Threshold for repetitive activity for a slow stimulus ramp: a memory effect and its dependence on fluctuations

We have obtained new insights into the behavior of a class of excitable systems when a stimulus, or parameter, is slowly tuned through a threshold value. Such systems do not accommodate no matter how slowly a stimulus ramp is applied, and the stimulus value at onset of repetitive activity shows a curious, nonmonotonic dependence on ramp speed. (Jakobsson, E. and R. Guttman. Biophys. J. 1980. 31:293-298.) demonstrated this for squid axon and for the Hodgkin-Huxley (HH) model. Furthermore, they showed theoretically that for moderately slow ramps the threshold increases as the ramp speed decreases, but for much slower ramp speeds threshold decreases as the ramp speed decreases. This latter feature was found surprising and it was suggested that the HH model, and squid axon in low calcium, exhibits reverse accommodation. We have found that reverse accommodation reflects the influence of persistent random fluctuations, and is a feature of all such excitable systems. We have derived an analytic condition which yields an approximation for threshold in the case of a slow ramp when the effect of fluctuations are negligible. This condition predicts, and numerical calculations confirm, that the onset of oscillations occurs beyond the critical stimulus value which is predicted by treating the stimulus intensity as a static parameter, i.e., the dynamic aspect of a ramp leads to a delay in the onset. The condition further demonstrates a memory effect, i.e., firing threshold is dependent on the initial state of the system. For very slow ramps then, fluctuations diminish both the delay and memory effects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Estimates of regional work in the canine left ventricle

Assessment of the magnitude of regional myocardial work requires knowledge of regional fiber stress and fiber shortening. The theoretical development and experimental validation of a method is presented which used values of estimated active and passive fiber stress according to a fluid-fiber model, and measured fiber strain values. This enables the construction of regional stress-strain diagrams, a regional analog of the pressure-volume area model by Suga and co-investigators, which can be linked to regional oxygen consumption. In the left ventricle, either normally or asynchronously activated, the method yields reliable data on strain and active and passive fiber stress. The relation between estimated regional work and myocardial oxygen demand is in quantitative agreement with previously reported relations between global oxygen demand and measured pressure-volume area. During coronary artery occlusion, however, these values were less reliable, which might be due to inaqdequate knowledge of the (passive) material properties of the myocardium.     

In vivo activation of an omega-6 oxygenase in human skin

To test the hypothesis that an epidermal fatty acid oxygenase is activated in vivo under physiologic conditions, surface lipids from normal human skin were analyzed for oxygenase products. With high-performance liquid chromatography on reversed-phase and straight-phase chiral columns and gas-liquid chromatography/mass spectrometry, these lipids were found to contain free 13-hydroxyoctadeca-9Z,11E-dienoic acid and 9-hydroxyoctadeca-10E,12Z-dienoic acid. The 13-hydroxyoctadecadienoic acid was present as a stereoisomeric mixture, with an average S/R ratio of 2.2, and exceeded the concentration of 9-hydroxyoctadecadienoic acid by a factor of 2. These observations and others indicate that the 13-hydroxyoctadecadienoic acid was derived mostly from an omega-6 oxygenase (probably 15-lipoxygenase) which is activated in vivo in normal skin.     

The Australian Dominative Medical System: A Reflection of Social Relations in the Larger Society

This paper posits a working or tentative model of medical pluralism, a pattern in which multiple medical sub‐systems co‐exist, or what I term the Australian dominative medical system. I argue that whereas the Australian medical system with its various medical sub‐systems was pluralistic, that is more or less on an equal footing, in the nineteenth century, by the early twentieth century it became a plural or dominative one in the sense that biomedicine came to clearly dominate other medical sub‐systems. This paper also explores the growing interest of biomedicine and the Australian Government in complementary medicine to which Australians have increasingly turned over the course of the past three decades or so.     

Single-Batch Production of Recombinant Human Polyclonal Antibodies

We have previously described the development and implementation of a strategy for production of recombinant polyclonal antibodies (rpAb) in single batches employing CHO cells generated by site-specific integration, the Sympress^TM I technology. The Sympress^TM I technology is implemented at industrial scale, supporting a phase II clinical development program. Production of recombinant proteins by site-specific integration, which is based on incorporation of a single copy of the gene of interest, makes the Sympress^TM I technology best suited to support niche indications. To improve titers while maintaining a cost-efficient, highly reproducible single-batch manufacturing mode, we have evaluated a number of different approaches. The most successful results were obtained using random integration in a new producer cell termed ECHO, a CHO DG44 cell derivative engineered for improved productivity at Symphogen. This new expression process is termed the Sympress^TM II technology. Here we describe proof-of-principle data demonstrating the feasibility of the Sympress^TM II technology for single-batch rpAb manufacturing using two model systems each composed of six target-specific antibodies. The compositional stability and the batch-to-batch reproducibility of rpAb produced by the ECHO cells were at least as good as observed previously using site-specific integration technology. Furthermore, the new process had a significant titer increase.