Development of health diagnostics based on personalized medical models.

Due to rapid evolution of new technologies the concept of personalized medicine has evolved. Components include molecular biology, proteomics, metabolomic analysis, genetic testing, and molecular medicine for diagnostics. In addition to diagnostics these methods can be used to determine individual susceptibility to diseases and conditions. In conjunction with new diagnostic methods, new therapies can be tailored to the individual. These new technologies present a challenge in terms of the expansion of the medical record as well as the development of new methods for creating disease profiles. This article focuses on a computer-aided support for personalized medicine. Specific approaches are explored that permit automated data analysis for prognosis and treatment based on analysis methods for numeric and pictorial data. Although personalized medicine based on the genome of the patient are occasionally performed, because of the large amount of data new methods are needed to form general disease models as well as specific profiles of the individual patient.

The use of consequential reasoning in cancer chemotherapy.

Knowledge-based decision support systems traditionally rely on condition-action rule structures, an adequate representation for simple decisions. In complex domains an important part of decision-making includes analysis of the consequences of a decision. Consequential reasoning is particularly important in medicine as potential risk and/or benefit can be included. In this paper, a knowledge structure and inference engine is described that permits the representation and analysis of consequential reasoning in a computer-assisted decision support system. The use of consequential reasoning is then illustrated in an application designed to assist in cancer chemotherapy decisions. The result is a method that is sensitive to individual patient reactions to chemotherapy agents, permitting an individualized approach to therapy. Individualized drug therapy is becoming increasingly feasible due to advances made in the field of genomics. The system is structured so that new information can be incorporated easily. Although the application shown here is to chemotherapy, the general methodology can be used in any area in which the consequences should significantly influence the decision.

Oxygen transfer reactions by synthetic analogues of iron-bleomycin.

Synthetic analogues of the iron-bleomycins, namely [Fe(PMA)]2+ and [Fe(PMA)]+, have been studied as oxotransfer agents. Oxygen transfer has been observed using iodosobenzene (PhIO), hydrogen peroxide, and dioxygen as oxygen sources. The primary substrates were cis- and trans-stilbene. The products were determined to be cis- and trans-stilbene oxide, benzaldehyde, and deoxybenzoin. These products were recovered in ratios similar to those reported for the iron-bleomycins, albeit in lower yields. Iron complexes of simpler analogues are inactive as oxotransfer agents. This study provides further support that PMAH is an accurate model of the metal binding region of bleomycin.

Measurement of free radicals from smoke inhalation and oxygen exposure by spin trapping and ESR spectroscopy.

Research in smoke inhalation has established that free radicals are produced from gases released during combustion and these species impair lung function. Using spin traps and their adducts in an animal model free radicals were measured. Various hyperbaric oxygen regimens were tested in an attempt to attenuate pulmonary damage caused by free radical reactions. Our data demonstrated that persistent oxygen- and carbon-centered free radicals are detectable in intravascular fluids after smoke inhalation. The smoke inhalation model showed however, clearing of spin trap adducts one hour after smoke exposure. Other researchers have found that when 100% oxygen is given at 1 atmosphere absolute (ATA) for 1 h, free radicals were not detectable. However, oxygen given at 2.5 ATA does produce detectable free radicals. With continued exposure at this pressure, the levels of free radicals increase for up to 60 min. This study suggests that the level of free radical induced oxygen toxicity may be a function of oxygen pressure and duration of oxygen exposure.

Convergence of multi-modal sensory signals at thoracic interneurons of the escape system of the cockroach, Periplaneta americana.

Research on the escape system of the cockroach has focused upon the role of giant interneurons in conveying information on wind stimulation from the cerci located on the abdomen to motor control centers in the thoracic ganglia. In the thoracic ganglia the ventral giant interneurons connect to a population of interganglionic interneurons referred to as type A thoracic interneurons. In this paper we have tested the type A interneurons for additional sensory inputs in the absence of ventral giant interneuron activity. We find that the cells that receive ventral giant interneuron activity are also influenced by a variety of additional sensory inputs; wind mediated activity in a pathway that descends from the head, tactile inputs from several loci, auditory stimuli and light responses. Moreover, behavioral observations indicate that at least some of these activities can alter the escape movements. The results suggest that these interneurons serve as a site of convergence for numerous types of sensory activity. They further suggest that the escape system is capable of responding to directional wind information encoded in the ventral giant interneurons in the context of a wealth of additional information.

Radical-induced DNA damage by a synthetic analogue of copper(II)-bleomycin.

The capacity of free-radical formation and concomitant radical-induced DNA damage by [Cu(PMA)]X (X = ClO4-, BF4-), the first crystalline synthetic analogue of Cu(II)-BLM, have been studied. In phosphate buffer, [Cu(PMA)]+ can be reduced by thiols like DTT to a Cu(I) species that can be reoxidized with dioxygen. During oxygenation of the Cu(I) analogue, appreciable amounts of .OH radical are formed. This fact has been established by spin-trapping experiments. Effects of SOD and catalase as well as pH on the ESR signal of the spin adduct have identified a set of reactions that eventually leads to .OH radical formation by [Cu(PMA)]+. Interestingly, the same reaction scheme has been proposed earlier for Cu(II)-BLM. In the presence of DTT and dioxygen, [Cu(PMA)]+ inflicts significant damage to plasmid DNA. That the damage does not arise from iron contamination has been established. The DNA damage is hindered when SOD or catalase is present in the incubation mixture. Less strand scission is observed at higher pH. Modulation of DNA cleavage efficiency with systematic variations in DTT concentration indicates that the conflicting reports on the ability of Cu(II)-BLM to mediate in vitro DNA damage might have resulted from the different DTT concentrations used by different groups.