Brain hypoxia preferentially stimulates genioglossal EMG responses to CO2

Although the dominant respiratory response to hypoxia is stimulation of breathing via the peripheral chemoreflex, brain hypoxia may inhibit respiration. We studied the effects of two levels of brain hypoxia without carotid body stimulation, produced by inhalation of CO, on ventilatory (VI) and genioglossal (EMGgg) and diaphragmatic (EMGdi) responses to CO2 rebreathing in awake, unanesthetized goats. Neither delta VI/delta PCO2 nor VI at a PCO2 of 60 Torr was significantly different between the three conditions studied (0%, 25%, and 50% carboxyhemoglobin, HbCO). There were also no significant changes in delta EMGdi/delta PCO2 or EMGdi at a PCO2 of 60 Torr during progressive brain hypoxia. In contrast, delta EMGgg/delta PCO2 and EMGgg at a PCO2 of 60 Torr were significantly increased at 50% HbCO compared with either normoxia or 25% HbCO (P less than 0.05). The PCO2 threshold at which inspiratory EMGgg appeared was also decreased at 50% HbCO (45.6 +/- 2.6 Torr) compared with normoxia (55.0 +/- 1.4 Torr, P less than 0.02) or 25% HbCO (53.4 +/- 1.6 Torr, P less than 0.02). We conclude that moderate brain hypoxia (50% HbCO) in awake, unanesthetized animals results in disproportionate augmentation of EMGgg relative to EMGdi during CO2 rebreathing. This finding is most likely due to hypoxic cortical depression with consequent withdrawal of tonic inhibition of hypoglossal inspiratory activity.     

Asymmetric metabolic N-oxidation of N-ethyl-N-methylaniline by purified flavin-containing monooxygenase

The prochiral tertiary amine N-ethyl-N-methylaniline (EMA) is known to be metabolically N-oxygenated in vitro with microsomal preparations. This biotransformation is thought to be mediated predominantly by the flavin-containing monooxygenase (FMO) enzyme system. Microsomal N-oxygenation of EMA is known to be stereoselective and varies between species. In order to further characterise this metabolic transformation, we have examined the in vitro metabolism of EMA using purified porcine hepatic FMO. Following incubation of EMA with purified FMO, EMA N-oxide, the only metabolite detected, was found to be produced stereoselectively [ratio (?)-(S):(+)-(R), ca. 4:1]. The enantiomeric ratio of the N-oxide product did not change markedly with respect to time, enzyme or substrate concentration. Determination of the kinetics of formation of the N-oxide indicated a single affinity for the prochiral substrate with differential rates of formation of the enantiomers. The extent of EMA N-oxide formation was shown to be affected by activators and inhibitors of FMO and pH, but its stereoselectively was unaltered. © 1994 Wiley-Liss, Inc.     

Prevalence of gall stones at necropsy in nine British towns: a collaborative study.

A prospective study of the prevalence of gall stones at necropsy in nine towns in England and Wales showed considerable geographical variations. The age- and sex-standardised prevalence ranged from 20.6% in Ipswich to 9.2% in Wakefield. The distribution of gall stones differed from that of all-cause mortality and was negatively correlated with that of mortality from ischaemic heart disease. Socioeconomic influences related to affluence do not appear to be major determinants of the distribution of gall stones.     

Demonstration of the chiral inversion of ibuprofen by Verticillium lecanii in non-growing cultures

Racemic ibuprofen has previously been shown to undergo metabolism by Verticillium lecanii to yield (S)-2-[4-(2-hydroxy-2-methylpropyl)phenyl] propionic acid which is enriched in the (S)-enantiomer. However, it had not been possible to elucidate whether ibuprofen or the metabolite was inverted. This paper describes the incubation of ibuprofen in non-growing cultures of V. lecanii , the results of which indicate that racemic ibuprofen is converted into a 70 : 30 (S : R) enantiomeric mixture after 6 d incubation in the absence of any metabolism. This suggests that V. lecanii could be a useful model for the investigation of the mechanism of mammalian chiral inversion of iburprofen.