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Cell kinetic studies in the murine ventral tongue epithelium: thymidine metabolism studies and circadian rhythm determination

Abstract.  The oral mucosa is a rapidly replacing body tissue that has received relatively little attention in terms of defining its cell kinetics and cellular organization. The tissue is sensitive to the effects of cytotoxic agents, the consequence of which can be stem cell death with the subsequent development of ulcers and the symptoms of oral mucositis. There is considerable interest in designing strategies to protect oral stem cells and, hence, reduce the mucositis side-effects in cancer therapy patients. Here we present details of a new histometric approach designed to investigate the changing patterns in cellularity in the ventral tongue mucosa. This initial paper in a series of four papers presents observations on the changing patterns in the labelling index following tritiated thymidine administration, which suggest a delayed uptake of tritiated thymidine from a long-term intracellular thymidine pool, a phenomenon that will complicate cell kinetic interpretations in a variety of experimental situations. We also provide data on the changing pattern of mitotic activity through a 24-h period (circadian rhythms). Using vincristine-induced stathmokinesis, the data indicate that 54% of the basal cells divide each day and that there is a high degree of synchrony in mitotic activity with a mitotic peak occurring around 13.00 h. The mitotic circadian peak occurs 9-12 h after the circadian peak in DNA synthesis. The data presented here and in the subsequent papers could be interpreted to indicate that basal cells of BDF1 mice have an average turnover time of about 26-44 h with some cells cycling once a day and others with a 2- or 3-day cell cycle time.     

ProCKSI: a decision support system for Protein (Structure) Comparison,Knowledge, Similarity and Information

Background  

We introduce the decision support system for Protein (Structure) Comparison, Knowledge, Similarity and Information (ProCKSI). ProCKSI integrates various protein similarity measures through an easy to use interface that allows the comparison of multiple proteins simultaneously. It employs the Universal Similarity Metric (USM), the Maximum Contact Map Overlap (MaxCMO) of protein structures and other external methods such as the DaliLite and the TM-align methods, the Combinatorial Extension (CE) of the optimal path, and the FAST Align and Search Tool (FAST). Additionally, ProCKSI allows the user to upload a user-defined similarity matrix supplementing the methods mentioned, and computes a similarity consensus in order to provide a rich, integrated, multicriteria view of large datasets of protein structures.     

Interaction of electrically charged drug molecules with phospholipid membranes

Model membranes (egg-yolk PC liposomes) were exposed to the cationic form of amphiphilic drugs. Microelectrophoresis was used to measure the change of the electrokinetic potential as a function of the drug concentration. By use of the Gouy-Chapman theory the surface potential and surface charge density were calculated. A theoretical model postulating a simple partition equilibrium of the charged drug molecules between the membrane and the aqueous phase in the vicinity of the membrane failed to describe the experimental results. Modification of the partition law by introducing a mechanism of saturation at high drug concentrations, however, resulted in concordance of model and experiment. Some parameters of the model can be used as a means of evaluating the efficiency of neuroactive drugs.     

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Simulating flow microfluorometry experiments with the computer language cellsim

CELLSIM is a digital simulation language specifically designed for simulating cell kinetics models. Recently a flow microfluorometry (FMF) command has been added to the language. In the command, the modeler indicates when his simulated FMF analyses are to take place, and what cell states are to be included. He may specify different coefficients of variance and a non-linear DNA synthesis rate for S phase cells. The FMF capability of the language has proved to be a useful tool in several applications.     

A pharmacokinetic model of the adjustment of phenprocoumon (Falithrom) dosage

The model presented here is based on a phenprocoumon (PPC) standard dose calculated per kg body weight by adapting it to experimentally obtained mean values of biological half-life (t1/2) and relative volume of distribution (Vrel) of PPC taken from the literature. Moreover, this dose is apt to produce a desired plasma PPC concentration leading to an optimum pharmacodynamic effect. This dose which amounts to 35.2 micrograms PPC per kg body weight will nearly be equal to the clinically used 3-mg dose related to a normal subject of 70 kg, if an absorption loss of 15 per cent is taken into consideration. By means of mathematical equations derived for this purpose, the course of plasma PPC concentration versus time curves is simulated over a time period from the administration of a standard loading dose of 376.8 micrograms PPC per kg body weight until steady state is reached. The simulation of curves is based on the presupposition that the values of t1/2 and Vrel of PPC in an individual subject do not correspond to the values of these parameters underlying the calculation of the standard dose. More than 50 per cent of the combinations of t1/2 and Vrel tested leads to the desired plasma PPC concentration at steady state. The model is suited to estimate the extent of extreme deviations of plasma PPC concentration, i.e., further accumulation of PPC or decrease in plasma PPC level, and to obtain information about the respective combinations of t1/2 and Vrel causing these deviations. Application of the basic principles of the present model to clinical practice would allow to further optimize and individualize the adjustment of multiple dosing regimen of the oral anticoagulant PPC.