Cysteine Conjugate beta-Lyase-Dependent Metabolism of Compound A (2-[fluoromethoxy]-1,1,3,3,3-pentafluoro-1-propene) in Human Subjects Anesthetized with Sevoflurane and in Rats Given Compound A

Background: Sevoflurane undergoes Baralyme- or soda lime-catalyzed degradation in the anesthesia circuit to yield compound A (2-[fluoromethoxy]-1,1,3,3,3-pentafluoro-1-propene), which is nephrotoxic in rats and undergoes metabolism via the cysteine conjugate beta-lyase pathway in those animals. The objective of these experiments was to test the hypothesis that compound A undergoes beta-lyase-dependent metabolism in humans.

Methods: Human volunteers were anesthetized with sevoflurane (1.25 minimum alveolar concentration, 3%, 2 l/min, 8 h) and thereby exposed to compound A. Urine was collected at 24-h intervals for 72 h after anesthesia. Rats, which served as a positive control, were given compound A intraperitoneally, and urine was collected for 24 h afterward. Human and rat urine samples were analyzed by19 F nuclear magnetic resonance spectroscopy and gas chromatography-mass spectrometry for the presence of compound A metabolites.

Results: Analysis of human and rat urine showed the presence of the compound A metabolites [S-[2-(fluoromethoxy)-1,1,3,3,3-pentafluoropropyl]-N-acetyl-L-cysteine, (E)- and (Z)-S-[2-(fluoromethoxy)-1,3,3,3-tetrafluoro-1-propenyl]-N-acetyl-L-cyst eine, 2-(fluoromethoxy)-3,3,3-trifluoropropanoic acid, 3,3,3-trifluorolactic acid, and inorganic fluoride. The presence of 2-(fluoromethoxy)-3,3,3-trifluoropropanoic acid and 3,3,3-trifluorolactic acid in human urine was confirmed by gas chromatography-mass spectrometry.     

Mutations in the retinal guanylate cyclase (RETGC-1) gene in dominant cone-rod dystrophy

The dominant cone-rod dystrophy gene CORD6 has previously been mapped to within an 8 cM interval on chromosome 17p12-p13. The retinal- specific guanylate cyclase gene (RETGC-1), which maps to within this genetic interval and previously was implicated in Leber's congenital amaurosis, was screened for mutations within this family and in a panel of small families and individuals with various cone and cone- rod dystrophy phenotypes. A missense mutation (E837D) was identified in affected members of the CORD6 family, as well as a second missense mutation (R838C) in three other families with dominant cone-rod dystrophy. RETGC-1 is only the fourth gene to be implicated in cone-rod dystrophy and this is the first report of dominant mutations in this gene.      

Drinking spout orifice size affects licking behavior in inbred mice

Using a lickometer, we assessed the effect of drinking spout orifice size on the licking behavior of inbred mice [C57BL/6J, SWR/J, 129P3/J and DBA/2J]. Animals licked from drinking spout sipper tubes that had what were defined as either a large (2.7 mm) or a small (1.5 mm) orifice. Mice took approximately twice as many licks from a stationary single small orifice drinking spout than when licking from a spout with a large orifice during separate 30-min sessions. However, their total intake volume was approximately the same. We calculated that mice received a mean of 0.55 muL per lick from the drinking tubes with a small orifice and a mean of 1.15 muL per lick from the drinking tubes with a large orifice. Thus, the animals appear to have regulated their fluid intake by proportionally adjusting their licking as a function of the lick volume. On average, this regulation occurred through modulation of the size of licking bursts and not their frequency. However, strain differences in compensation strategy were observed. When licking was restricted to a series of 5-s trials in a 30-min brief access test session, the smaller orifice size increased the range of responsiveness that was expressed. Mice increased their average licks per trial by 20% and took 60% more trials when licking from a spout with a small orifice. Interestingly, when the orifice size was quasi-randomly varied within a brief access session, licking was greater from large orifice drinking spouts, suggesting that water delivered from the two orifice sizes differs in its reinforcement efficacy. These findings demonstrate that drinking spout orifice size can significantly influence experimental outcomes in licking tests involving mice and care should be taken in controlling this variable in testing the effects of taste or other factors on ingestive behavior.     

Medical outcome in asthmatic patients: effects of airways hyperreactivity and symptom-focused anxiety.

Hypotheses about medical outcome in asthma, indexed by rates of rehospitalization within 6 months after discharge from long-term intensive care, were evaluated. Predictions for rehospitalization were based on the levels of airways hyperreactivity, indexed by inhalation challenges with histamine or methacholine, and levels of anxiety focused upon and concurrent with periods of asthmatic distress, indexed by Panic-Fear symptomatology. Results indicated that, although some prediction could be made on the basis of levels of anxiety and airways hyperreactivity alone, the best predictions resulted from the combined effects of these factors. Almost half of the patients who had highly hyperreactive airways and a tendency to disregard symptoms of breathing difficulty were rehospitalized. By comparison, none of the patients who had less hyperreactive airways and a tendency to be vigilant about their symptoms were rehospitalized. The hypotheses and results are discussed with respect to symptom-focused and general, illness-dependent types of anxiety which have different effects upon medical outcome in chronic asthma. The results have implications for the application of anxiety-reducing forms of intervention in asthma.     

Thiamine transport in the central nervous system.

Total thiamine (free thiamine and thiamine phosphates) transport into the cerebrospinal fluid (CSF), brain, and choroid plexus and out of the CSF was measured in rabbits. In vivo, total thiamine transport into CSF, choroid plexus, and brain was saturable. At the normal plasma total thiamine concentration, less than 5% of total thiamine entry into CSF, choroid plexus, and brain was by simple diffusion. The relative turnovers of total thiamine in choroid plexus, whole brain, and CSF were 5, 2, and 14% per h, respectively, when measured by the penetration of 35S-labeled thiamine injected into blood. From the CSF, clearance of [35S]thiamine relative to mannitol was not saturable after the intraventricular injection of various concentrations of thiamine. However, a portion of the [35S]thiamine cleared from the CSF entered brain by a saturable mechanism. In vitro, choroid plexuses, isolated from rabbits and incubated in artificial CSF, accumulated [35S]thiamine against a concentration gradient by an active saturable process that did not depend on pyrophosphorylation of the [35S]thiamine. The [35S]thiamine accumulated within the choroid plexus in vitro was readily released. These results were interpreted as showing that the entry of total thiamine into the brain and CSF from blood is regulated by a saturable transport system, and that the locus of this system may be, in part, in the choroid plexus.     

Resistance exercise training and the orthostatic response

Resistance exercise has been suggested to increase blood volume, increase the sensitivity of the carotid baroreceptor cardiac reflex response (BARO), and decrease leg compliance, all factors that are expected to improve orthostatic tolerance. To further test these hypotheses, cardiovascular responses to standing and to pre-syncopal limited lower body negative pressure (LBNP) were measured in two groups of sedentary men before and after a 12-week period of either exercise (n = 10) or no exercise (control, n = 9). Resistance exercise training consisted of nine isotonic exercises, four sets of each, 3 days per week, stressing all major muscle groups. After exercise training, leg muscle volumes increased (P?P = 0.00) by 2.0 (0.5)?kg, leg compliance and BARO were not significantly altered, and the maximal LBNP tolerated without pre-syncope was not significantly different. Supine resting heart rate was reduced (P = 0.03) without attenuating the heart rate or blood pressure responses during the stand test or LBNP. Also, blood volume (¹²⁵I and ⁵¹Cr) and red cell mass were increased (P?相似文献