pathway. Here, we studied variants of Y227, N293 and Y321. Our results show that in the N293L variant, proton-coupled electron transfer is slowed during single-turnover oxygen reduction, and moreover it shows a pH dependence that is not observed in wildtype. This suggests that there is a shift in the pKa of an internal proton donor into an experimentally accessible range, from >10 in wildtype to ~8.8 in N293L. Furthermore, we show that there are distinct roles for the conserved Y321 and Y227. In Y321F, proton uptake from bulk solution is greatly impaired, whereas Y227F shows wildtype-like rates and retains ~50% turnover activity. These tyrosines have evolutionary counterparts in the K-pathway of B-family HCuOs, but they do not have the same roles, indicating diversity in the proton transfer dynamics in the HCuO superfamily.
Assuntos
Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Prótons , Vibrio cholerae/enzimologia , Complexo IV da Cadeia de Transporte de Elétrons/química , Concentração de Íons de Hidrogênio , Cinética , Mutagênese Sítio-Dirigida , Oxigênio/metabolismoRESUMO
Anaerobic digestate of piggery wastewater (ADPW) contains high concentrations of ammonia and phosphorus with unbalanced molar ratio. Thus, ammonia remains at a high level even after phosphorus is completely removed through struvite formation. In this study, both ammonia and phosphorus were recovered by adding leachate of sewage sludge ash (SSA) into ADPW. It was demonstrated that 11,600â mgâ L-1 of total phosphorus and 7266.7â mgâ L-1 of [Formula: see text]-P were extracted from SSA by using sulfuric acid at the H2SO4/SSA mass ratio of 0.35. ADPW and the leachate of SSA were mixed at the volumetric ratio of 1:1.29, and then struvite was formed at the molar ratio of 1.2 (Mg2+):1.0 ([Formula: see text]-P):1.0 (NH3-N). Removal efficiencies of ammonia and phosphorus were 91.95% and 99.65%, respectively. The obtained struvite was analyzed by various methods and was found to meet the Korean fertilizer standards, except for copper.