Exploring the Effects of Glycosylation and Etherification of the Side Chains of the Anticancer Drug Mitoxantrone

Herein we report the synthesis and biological evaluation of symmetric and asymmetric analogues of the DNA intercalating drug mitoxantrone (MTX) in which the side chains of the parent drug were modified through glycosylation or methyl etherification. Several analogues with glycosylated side chains exhibited higher DNA affinity than the parent MTX. The most potent in vitro cytotoxicity was observed for MTX analogue 8 (1,4‐dimethoxy‐5,8‐bis[2‐(2‐methoxyethylamino)ethylamino]anthracene‐9,10‐dione) with methoxy ether containing side chains. Treatment of melanoma‐bearing mice with MTX or analogue 8 decreased the intraperitoneal tumor burden relative to untreated mice; the effect of 8 was less pronounced than that of MTX. In vitro metabolism assays of MTX with rabbit liver S9 fraction gave rise to several metabolites; almost no metabolites were detected for MTX analogue 8 . The results presented indicate that derivatization of the MTX side chain primary hydroxy groups may result in a significant improvement in DNA affinity and lower susceptibility to the formation of potentially toxic metabolites.     

A model of non‐isothermal degradation of nutrients,pigments and enzymes

Published isothermal degradation curves for chlorophyll A and thiamine in the range 100–150 °C and the inactivation curves of polyphenol oxidase (PPO) in the range 50–80 °C could be described by the model C(t)/C₀ = exp[?b(T)tⁿ] where C(t) and C₀ are the momentary and initial concentrations, respectively, b(T) a temperature dependent ‘rate parameter’ and n, a constant. This suggested that the temporal degradation/inactivation events of all three had a Weibull distribution with a practically constant shape factor. The temperature dependence of the ‘rate parameter’ could be described by the log logistic model, b(T) = log_e[1 + exp[k(T ? T_c)], where T_c is a marker of the temperature level where the degradation/inactivation occurs at a significant rate and k the steepness of the b(T) increase once this temperature range has been exceeded. These two models were combined to produce a non‐isothermal degradation/inactivation model, similar to one recently developed for microbial inactivation. It is based on the assumption that the local slope of the non‐isothermal decay curve, ie the momentary decay rate, is the slope of the isothermal curve at the momentary temperature at a time that corresponds to the momentary concentration of the still intact or active molecules. This model, in the form of a differential equation, was solved numerically to produce degradation/inactivation curves under temperature profiles that included heating and cooling and oscillating temperatures. Such simulations can be used to assess the impact of planned commercial heat processes on the stability of compounds of nutritional and quality concerns and the efficacy of methods to inactivate enzymes. Simulated decay curves on which a random noise was superimposed were used to demonstrate that the degradation/inactivation parameters, k and T_c, can be calculated directly from non‐isothermal decay curves, provided that the validity of the Weibullian and log logistic models and the constancy of the shape factor n could be assumed. Copyright © 2004 Society of Chemical Industry     

From expert-driven to user-oriented communication of infection control guidelines

Currently, infection control guidelines in hospitals and other health care institutions are more expert-driven than user-oriented. In order to enhance the usability of the expert-driven guideline format, we developed a website for the communication of existing guidelines that better fit the practical information needs of health care workers (HCWs). We employed a user-centered design process that involved two studies.In the initial study, 28 HCWs were asked to solve tasks using existing, paper-based infection control guidelines. In order to detect their strategies and problems, the participants were asked to think aloud. Usability problems occurred due to poorly structured information, insufficient quality of information, and a mismatch between experts’ and HCWs’ vocabulary. To overcome these shortcomings, three design principles were applied for communicating infection control guidelines: better navigation (the guidelines should be searchable in several ways); multimodality (the guidelines should not be presented as text only), and action-orientation (the guidelines should be presented as HCWs’ behaviors). A website was developed to meet these principles.In the second study, the same 28 HCWs completed tasks identical to those of the first study while thinking aloud, but this time using the website. The percentage of correctly completed tasks increased and the mean time for task completion decreased significantly. Also, respondents were more satisfied with the website than the paper-based guidelines. The number of problems due to poor information quality and a mismatch in vocabulary declined, although the number of structural problems increased. This can probably be explained by the fact that the navigation structure was user-generated (using Card Sort), in contrast to a standardized answer format based on common usability principles.Overall, we found that involving HCWs in the development process is important to create a sense of ownership and to foster the implementation of the guidelines, which might eventually result in compliance and reduce health care-associated infections. This paper outlines concrete steps for how to involve HCWs in the design process.     

