Identification of chronic heart failure patients with a high 12-month mortality risk using biomarkers including plasma C-terminal pro-endothelin-1

Objectives

We hypothesised that assessment of plasma C-terminal pro-endothelin-1 (CT-proET-1), a stable endothelin-1 precursor fragment, is of prognostic value in patients with chronic heart failure (CHF), beyond other prognosticators, including N-terminal pro-B-type natriuretic peptide (NT-proBNP).

Methods

We examined 491 patients with systolic CHF (age: 63±11 years, 91% men, New York Heart Association [NYHA] class [I/II/III/IV]: 9%/45%/38%/8%, 69% ischemic etiology). Plasma CT-proET-1 was detected using a chemiluminescence immunoassay.

Results

Increasing CT-proET-1 was a predictor of increased cardiovascular mortality at 12-months of follow-up (standardized hazard ratio 1.42, 95% confidence interval [CI] 1.04–1.95, p = 0.03) after adjusting for NT-proBNP, left ventricular ejection fraction (LVEF), age, creatinine, NYHA class. In receiver operating characteristic curve analysis, areas under curve for 12-month follow-up were similar for CT-proET-1 and NT-proBNP (p = 0.40). Both NT-proBNP and CT-proET-1 added prognostic value to a base model that included LVEF, age, creatinine, and NYHA class. Adding CT-proET-1 to the base model had stronger prognostic power (p<0.01) than adding NT-proBNP (p<0.01). Adding CT-proET-1 to NT-proBNP in this model yielded further prognostic information (p = 0.02).

Conclusions

Plasma CT-proET-1 constitutes a novel predictor of increased 12-month cardiovascular mortality in patients with CHF. High CT-proET-1 together with high NT-proBNP enable to identify patients with CHF and particularly unfavourable outcomes.     

Age-dependent changes in 8-oxoguanine-DNA glycosylase activity are modulated by adaptive responses to physical exercise in human skeletal muscle

8-Oxo-7,8-dihydroguanine (8-oxoG) accumulates in the genome over time and is believed to contribute to the development of aging characteristics of skeletal muscle and various aging-related diseases. Here, we show a significantly increased level of intrahelical 8-oxoG and 8-oxoguanine-DNA glycosylase (OGG1) expression in aged human skeletal muscle compared to that of young individuals. In response to exercise, the 8-oxoG level was lastingly elevated in sedentary young and old subjects, but returned rapidly to preexercise levels in the DNA of physically active individuals independent of age. 8-OxoG levels in DNA were inversely correlated with the abundance of acetylated OGG1 (Ac-OGG1), but not with total OGG1, apurinic/apyrimidinic endonuclease 1 (APE1), or Ac-APE1. The actual Ac-OGG1 level was linked to exercise-induced oxidative stress, as shown by changes in lipid peroxide levels and expression of Cu,Zn-SOD, Mn-SOD, and SIRT3, as well as the balance between acetyltransferase p300/CBP and deacetylase SIRT1, but not SIRT6 expression. Together these data suggest that that acetylated form of OGG1, and not OGG1 itself, correlates inversely with the 8-oxoG level in the DNA of human skeletal muscle, and the Ac-OGG1 level is dependent on adaptive cellular responses to physical activity, but is age independent.     

Cortical microtubule patterning in roots of Arabidopsis thaliana primary cell wall mutants reveals the bidirectional interplay with cell expansion

Cell elongation requires directional deposition of cellulose microfibrils regulated by transverse cortical microtubules. Microtubules respond differentially to suppression of cell elongation along the developmental zones of Arabidopsis thaliana root apex. Cortical microtubule orientation is particularly affected in the fast elongation zone but not in the meristematic or transition zones of thanatos and pom2–4 cellulose-deficient mutants of Arabidopsis thaliana. Here, we report that a uniform phenotype is established among the primary cell wall mutants, as cortical microtubules of root epidermal cells of rsw1 and prc1 mutants exhibit the same pattern described in thanatos and pom2–4. Whether cortical microtubules assume transverse orientation or not is determined by the demand for cellulose synthesis, according to each root zone''s expansion rate. It is suggested that cessation of cell expansion may provide a biophysical signal resulting in microtubule reorientation.     

