Jefferson\u27s Equality Inconsistencies

Thomas Jefferson’s own work, accounts from his family, and several sources concerning his relationship with notions of slavery and equality, show the inconsistencies in Jefferson’s ideas about equality. This can be solved by classifying them into two spheres: the political and personal. Although it was useful to classify his paradoxes into two spheres of thought, it became evident that the contradictions were not absolutely confined to them. Even within the spheres of the political and personal, Jefferson’s ideas and actions concerning equality were not consistent

THERAPEUTIC EFFICACY OF COMBINATION OF MTOR INHIBITORS AND AMPK ACTIVATORS IN NON-SMALL CELL LUNG CANCER.

Pemetrexed (PTX), an antifolate drug, has been approved by the US FDA for first line therapy of mesothelioma and non-small cell lung cancer. In addition to its primary site of action on thymidylate synthase (TS), PTX also inhibits the second folate-dependent enzyme of purine biosynthesis aminoimidazolecarboxamide ribonucleotide formyltransferase (AICART). The accumulation of the substrate for AICART, ZMP, in PTX-inhibited cancer cells leads to activation of AMP-activated protein kinase (AMPK) with subsequent inhibition of mammalian target of rapamycin (mTOR) and hypophosphorylation of its downstream targets responsible for protein synthesis and cell proliferation. Inhibitors of mTORC1 like Rapamycin and its analogs (rapalogs) have only partial effects on tumor cells as they do not inhibit mTORC2, which phosphorylates Akt subsequently relieving the inhibition of mTORC1, thus leading to poor cytotoxicity by rapalogs. AMPK exerts control on mTORC1 kinase activity and PTX mediated activation of AMPK leads to its subsequent downregulation and hence, would be expected to have a therapeutic interaction with direct mTOR inhibitors. AZD8055, an ATP-competitive inhibitor of mTOR kinase, potently inhibits both mTORC1 and mTORC2 and therefore, can overcome the feedback mechanism(s) limiting the action of rapalogs to cytostatic effects. To study the effects of AMPK activation and mTOR inhibition pharmacologically, we performed growth suppression assays using pemetrexed, AICAR, RAD001, and AZD8055. The effect of inhibition of mTOR with these drugs was assessed by examining the dephosphorylation of mTORC1 substrates S6K1 and 4E-BP1, as single agents and in combination, at their 50% inhibitory concentrations (IC50) by western blotting. Our data suggested that AMPK activation via PTX mediated AICART inhibition in combination with direct mTOR inhibition by AZD8055 has a synergistic interaction on the proliferation of NSCLC cells in culture. Inhibition of mTOR endogenously by pemetrexed, along with direct pharmacological inhibition of mTOR prevents the feedback circuit which may compromise the therapeutic efficacy of rapamycin analogs. Pemetrexed and AZD8055, as single agents, demonstrated inhibitory activity on phosphorylation events of mTORC1 substrates. This activity was markedly increased by combining both the drugs. Our findings suggest that direct inhibitors of mTOR enhance the effects of activators of AMPK. These effects appear to be mediated via combined effects on mTORC1. Taken together, the combination of catalytic site mTOR inhibitors and pemetrexed is a promising therapeutic strategy and calls for further preclinical and clinical investigations

A simplified (modified) Duke Activity Status Index (M-DASI) to characterise functional capacity: A secondary analysis of the Measurement of Exercise Tolerance before Surgery (METS) study