The Influence of Selected Osmotic Dehydration and Pretreatment Parameters on Dry Matter and Polyphenol Content in Highbush Blueberry (Vaccinium corymbosum L.) Fruits

The paper presents an assessment of the influence of selected highbush blueberry pretreatment methods and parameters on the process of osmotic dehydration conducted in 65 °Brix sucrose solution for 5 to 240 min at 30–70 °C. The pretreatment methods used included: fruit immersion in boiling water (15 s) and in 0.5 % NaOH solution (15 s at 95 °C), exposure to ultrasound at atmospheric pressure (vibration frequency of 35?±?5 kHz, 500 W, for 15 min.) and at low pressure (0.92 kg?cm^?1), and enzymatic processing; pectinase (enzyme activity of 46,000 PGU/mL; 0.6 mL/90 g of fruits; 30 min at approx. 22 °C) and lipase (enzyme activity of 750 PGU/mL; 0.7 mL/90 g of fruits; 30 min at approx. 22 °C) were used. Dehydration was also conducted in the presence of pectinolytic enzymes. The dehydrated material was analyzed in terms of the content of dry matter, total polyphenols, and particular polyphenols using high performance liquid chromatography. It was observed that dehydration was much more intensive at 60 and 70 °C, but such temperatures led to substantial losses of phenolic compounds (by 15–30 % after 2-h dehydration) and unfavorable changes in the texture of the final product. A promising method of pretreatment is fruit immersion in solutions containing pectinolytic and lipolytic enzymes, which increase dry matter content by 26 % (after 1 h of dehydration at 30 °C) with a low loss of phenolic compounds (4 %). Among the identified anthocyanins, the greatest retention during dehydration at various temperatures was displayed by petunidin-3-galactoside (over 80 % after 1 h of dehydration) and petunidin-3-glucoside (over 78 %).     

Effects of metal cations on betanin stability in aqueous-organic solutions

An effect of metal cations on betanin stability was investigated in aqueous and organic-aqueous solutions. The presence of organic solvents (methanol, ethanol, and acetonitrile) affects substantially the pigments decomposition in acidic media induced by metal cations whose degrading action in such media is significantly higher than in aqueous solutions. The influence of Cu²⁺ on the stability was studied by spectrophotometry in more detailed manner, because of its ability to form complexes with betanin. The possibility of a complex formation between betanin and Ni²⁺ was also stated at pH 7–8; its relatively high stability in aqueous samples was observed. A presence of numerous products of betanin decomposition was detected in the wavelength range 380–500 nm in spectra obtained for most of metal cations investigated, especially for higher concentrations of the organic solvents.     

Dynamic modelling for thermal micro-actuators using thermal networks

Thermal actuators are extensively used in microelectromechanical systems (MEMS). Heat transfer through and around these microstructures are very complex. Knowing and controlling them in order to improve the performance of the micro-actuator, is currently a great challenge. This paper deals with this topic and proposes a dynamic thermal modelling of thermal micro-actuators. Thermal problems may be modelled using electrical analogy. However, current equivalent electrical models (thermal networks) are generally obtained considering only heat transfers through the thickness of structures having considerable height and length in relation to width (walls). These models cannot be directly applied to micro-actuators. In fact, micro-actuator configurations are based on 3D beam structures, and heat transfers occur through and around length. New dynamic and static thermal networks are then proposed in this paper. The validities of both types of thermal networks have been studied. They are successfully validated by comparison with finite elements simulation and analytical calculations.     

A Phenomenological Model of the Peroxide Value’s Rise and Fall During Lipid Oxidation

During isothermal lipid oxidation at relatively high temperatures, the peroxide concentration frequently peaks while at relatively low temperatures it only rises slowly. These are two manifestations of a process where formation and degradation happen simultaneously on different time scales. A phenomenological mathematical model, comprising a decay factor superimposed on an accumulation term can describe these scenarios. Each has a characteristic time constant shortened by raising the temperature and a rate constant that increases with it. The model’s mathematical structure and the magnitude of its coefficients depend on the particular system. However, regardless of the chosen expressions, if the degradation characteristic time falls within or just beyond the experiment’s duration, a peak peroxide value will be observed whose height and shape will primarily depend on the other model’s parameters. If this characteristic time is far outside the time of the experiment , no peak will be recorded. The model need not be unique and no detailed knowledge of the oxidation mechanisms is required for its formulation. Consequently it can be derived directly from experimental peroxide value versus time relationships, without the need to monitor the intermediate reactions by specialized instrumental methods such as DSC. Through the formation term adjustment, the model can also account for the temperature dependent lag in the rise of the peroxide value and/or the appearance of its peak.     

Theoretical comparison of a new and the traditional method to calculate Clostridium botulinum survival during thermal inactivation

When published isothermal survival data of Clostridium botulinum spores in the range 101–121 °C were plotted in the form of logS(t) vs t relationships, where S(t) is the momentary survival ratio, they were all non‐linear. They had a noticeable upward concavity, in violation of the assumption that sporal inactivation is a process that follows first‐order reaction order kinetics. They could be described by the power law model logS(t) = ? b(T)t ^n(T), where b(T) and n(T) are temperature‐dependent coefficients of the order of 0.1–6 and about 0.4 respectively. These coefficients were used to construct simulated survival curves under different heating regimes with a recently proposed model. The model is based on the assumption that the local slope of the non‐isothermal survival curve, or the momentary inactivation rate, is determined solely by the momentary temperature and survival ratio, which in turn are functions of the population thermal history. The survival curves calculated with this model differ considerably from those produced by the standard method based on the traditional D and Z values. The shortcomings of the standard model are that these values depend on the number of points taken for the regression, and that its predicted survival ratios depend on the selected reference temperature. The differential equation which is proposed to replace it can be solved numerically using a program such as Mathematica®. Its predictions solely depend on the observed survival patterns under isothermal conditions and not on any preconceived kinetic model. Nevertheless, the method still needs verification with experimental non‐isothermal survival data, as has already been done with Listeria and Salmonella cells. © 2001 Society of Chemical Industry