Periodic optimization of continuous microbial growth processes

Steady-state operation of continuous bioreactors is not necessarily the optimum type of operation. The method of pi-criterion is used in this work to determine whether periodic variation of the dilution rate can enhance the performance of continuous fermentation processes. It is found that the presence of time delay in the dynamic response of the chemostat renders a periodic operation of bioreactors, used for biomass production, superior to any steady-state operation. Also, employing Williams' structured model it is shown that cycling improves the average protein productivity.     

Adaptive steady-state optimization of biomass productivity in continuous fermentors

An adaptive steady-state optimization algorithm is presented and applied to the problem of optimizing the production of biomass in continuous fermentation processes. The algorithm requires no modeling information but is based on an on-line identified linear model, locates the optimum dilution rate, and maintains the chemostat at its optimum operating condition at all times. The behavior of the algorithm is tested against a dynamic model of a chemostat that incorporates metabolic time delay, and it is shown that large disturbances in the subtrate feed concentration and the specific growth rate, causing a shift in the optimum, are handled well. The developed algorithm is also used to drive a methylotroph single-cell production process to its optimum.     

A simple model to describe transient differences between cell number and biomass growth rates of Escherichia coli

Information on the response of a microbial culture to dynamic environmental conditions is necessary for the design of transient operation processes. However, most attempts at modelling culture response have been directed at describing the steady-state behavior. Thus, there is a need for adequate dynamic models for process design. Simulations of nutrient shifts were completed using a "single-cell" model for Escherichia coli. It was discovered that the specific mass growth rate and the specific number of cells growth rate were different under transient conditions, whereas at steady state (balanced growth) these rates are equivalent. Using these observations, a simple delay model to describe the transient behavior of the two growth rates is formulated and tested. The model contains as state variables only the readily measurable macroscopic quantities (biomass, cell number, and limiting nutrient). This model agreed well with the predictions of the single-cell model.     

Defining synchrony of cell cultures

A method was developed for the statistical analysis of growth data from synchronized growth experiments. The analysis provided a firm basis for the recognition of synchrony and the objective graphical presentation of the growth pattern of a synchronized culture. The latter could then supply reliably the parameters required for the calculation of a synchronization index, i.e. for the synchrony evaluation.     

Expert system for control of anaerobic digesters

Continuous anaerobic digesters are systems that present challenging control problems including the possibility that an unmeasured disturbance can change the sign of the steady-state process gain. An expert system is developed that recognizes changes in the sign of process gain and implements appropriate control laws. The sole on-line measured variable is the methane production rate, and the manipulated input is the dilution rate. The expert system changes the dilution rate according to one of four possible strategies: a constrained conventional set-point control law, a constant yield control law (CYCL) that is nearly optimal for the most common cause of change in the sign of the process gain, batch operation, or constant dilution rate. The algorithm uses a t test for determining when to switch to the CYCL and returns to the conventional set-point control law with bumpless transfer. The expert system has proved successful in several experimental tests: severe overload; mild, moderate, and severe underload; and addition of phenol in low and high levels. Phenol is an inhibitor that in high concentrations changes the sign of the process gain.     

A new method for the adaptive determination of optimum pH and temperature

An adaptive control algorithm for the on-line determination of optimal temperature or pH for biomass production in a continuous fermentor is presented. The algorithm requires no prior information and uses a dynamic Hammerstein model to identify parameters and to estimate an optimal steady-state control value. A check of the estimated performance measure second derivative is included to ensure that the target extremum is an optimum. The process is driven towards this optimum with a variable step size that depends on the quality of the on-line identified model. Numerical simulations are performed on a dynamic chemostat model that incorporates a metabolic time delay. The algorithm successfully finds the optimum temperature or pH values and maintains the reactor at the optimum steady state.