Background Accurate assessment of functional capacity, a predictor of postoperative morbidity and mortality, is essential to improving surgical planning and outcomes. We assessed if all 12 items of the Duke Activity Status Index (DASI) were equally important in reflecting exercise capacity. Methods In this secondary cross-sectional analysis of the international, multicentre Measurement of Exercise Tolerance before Surgery (METS) study, we assessed cardiopulmonary exercise testing and DASI data from 1455 participants. Multivariable regression analyses were used to revise the DASI model in predicting an anaerobic threshold (AT) >11 ml kg −1 min −1 and peak oxygen consumption (VO 2 peak) >16 ml kg −1 min −1, cut-points that represent a reduced risk of postoperative complications. Results Five questions were identified to have dominance in predicting AT>11 ml kg −1 min −1 and VO 2 peak>16 ml.kg −1min −1. These items were included in the M-DASI-5Q and retained utility in predicting AT>11 ml.kg −1.min −1 (area under the receiver-operating-characteristic [AUROC]-AT: M-DASI-5Q=0.67 vs original 12-question DASI=0.66) and VO 2 peak (AUROC-VO2 peak: M-DASI-5Q 0.73 vs original 12-question DASI 0.71). Conversely, in a sensitivity analysis we removed one potentially sensitive question related to the ability to have sexual relations, and the ability of the remaining four questions (M-DASI-4Q) to predict an adequate functional threshold remained no worse than the original 12-question DASI model. Adding a dynamic component to the M-DASI-4Q by assessing the chronotropic response to exercise improved its ability to discriminate between those with VO 2 peak>16 ml.kg −1.min −1 and VO 2 peak<16 ml.kg −1.min −1. Conclusions The M-DASI provides a simple screening tool for further preoperative evaluation, including with cardiopulmonary exercise testing, to guide perioperative management

Integration of the Duke Activity Status Index into preoperative risk evaluation: a multicentre prospective cohort study.

BACKGROUND: The Duke Activity Status Index (DASI) questionnaire might help incorporate self-reported functional capacity into preoperative risk assessment. Nonetheless, prognostically important thresholds in DASI scores remain unclear. We conducted a nested cohort analysis of the Measurement of Exercise Tolerance before Surgery (METS) study to characterise the association of preoperative DASI scores with postoperative death or complications. METHODS: The analysis included 1546 participants (≥40 yr of age) at an elevated cardiac risk who had inpatient noncardiac surgery. The primary outcome was 30-day death or myocardial injury. The secondary outcomes were 30-day death or myocardial infarction, in-hospital moderate-to-severe complications, and 1 yr death or new disability. Multivariable logistic regression modelling was used to characterise the adjusted association of preoperative DASI scores with outcomes. RESULTS: The DASI score had non-linear associations with outcomes. Self-reported functional capacity better than a DASI score of 34 was associated with reduced odds of 30-day death or myocardial injury (odds ratio: 0.97 per 1 point increase above 34; 95% confidence interval [CI]: 0.96-0.99) and 1 yr death or new disability (odds ratio: 0.96 per 1 point increase above 34; 95% CI: 0.92-0.99). Self-reported functional capacity worse than a DASI score of 34 was associated with increased odds of 30-day death or myocardial infarction (odds ratio: 1.05 per 1 point decrease below 34; 95% CI: 1.00-1.09), and moderate-to-severe complications (odds ratio: 1.03 per 1 point decrease below 34; 95% CI: 1.01-1.05). CONCLUSIONS: A DASI score of 34 represents a threshold for identifying patients at risk for myocardial injury, myocardial infarction, moderate-to-severe complications, and new disability

Respostas do lactato sanguíneo e da dor muscular de início tardio pós dois métodos distintos de treinamento de força

