The ability of the liver to simultaneously carry out multiple functions is dependent on the metabolic heterogeneity of hepatocytes spatially located within a liver lobule spanning from the portal triad to the central vein. This complex zonal architecture of the liver, however, makes accurate
in vitro
modeling a challenge and often standard culture systems assume a homogenous model which may lead to inaccurate translatability of results. Here, we use a combination of mathematical modeling and experimental data to demonstrate a readily constructible
in vitro
flow system capable of liver zonation in primary rat hepatocytes. We show the differential expression of zonation markers, enhanced functionality when compared to standard static cultures and zone-specific metabolism and cell damage in the presence of paracetamol, a known zone-specific toxin. This type of advanced system provides a more in-depth and essential understanding of liver physiology and pathophysiology as well as the accurate evaluation of pharmacological interventions at a zone-specific level.
Tolerance of additional external resistance to inspiration has been investigated in a group of coalworkers older than 45 years. Peak inspiratory pressure, external respiratory work rate, ventilation, and gas exchange were measured, during periods with and without one of four inspiratory resistances, on 41 subjects walking on a treadmill. Minute volume was reduced, breathing frequency was unchanged and oxygen uptake and carbon dioxide elimination were reduced by the presence of resistance. It was established that, at the workload studied, older men were able to tolerate inspiratory resistance to at least the same extent as younger men, when the respiratory work was expressed in terms of unit ventilation. It is suggested that the acceptable level of breathing resistance established for younger men can also be applied to older workers.An acceptable level of inspiratory resistance for subjects used to wearing breathing apparatus has recently been established, following investigation of the tolerance limits of 158 coalworkers (Bentley et al., 1973). These men were all under 45 years of age, either full-time or part-time mine-rescue workers, with above-average physical fitness. Previous investigators (Silverman et al., 1943;1945) In a previous paper (Bentley et al., 1973) a standard was suggested such that 90% of a population, breathing through apparatus with low expiratory resistance, would experience no discomfort if the mean inspiratory work rate did not exceed 1-37 J l-1. The results of a similar study conducted on a group of older men are discussed in this paper. The effects of resistance on ventilation and gas exchange are also described and compared with a control period.
MethodsThe experimental apparatus was similar to that described elsewhere (Bentley et al., 1973). In addition a length of wide-bore, low-resistance tubing was connected to the expiratory valve of the mouthpiece assembly, so that expired air passed through a 10 litre mixing bottle. A continuous sample was drawn from this bottle through a drying agent to a fast-response oxygen analyser (Beckman Model E2 rapid-response analyser) and a katharometer (Gow-Mac Model 20-100) linked to a potentiometric chart recorder
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