A thermodynamically consistent model was developed for representing vapor-liquid equilibria in the acid gas (H2S, COJ-alkanolamine-water system. The model accounts for chemical equilibria in a rigorous manner. Activity coefficients are represented, with the Electrolyte-NRTL equation treating both long-range ion-ion interactions and local interactions between all true liquid-phase species. Both water and alkanolamine are treated as solvents. Adjustable parameters of the Electrolyte-NRTL equation, representing short-range binary interactions, were fitted on binary and Previous ModelsBecause of the difficulty in representing activity coefficients in concentrated electrolyte solutions, early VLE models for weak electrolyte models adopted empirical approaches that did not account for physical interactions. Van Krevelen et al. (1949) proposed a method for representing H2S, COz, and NH3 equilibrium partial pressures over aqueous solutions. In equations governing chemical equilibria, they used "apparent" equilibrium constants related to component concentrations rather than activities. In effect, they set, activity coefficients of all species to unity. Apparent equilibrium constants were fitted on experimental data to functions of ionic strength. Dankwerts and McNeil (1967) used this method to calculate vapor-and liquid-phase compositions in amine-C02-H20 systems.Kent and Eisenberg (1976) used a similar approach to represent H2S and COP equilibrium partial pressures over aqueous solutions of MEA and DEA. They also employed

SummaryAnthracycline antibiotics have saved the lives of many cancer victims in the 50 plus years since their discovery. A major limitation of their use is the dose-limiting cardiotoxicity. Efforts focusing on understanding the biochemical basis for anthracycline cardiac effects have provided several strategies currently in clinical use: limit dose exposure; encapsulate anthracyclines in liposomes to reduce myocardial uptake; administer concurrently with the iron chelator dexrazoxane to reduce free ironcatalyzed reactive oxygen species formation; modification of anthracycline structure in an effort to reduce myocardial toxicity. In spite of these efforts, anthracycline-induced heart failure continues to occur with consequences for both morbidity and mortality. Our inability to predict and prevent anthracycline cardiotoxicity is in part due to the fact that the molecular and cellular mechanisms remain controversial and incompletely understood. Studies examining the effects of anthracyclines in cardiac myocytes in vitro and small animals in vivo have demonstrated several forms of cardiac injury, and it remains unclear how these translate to the clinical setting. Given the clinical evidence that myocyte death occurs after anthracycline exposure in the form of elevations in serum troponin, myocyte cell death appears to be a probable mechanism for anthracycline-induced cardiac injury. Other mechanisms of myocyte injury include the development of cellular 'sarcopenia' characterized by disruption of normal sarcomere structure. Anthracyclines suppress expression of several cardiac transcription factors, and this may play a role in the development of myocyte death as well as sarcopenia. Degradation of the giant myofilament protein titin may represent an important proximal step that leads to accelerated myofilament degradation. An interesting interaction has been noted clinically between anthracyclines and newer cancer therapies that target the erbB2 receptor tyrosine kinase. There is now evidence that erbB2 signaling in response to the ligand neuregulin regulates anthracycline uptake into cells via the multidrug-resistance protein. Therefore upregulation of cardiac neuregulin signaling may be one strategy to limit myocardial anthracycline injury. Moreover, assessing an individual's risk for anthracycline injury may be improved by having some measure of endogenous activity of this and other myocardial protective signals. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. 1]): 1) inhibition of both DNA replication and RNA transcription; 2) free radical generation, leading to DNA damag...