ABSTRACTIntroduction: Strength training has been recommended due to the numerous benefits related to aesthetics, health and fitness. Objective: To analyze the responses of blood lactate and delayed onset muscle soreness after two strength training methods. Methods: Eleven men, 30.0 ± 8.81 years, were subjected to randomized and halftone form of 96 hours, the decreasing pyramid method (4 set 10,12,14 and 16MR and 60-second interval) and forced reps (4 set: 6MR, and interval of 90 seconds) for the exercise bench press, incline bench press and crucifix. To measure the impact of each method the blood lactate and delayed onset muscle soreness were measured before and after each intervention. Results: The method descending pyramid generated higher (p <0.05) blood lactate concentrations (before 1.21 ± 0.65 and 8.42 ± 1.81 mmol / l after) compared to the method of forced repetitions (before 1.28 ± 0.62 and 6.30 ± 1.87 mmol after) and delayed onset muscle soreness did not differ between them. Conclusion: The investigated strength training methods promote important changes in blood lactate concentrations, especially the protocol (descending pyramid) with features of metabolic overload. Therefore, these methods can be a valuable alternative when it aims to switch the type of overload (mechanical and metabolic) of the training session and thus should be chosen prudently and by the needs and goals of the training.Introdução: O treinamento de força tem sido recomendado devido aos inúmeros benefícios relacionados à estética, saúde e condicionamento físico. Objetivo: Analisar as respostas do lactato sanguíneo e da dor muscular de início tardio pós dois métodos de treinamento de força. Metodologia: Onze homens, com 30,0 ± 8,81 anos, foram submetidos de forma randomizada e com intervalo mínimo de 96 horas, ao método pirâmide decrescente (4 séries: 10,12,14 e 16RM e intervalo de 60 segundos) e repetições forçadas (4 séries: 6RM, e intervalo de 90 segundos) para os de supino reto, supino inclinado e crucifixo. Para medir o impacto de cada método o lactato sanguíneo e a dor muscular de início tardio foram mensuradas pré e pós cada intervenção. Resultados: O método pirâmide decrescente gerou maiores (p <0,05) concentrações de lactato sanguíneo (pré 1,21 ± 0,65 e pós 8,42 ± 1,81 mmols/l) quando comparado com o método de repetições forçadas (pré 1,28 ± 0,62 e pós 6,30 ± 1,87 mmols) e a dor muscular de início tardio não diferiu entre eles. Conclusão: Os métodos de treinamento de força investigados promovem importantes alterações nas concentrações de lactato sanguíneo, com destaque ao protocolo (pirâmide decrescente) com característica de sobrecarga metabólica.  Portanto, estes métodos podem ser uma alternativa de grande valia quando se tem como objetivo alternar o tipo de sobrecarga (mecânica e metabólica) da sessão de treinamento e dessa forma, devem ser escolhidos com prudência e mediante as necessidades e objetivos do treinamento.

A Service of zbw Convergence and Overtaking in a Dynamic Two Country Model Convergence and Overtaking in a Dynamic Two Country Model

Standard-Nutzungsbedingungen: Die Dokumente auf EconStor dürfen zu eigenen wissenschaftlichen Zwecken und zum Privatgebrauch gespeichert und kopiert werden. Sie dürfen die Dokumente nicht für öffentliche oder kommerzielle Zwecke vervielfältigen, öffentlich ausstellen, öffentlich zugänglich machen, vertreiben oder anderweitig nutzen. Sofern die Verfasser die Dokumente unter Open-Content-Lizenzen (insbesondere CC-Lizenzen) zur Verfügung gestellt haben sollten, gelten abweichend von diesen Nutzungsbedingungen die in der dort genannten Lizenz gewährten Nutzungsrechte. In two-sector infinite-horizon trade models with factor-price-equalization, convergence of aggregate capital-labor ratios and incomes does not occur because the Euler equations imply equal growth rate of consumption in all economies. In a two-country dynamic specific factors model, we show that factor-price-equalization occurs only in the long run. Per capita incomes and consumptions do not necessarily converge. These depend on the endowments of the primary factors. Depending on these endowments, an initially poorer economy may end up as the richer economy in the steady state, overtaking the initially richer one. Terms of use: Documents in EconStor may JEL-Codes: F110

Characterising and modelling variability of tow orientation in engineering fabrics and textile composites

Variability of tow orientation is unavoidable for biaxial engineering fabrics and their composites. Since the mechanical behaviour of these materials is strongly dependent on the fibre direction, variability should be considered and modelled as exactly as possible for more realistic estimation of their forming and infusion behaviour and their final composite mechanical properties. In this study, a numerical code, ‘VariFab’, has been written to model realistic full-field variability of the tow directions across flat sheets of biaxial engineering fabrics and woven textile composites. The algorithm is based on pin-jointed net kinematics and can produce a mesh of arbitrary perimeter shape, suitable for subsequent computational analysis such as finite element forming simulations. While the shear angle in each element is varied, the side-length of all unit cells within the mesh is constant. This simplification ensures that spurious tensile stresses are not generated during deformation of the mesh during forming simulations. Variability is controlled using six parameters that can take on arbitrary values within certain ranges, allowing flexibility in mesh generation. The distribution of tow angles within a pre-consolidated glass–polypropylene composite and self-reinforced polypropylene and glass fabrics has been characterised over various length scales. Reproduction of the same statistical variability of tow orientation as in these experiments is successfully achieved by combining the VariFab code with a simple genetic algorithm