Abstract-In patients with chronic renal failure (CRF), atherosclerosis is a major cause of cardiovascular morbidity and mortality. Generally, atherosclerosis has been associated with a reduced bioavailability of nitric oxide (NO). Experimental studies have indicated the presence of enhanced NO degradation by reactive oxygen species as well as decreased NO production as possible causes for this reduced NO bioavailability. So far, the question whether or not NO production is impaired in patients with CRF has never been investigated. Therefore, we measured whole body NO production in 7 patients with CRF, and in 7 matched healthy subjects. To assess the relative importance of a dysfunction of NO synthase (NOS), we compared the NO production of these patients to that of 2 other groups known to have endothelial dysfunction, ie, 7 patients with familial hypercholesterolemia (FH) who did not yet have signs of clinical cardiovascular disease (all nonsmokers), and 5 cigarette smokers. These groups were also compared with 7 nonsmoking, age-matched healthy subjects. Whole body NO production, determined as in vivo arginine-to-citrulline conversion, was assessed by giving an intravenous infusion of [ 15 N 2 ]-arginine as a substrate for NOS and measuring isotopic plasma enrichment of [15 N]-citrulline by LC-MS. NO production in the CRF patients (0.13Ϯ0.02 mol ⅐ kg -1 ⅐ h -1 ) was significantly lower (PϽ0.05) than in the corresponding control group (0.23Ϯ0.09 mol ⅐ kg -1 ⅐ h -1 ). NO production also tended to be lower in the FH patients (0.16Ϯ0.04 mol ⅐ kg -1 ⅐ h -1 ), but the difference with the corresponding control group did not reach significance (0.22Ϯ0.06 mol ⅐ kg -1 ⅐ h -1 ). In the group of smokers, NO production was similar to that in nonsmokers (0.22Ϯ0.09 mol ⅐ kg -1 ⅐ h -1 ).In conclusion, it is demonstrated for the first time that basal whole body NO production is reduced in patients with CRF. This finding implies that therapeutic interventions to endothelial dysfunction in these patients should be primarily directed toward improvement of NO production. The finding of only a tendency toward reduction of NO production in patients with FH and the absence of a reduction in cigarette smokers suggests that other mechanisms such as enhanced NO degradation may be involved in the decrease of NO bioavailability in these groups. (Arterioscler Thromb Vasc Biol. 1999;19:1168-1172.) Key Words: nitric oxide Ⅲ chronic renal failure Ⅲ atherosclerosis Ⅲ endothelium Ⅲ hypercholesterolemia P remature atherosclerosis is one of the primary causes of morbidity and mortality in patients with chronic renal insufficiency. 1 Over the last decade endothelial dysfunction has been identified as an early mediator in this process. Nitric oxide (NO) is one of the main factors involved in the antiatherosclerotic effects of the endothelium, 2 and chronic renal failure (CRF) has been associated with impaired NO bioavailability in the absence of concomitant risk factors, [3][4][5] even in children. 6,7 However, the finding of a reduced NO bioavailabi...

Temporal preparation is the cognitive function that takes place when anticipating future events. This is commonly considered to involve a process that maximizes preparation at time points that yield a high hazard. However, despite their prominence in the literature, hazard-based theories fail to explain the full range of empirical preparation phenomena. Here, we present the formalized multiple trace theory of temporal preparation (fMTP), an integrative model which develops the alternative perspective that temporal preparation results from associative learning. fMTP builds on established computational principles from the domains of interval timing, motor planning, and associative memory. In fMTP, temporal preparation results from associative learning between a representation of time on the one hand and inhibitory and activating motor units on the other hand. Simulations demonstrate that fMTP can explain phenomena across a range of time scales, from sequential effects operating on a time scale of seconds to long-term memory effects occurring over weeks. We contrast fMTP with models that rely on the hazard function and show that fMTP’s learning mechanisms are essential to capture the full range of empirical effects. In a critical experiment using a Gaussian distribution of foreperiods, we show the data to be consistent with fMTP’s predictions and to deviate from the hazard function. Additionally, we demonstrate how changing fMTP’s parameters can account for participant-to-participant variations in preparation. In sum, with fMTP we put forward a unifying computational framework that explains a family of phenomena in temporal preparation that cannot be jointly explained by conventional theoretical frameworks.

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