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The molecular and cellular mechanisms that cause cumulative dose-dependent anthracycline-cardiotoxicity remain controversial and incompletely understood. Studies examining the effects of anthracyclines in cardiac myocytes inA vitro have demonstrated several forms of cellular injury. Cell death in response to anthracyclines can be observed by one of several mechanisms including apoptosis and necrosis. Cell death by apoptosis can be inhibited by dexrazoxane, the iron chelator that is known to prevent clinical development of heart failure at high cumulative anthracycline exposure. Together with clinical evidence for myocyte death after anthracycline exposure, in the form of elevations in serum troponin, make myocyte cell death a probable mechanism for anthracycline-induced cardiac injury. Other mechanisms of myocyte injury include the development of cellular \'sarcopenia\' characterized by disruption of normal sarcomere structure. Anthracyclines suppress expression of several cardiac transcription factors, and this may play a role in the development of myocyte death as well as sarcopenia. Degradation of the giant myofilament protein titin may represent an important proximal step that leads to accelerated myofilament degradation. Titin is an entropic spring element in the sarcomere that regulates length-dependent calcium sensitivity. Thus titin degradation may lead to impaired diastolic as well as systolic dysfunction, as well as potentiate the effect of suppression of transcription of sarcomere proteins. An interesting interaction has been noted clinically between anthracyclines and newer cancer therapies that target the erbB2 receptor tyrosine kinase. Studies of erbB2 function in viro suggest that signaling through erbB2 by the growth factor neuregulin may regulate cardiac myocyte sarcomere turnover, as well as myocyte-myocyte/myocyte-matrix force coupling. A combination of further in vitro studies, with more careful monitoring of cardiac function after exposure to these cancer therapies, may help to understand to what extent these mechanisms are at work during clinical exposure of the heart to these important pharmaceuticals.

Objective-The metabolic and genetic correlates of circulating insulin-like growth factor-1 (IGF-1) and its main circulating carrier, IGF-1-binding-protein-3 (IGFBP-3), are unclear. Methods and Results-We measured serum IGF-1 and IGFBP-3 concentrations in a sample of the Framingham Heart Study (Nϭ3977, aged 40Ϯ9 years, 46% male) and evaluated their relations to cardiovascular risk factors using multivariable regression. Serum IGF-1 was inversely correlated with age, body mass index, total cholesterol, the presence of diabetes, alcohol consumption, and glomerular filtration rate (all PϽ0.01), whereas the ratio of IGF-1:IGFBP-3 was lower in women and inversely related to age, triglycerides, high-density lipoprotein cholesterol, systolic blood pressure, and alcohol consumption (all PϽ0.0001). Circulating IGF-1 correlated negatively with insulin resistance (homeostatic model assessment) (rϭϪ0.1; PϽ0.0001) and was lower in participants with more components of the metabolic syndrome (Adult Treatment Panel III criteria) (PϽ0.0001). Additive genetic factors (heritability) accounted for 43% and 39% of the variation of IGF-1 and IGFBP-3, respectively (both PϽ10 Ϫ27 ). Conclusion-Our cross-sectional observations in a large community-based sample link lower circulating IGF-1 to greater metabolic risk burden and underscore substantial genetic influences on IGF-1 concentrations. Prospective studies are warranted to elucidate whether lower IGF-1 concentrations predict greater metabolic risk longitudinally. (Arterioscler

Anthracyclines remain a mainstay of chemotherapy in spite of their well-recognized cardiotoxicity. Recent experience with trastuzumab (Herceptin) and anthracycline therapy has prompted a detailed analysis of the function of erbB2 in the heart. These studies demonstrate a cardioprotective effect of neuregulin, the endogenous ligand for the erbB4/erbB2 heterodimeric receptor complex. Although the mechanisms of cytoprotection remain incompletely understood, these studies have triggered the question of whether physiological manipulation of cardioprotective pathways that involve erbB can be used to improve outcome in patients treated with anthracyclines. The local activation of cardioprotection by cardiovascular exercise may be such a manipulation and warrants further investigation.

