Antiasthmatic activity of the second-generation phosphodiesterase 4 (PDE4) inhibitor SB 207499 (Ariflo) in the guinea pig

We evaluated the airway activity of the novel phosphodiesterase type 4 inhibitor SB 207499 [Ariflo; c-4-cyano-4-(3-cyclopentyloxy-4-methoxyp henyl-r-1-cyclohexane carboxylic acid)], in the guinea pig. Ovalbumin (OA)-induced contractions of guinea pig isolated tracheal strips were inhibited by SB 207499 with an EC50 of 1 microM but had little or no effect on exogenous agonist-induced contraction, which suggests that its effect on OA-induced contraction in vitro is primarily due to inhibition of mediator release from mast cells. In anesthetized guinea pigs, SB 207499 inhibited OA-induced bronchoconstriction with i.v. and p.o. ID50 values of 1.7 and 17 mg/kg, respectively. At 1, 3 and 6 hr after SB 207499 (30 mg/kg p.o.), OA-induced bronchospasm was inhibited by 92%, 70% and 58%, respectively, corresponding to elevated plasma concentrations of 1.62 +/- 0.19, 1.65 +/- 0.29 and 0. 93 +/- 0.24 microg/ml, respectively, of SB 207499. SB 207499 also inhibited house dust mite-induced bronchoconstriction (ID50 = 0.9 mg/kg i.v. and 8.9 mg/kg p.o.). In contrast to its lack of bronchorelaxant activity in vitro, SB 207499 inhibited bronchospasm induced by i.v. leukotriene D4 (LTD4) [ID50 = 3 mg/kg i.v.]. The bronchorelaxant effect of i.v.-administered SB 207499 was at least additive with that of salbutamol in reversing infused histamine-enhanced airway tone, but it did not alter base line or enhance salbutamol-induced cardiovascular effects. In conscious guinea pigs, SB 207499 (10 or 30 mg/kg p.o.), 1 hr before antigen or LTD4 challenge, markedly reduced bronchospasm and subsequent eosinophil influx as measured by bronchoalveolar lavage 24 hr after provocation. SB 207499 administered after OA or LTD4 challenge also reduced airway eosinophilia measured at 24 hr after OA challenge or 96 hr after LTD4 challenge. These results, coupled with the broad anti-inflammatory activity of SB 207499 previously described (Barnett et al., 1998), suggest that SB 207499 will be useful in the treatment of asthma and other inflammatory disorders.     

Integrated MRI assessment of regional function and perfusion in canine myocardial infarction

A single integrated examination using regional measurements of perfusion from contrast-enhanced MRI and three-dimensional (3D) strain from tissue-tagged MRI was developed to differentiate infarcted myocardium from adjacent tissue with functional abnormalities. Ten dogs were studied at baseline and 10 days after a 2-hour occlusion of the left anterior descending coronary artery (LAD). Strain was determined using a 3D finite element model. Two-dimensional measurements of hypoenhancing regions were highly correlated with myocardial viability (r = 0.96). Signal intensity versus time curves obtained from contrast-enhanced MRI were used for quantitative perfusion analysis. The remote and adjacent noninfarcted tissue of the dogs with LAD occlusion, as well as the infarcted tissue, exhibited abnormal deformation patterns as compared to normal dogs (positive predictive value (PPV) of strain determination of infarction = 66%). Integration of contrast-enhanced MRI results with 3D strain analysis enabled the delineation of the myocardial infarction (PPV = 100%) from functionally compromised myocardium. This integrated cardiac examination shows promise for noninvasive serial assessment of potentially jeopardized noninfarcted myocardium to study the process of infarct remodeling and expansion.     

A simplified modeling approach using microbial growth kinetics for predicting exposure concentrations of organic chemicals in treated wastewater effluents

Various mathematical relationships have been used to assess exposure concentrations of organic chemicals when emissions occur via wastewater treatment. These relationships range from a simple removal factor calculation to more sophisticated approaches using kinetic based mathematical models. While these existing approaches have been used by decision makers to screen new chemicals for exposure assessments, they all have limitations in the predictive capabilities. Thus, a simplified modeling approach grounded in sound scientific fundamentals that utilizes relatively easy to obtain input parameters is needed. In this paper a simplified modeling approach that utilizes microbial growth kinetics was developed for predicting effluent concentrations in secondary biological wastewater treatment systems. Receiving water predicted exposure concentrations (PEC) are assessed by using a dilution factor. One advantage of this approach is that it allows for wastewater treatment plant effluent concentrations, and therefore receiving water exposure levels, to be predicted with a minimum amount of experimental data. It also provides quantitative data that can be used to assess the relative biodegradability of different chemicals for use in regulatory and risk assessment activities.     

Sclerotome distribution of melorheostosis and multicentric fibromatosis

A case of melorheostosis affecting the C7 sclerotome is described, in association with synchronous multicentric fibromatosis. The foci of fibromatosis also affected the C7 sclerotome, suggesting a similar underlying pathogenesis for both diseases.     

Complexity, communication between cells, and identifying the functional components of living systems: some observations

The concept of 'complexity' has become very important in theoretical biology. It is a many faceted concept and too new and ill defined to have a universally accepted meaning. This review examines the development of this concept from the point of view of its usefulness as a criteria for the study of living systems to see what it has to offer as a new approach. In particular, one definition of complexity has been put forth which has the necessary precision and rigor to be considered as a useful categorization of systems, especially as it pertains to those we call 'living'. This definition, due to Robert Rosen, has been developed in a number of works and involves some deep new concepts about the way we view systems. In particular, it focuses on the way we view the world and actually practice science through the use of the modelling relation. This mathematical object models the process by which we assign meaning to the world we perceive. By using the modelling relation, it is possible to identify the subjective nature of our practices and deal with this issue explicitly. By so doing, it becomes clear that our notion of complexity and especially its most popular manifestations, is in large part a product of the historical processes which lead to the present state of scientific epistemology. In particular, it is a reaction to the reductionist/mechanistic view of nature which can be termed the 'Newtonian Paradigm'. This approach to epistemology has dominated for so that its use as a model has become implicit in most of what we do in and out of science. The alternative to this approach is examined and related to the special definition of complexity given by Rosen. Some historical examples are used to emphasize the dependence of our view of what is complex in a popular sense on the ever changing state of our knowledge. The role of some popular concepts such as chaotic dynamics are examined in this context. The fields of artificial life and related areas are also viewed from the perspective of this rigorous view of complexity and found lacking. The notion that in some way life exists 'at the edge of chaos' is examined from the perspective of the second law of thermodynamics given by Schneider and Kay. Finally, the casual elements in complex systems are explored in relation to complexity. Rosen has shown that a clear difference in causal relations exists between complex and simple systems and that this difference leads to a uniquely useful definition of what we mean by 'living'. Rosen makes it very clear that the class of systems which are complex is a much larger class than those which we call living. For that reason, the focus of this review will be on complexity as a stepping stone towards the deeper question of what makes a system alive.