Flight Flutter Testing of the P6M

On the P6M the shake behavior, i.e., the response to random excitation at subcritical speeds of lowly damped airplane modes, is as important as the actual flutter speed. The approach is to first study the problem by means of analyses and wind-tunnel tests. These predictions are compared with flight test data obtained by spectral analysis of tape recordings of the airplane vibration responses to random aerodynamic turbulence. A similar spectrum analysis approach was used in high speed wind-tunnel tests. A resonance excitation technique was developed for low speed wind-tunnel testing, and well defined V-g curves were obtained. The effect of various parameters on both shake and flutter of T-tails with and without dihedral were studied. Preliminary flight tests yielded good correlation; they also yielded interesting information concerning a low frequency transonic snaking mode, and excitation by shed vortices

Reduced loop diuretic use in patients taking sacubitril/valsartan compared with enalapril: the PARADIGM-HF trial.

Aims: To assess differences in diuretic dose requirements in patients treated with sacubitril/valsartan compared with enalapril in the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure (PARADIGM‐HF) trial. Methods and results: Overall, 8399 patients with New York Heart Association class II–IV heart failure and reduced LVEF were randomized to sacubitril/valsartan 200 mg bid or enalapril 10 mg twice daily. Loop diuretic doses were assessed at baseline, 6, 12, and 24 months, and furosemide dose equivalents were calculated via multiplication factors (2x for torsemide and 40x for bumetanide). Percentages of participants with reductions or increases in loop diuretic dose were determined. At baseline, 80.8% of participants were taking any diuretics (n = 6290 for loop diuretics, n = 496 for other diuretics); of those, recorded dosage data for loop diuretics were available on 5487 participants. Mean baseline furosemide equivalent doses were 48.2 mg for sacubitril/valsartan and 49.6 mg for enalapril (P = 0.25). Patients treated with sacubitril/valsartan were more likely to reduce diuretic dose and less likely to increase diuretic dose relative to those randomized to enalapril at 6, 12, 24 months post‐randomization, with an overall decreased diuretic use of 2.0% (P = 0.02), 4.1% (P < 0.001), and 6.1% (P < 0.001) at 6, 12, and 24 months, respectively, with similar findings in an on‐treatment analysis. Conclusion: Treatment with sacubitril/valsartan was associated with more loop diuretic dose reductions and fewer dose increases compared with enalapril, suggesting that treatment with sacubitril/valsartan may reduce the requirement for loop diuretics relative to enalapril in patients with heart failure with reduced ejection fraction

The semisynthetic flavonoid monoHER sensitises human soft tissue sarcoma cells to doxorubicin-induced apoptosis via inhibition of nuclear factor-κB

Background:Despite therapeutic advances, the prognosis of patients with metastatic soft tissue sarcoma (STS) remains extremely poor. The results of a recent clinical phase II study, evaluating the protective effects of the semisynthetic flavonoid 7-mono-O-(beta-hydroxyethyl)-rutoside (monoHER) on doxorubicin-induced cardiotoxicity, suggest that monoHER enhances the antitumour activity of doxorubicin in STSs.Methods:To molecularly explain this unexpected finding, we investigated the effect of monoHER on the cytotoxicity of doxorubicin, and the potential involvement of glutathione (GSH) depletion and nuclear factor-kappaB (NF-kappaB) inactivation in the chemosensitising effect of monoHER.Results:MonoHER potentiated the antitumour activity of doxorubicin in the human liposarcoma cell line WLS-160. Moreover, the combination of monoHER with doxorubicin induced more apoptosis in WLS-160 cells compared with doxorubicin alone. MonoHER did not reduce intracellular GSH levels. On the other hand, monoHER pretreatment significantly reduced doxorubicin-induced NF-kappaB activation.Conclusion:These results suggest that reduction of doxorubicin-induced NF-kappaB activation by monoHER, which sensitises cancer cells to apoptosis, is involved in the chemosensitising effect of monoHER in human liposarcoma cells

Imposition, resistance, and alternatives in the face of an interregional water crisis in Mexico: El Zapotillo project

En este dossier se analizan los complejos aspectos socio-políticos, económicos, hidrológicos, legales, entre otros, relacionados con la construcción del proyecto El Zapotillo, que incluye un trasvase del Río Verde entre los estados mexicanos de Jalisco y Guanajuato con consecuencias significativas paras las comunidades humanas y los ecosistemas. El Cuaderno de Trabajo presenta doce artículos escritos por especialistas en las diferentes dimensiones del proceso, e incluye el trabajo de estudiantes de doctorado, activistas, y miembros de las comunidades locales afecadas directamente por el proyecto. It is a dossier focused on the complex socio-political, economic, hydrological, legal and other aspects involving the construction of El Zapotillo project, which includes an inter-basin transfer of the Verde River between the Mexican states of Jalisco and Guanajuato with significant consequences for human communities and ecosystems. The Working Paper features twelve articles written by specialists in the different dimensions of the process, and includes the work of doctoral students, activists, and members of the local communities directly affected by the project.ITESO, A.C.Universidad de BernaEl Colegio de JaliscoUNAMUniversidad de GuanajuatoUniversidad de GuadalajaraCartocríticaIMDECCIDEComité Salvemos Temacapulín, Acasico y PalmarejoColectivo de Abogad@

Non-irradiation-derived reactive oxygen species (ROS) and cancer: therapeutic implications

Owing to their chemical reactivity, radicals have cytocidal properties. Destruction of cells by irradiation-induced radical formation is one of the most frequent interventions in cancer therapy. An alternative to irradiation-induced radical formation is in principle drug-induced formation of radicals, and the formation of toxic metabolites by enzyme catalysed reactions. Although these developments are currently still in their infancy, they nevertheless deserve consideration. There are now numerous examples known of conventional anti-cancer drugs that may at least in part exert cytotoxicity by induction of radical formation. Some drugs, such as arsenic trioxide and 2-methoxy-estradiol, were shown to induce programmed cell death due to radical formation. Enzyme-catalysed radical formation has the advantage that cytotoxic products are produced continuously over an extended period of time in the vicinity of tumour cells. Up to now the enzymatic formation of toxic metabolites has nearly exclusively been investigated using bovine serum amine oxidase (BSAO), and spermine as substrate. The metabolites of this reaction, hydrogen peroxide and aldehydes are cytotoxic. The combination of BSAO and spermine is not only able to prevent tumour cell growth, but prevents also tumour growth, particularly well if the enzyme has been conjugated with a biocompatible gel. Since the tumour cells release substrates of BSAO, the administration of spermine is not required. Combination with cytotoxic drugs, and elevation of temperature improves the cytocidal effect of spermine metabolites. The fact that multidrug resistant cells are more sensitive to spermine metabolites than their wild type counterparts makes this new approach especially attractive, since the development of multidrug resistance is one of the major problems of conventional cancer therapy