Heat shock protein (Hsp) 90 is a ubiquitously expressed chaperone that stabilizes expression of multiple signaling kinases involved in growth regulation, including ErbB2, Raf-1, and Akt. The chaperone activity of Hsp90 requires ATP, which binds with ϳ10-fold lower affinity than ADP. This suggests that Hsp90 may be a physiological ATP sensor, regulating the stability of growth signaling cascades in relation to cellular energy charge. Here we show that lowering ATP concentration by inhibiting glycolysis or mitochondrial respiration in isolated myocytes triggers rapid dissociation of Hsp90 from ErbB2 and degradation of ErbB2 along with other client proteins. The effect of disrupting Hsp90 chaperone activity by ATP depletion was similar to the effect of the pharmacological Hsp90 inhibitor geldanamycin. ATP depletion-induced disruption of Hsp90 chaperone activity was associated with cellular resistance to growth factor activation of intracellular signaling. ErbB2 degradation was also induced by the physiological stress of ␤-adrenergic receptor stimulation in electrically stimulated cells. These results support a role for Hsp90 as an ATP sensor that modulates tissue growth factor responsiveness under metabolically stressed conditions and provide a novel mechanism by which cellular responsiveness to growth factor stimulation is modulated by cellular energy charge.The physiological mechanisms by which cells dynamically shift between steady states of tissue function, for example from tissue growth to cell survival during periods of metabolic stress, are incompletely understood. The activity of large sets of proteins must be coordinately regulated during these shifts. Many of the proteins involved in cell growth are stabilized by the constitutively expressed chaperone heat shock protein (Hsp) 1 90 (1, 2). Dissociation of Hsp90 from its client proteins induced by Hsp90 inhibitors leads to rapid degradation of proteins involved in cell growth and the activation of a stress response (3). Thus, pharmacologically induced disruption in Hsp90 chaperone function alone can cause a cell to "shift gears" to a stress-mode.Hsp90 inhibitors such as geldanamycin (GA) bind with high affinity to a conserved pocket in the Hsp90 family of proteins and thereby prevent the ATP binding that is required for chaperone function (4). The relative affinity of Hsp90 for GA, ADP, and ATP were recently measured and exhibited dissociation constants of 0.2, 12, and 124 M, respectively (5). The relatively high affinity of Hsp90 for GA is consistent with its established potency as an inhibitor of Hsp90 chaperone function. The ϳ10-fold higher affinity of Hsp90 for ADP versus ATP is intriguing. Under basal conditions, when the intracellular [ATP]/[ADP]ratio is between 2 and 10:1 (6), the higher affinity of Hsp90 for ADP suggests that a small drop in the ATP/ADP ratio will result in a relatively large drop in the proportion of Hsp90 occupied by ATP and, therefore, available for client protein stabilization.These observations led us to hypothesize that Hsp90 ...

Mean and pulsatile components of hemodynamic load are related to cardiovascular disease. Vascular growth factors play a fundamental role in vascular remodeling. The links between growth factors and hemodynamic load components are not well described. In 3496 participants from the Framingham Heart Study Third Generation cohort (mean age 40±9 years, 52% women) we related 4 tonometry derived measures of central arterial load (carotid femoral pulse wave velocity and forward pressure wave, mean arterial pressure, and the global reflection coefficient) to circulating concentrations of angiopoietin 2, its soluble receptor; vascular endothelial growth factor, its soluble receptor; hepatocyte growth factor; insulin-like growth factor-1, and its binding protein3. Using multivariable linear regression models, adjusted for standard cardiovascular risk factors, serum insulin-like growth factor-1concentrations were negatively associated with carotid femoral pulse wave velocity, mean arterial pressure, and reflection coefficient (p≤0.01 for all), whereas serum vascular endothelial growth factor levels were positively associated with carotid femoral pulse wave velocity and mean arterial pressure (p≤0.02). Serum insulin-like growth factor binding protein −3 and soluble angiopoietin-2 receptor levels were positively related to mean arterial pressure and to forward pressure wave, respectively (p<0.05). In our cross-sectional study of a large community-based sample, circulating vascular growth factor levels were related to measures of mean and pulsatile hemodynamic load in a pattern consistent with the known physiological effects of insulin-like growth factor-1 and vascular endothelial growth factor.