Event-related brain potentials during the visuomotor mental rotation task: The contingent negative variation scales to angle of rotation.

Perceptual judgments about the angular disparity of a character from its standard upright (i.e., mental rotation task) result in a concurrent increase in reaction time (RT) and modulation of the amplitude of the P300 event-related brain potential (ERP). It has therefore been proposed that the P300 represents the neural processes associated with a visual rotation. In turn, the visuomotor mental rotation (VMR) task requires reaching to a location that deviates from a target by a predetermined angle. Although the VMR task exhibits a linear increase in RT with increasing oblique angles of rotation, work has not examined whether the task is supported via a visual rotation analogous to its mental rotation task counterpart. This represents a notable issue because seminal work involving non-human primates has ascribed VMR performance to the motor-related rotation of directionally tuned neurons in the primary motor cortex. Here we examined the concurrent behavioral and ERP characteristics of a standard reaching task and VMR tasks of 35°, 70°, and 105° of rotation. Results showed that the P300 amplitude was larger for the standard compared to each VMR task--an effect independent of the angle of rotation. In turn, the amplitude of the contingent negative variation (CNV)--an ERP related to cognitive and visuomotor integration for movement preparation--was systematically modulated with angle of rotation. Thus, we propose that the CNV represents an ERP correlate related to the cognitive and/or visuomotor transformation demands of increasing the angular separation between a stimulus and a movement goal.

Effect of halogenated vinyl cysteine conjugates on renal tubular active transport.

Addition of halogenated vinyl cysteine conjugates to isolated rabbit kidney tubule suspensions resulted in a decrease in the active transport of para-aminohippuric acid (PAH) and tetraethylammonium bromide (TEA). At 10(-5) M vinyl cysteine conjugate, tubule to medium accumulation ratios (T/M) were similar to those of controls while at 10(-3) M the T/M values decreased to 1, indicating complete inhibition of active accumulation of PAH or TEA. The decreased active transport was not caused by inhibition of mitochondrial oxidation since incubations in the presence of 10(-3) M halogenated vinyl cysteine did not inhibit tubule O2 utilization or production of 14CO2 from [14C]glucose or [14C]succinate. A mechanism is proposed whereby toxicity may result from covalent binding of an active intermediate, produced by enzyme cleavage, to membrane associated nucleophilic groups thereby decreasing active transport.

Production of DNA single strand breaks in rabbit renal tissue after exposure to 1,2-dichlorovinylcysteine.

S-(trans-1,2-dichlorovinyl)-L-cysteine (DCVC) is a recognized nephrotoxin. To investigate the genotoxic effects of DCVC on the kidney, DNA strand breaks were measured as an indicator of DCVC induced damage. To ascertain if bioactivation of DCVC occurred in the kidney, 3 experimental systems were used: in vivo; isolated perfused kidneys; and isolated proximal tubules of albino male rabbits. A dose-dependent increase in strand breaks in the kidney tubular DNA occurred after in vivo dosing with 5-100 mg/kg DCVC and after in vitro exposure to 10(-5)-10(-2) M DCVC. These results demonstrate the genotoxic effect of this compound on renal tissue.

The formation and biotransformation of cysteine conjugates of halogenated ethylenes by rabbit renal tubules.

The nephrotoxicity of chlorotrifluoroethylene ( CTFE ) was examined using isolated rabbit renal tubules suspensions. Exposure of the tubules to CTFE resulted in consumption of CTFE , formation of a glutathione conjugate and inhibition of active organic acid transport. Synthetic cysteine, N-acetylcysteine or glutathione conjugates of CTFE inhibited transport indicating S-conjugation as a possible toxic pathway. 1,2-dichlorovinyl glutathione ( DCVG ), a model synthetic glutathione conjugate, was used to examine the degradation and toxicity of these conjugates. DCVG inhibited rabbit renal tubule transport in vivo and in vitro. The DCVG was found to be degraded with the evolution of glutamine and glycine to produce the ultimate nephro-toxicant, dichlorovinyl cysteine. Dichlorovinyl cysteine is then bioactivated with the release of ammonia. This sequential degradation explains the latency of DCVG -induced renal transport inhibition relative to dichlorovinyl cysteine. It is now evident that certain halogenated ethylenes are capable of being biotransformed to glutathione conjugates in the kidney with their subsequent hydrolysis to nephrotoxic cysteine conjugates.

What do I do now? An electroencephalographic investigation of the explore/exploit dilemma.

To maximize reward, we are faced with the dilemma of having to balance the exploration of new response options and the exploitation of previous choices. Here, we sought to determine if the event-related brain potential (ERP) in the P300 time range is sensitive to decisions to explore or exploit within the context of a sequential risk-taking task. Specifically, the task we used required participants to continually explore their options-whether they should "push their luck" and keep gambling or "take the money and run" and collect their winnings. Our behavioral analysis yielded two distinct distributions of response times: a larger group of short-decision times and a smaller group of long-decision times. Interestingly, these data suggest that participants adopted one of two modes of control on any given trial: a mode where they quickly decided to keep gambling (i.e. exploit), and a mode where they deliberated whether to the take the money they had already won or continue gambling (i.e. explore). Importantly, we found that the amplitude of the ERP in the P300 time range was larger for explorative decisions than for exploitative decisions and, further, was correlated with decision time. Our results are consistent with a recent theoretical account that links changes in ERP amplitude in the P300 time range with phasic activity of the locus coeruleus-norepinephrine system and decisions to engage in exploratory behavior.

Regulation of a S(trans-1,2-dichlorovinyl)-L-cysteine-induced renal tubular toxicity by glutathione.

The nephrotoxin S-(1,2-dichlorovinyl)-L-cysteine (DCVC) is cleaved in the renal tubules to produce a reactive electrophilic intermediate. If this intermediate is responsible for the toxicity, addition of the nucleophilic scavenger glutathione (GSH) should decrease toxicity, and depletion of tubular GSH should enhance toxicity. GSH was added to isolated rabbit renal tubules simultaneously with, 15 min before, and 15 min after the addition of DCVC. The active accumulation of the organic anion para-aminohippuric acid (PAH) and organic cation tetraethylammonium bromide (TEA) was used as an index of renal toxicity. Incubation of renal tubules with 0.01-1 mM DCVC for 15 min decreased active transport, with complete inhibition at 1 mM. This was accompanied by a 50% decrease in non-protein sulfhydryl concentration. The addition of GSH (6 mM) simultaneously with DCVC completely prevented any decrease in active transport. The addition of GSH (6 mM) to tubules in which active transport was inhibited by DCVC reversed the inhibition to 80% of control. Similar enhancement of active transport occurred when tubules isolated 1 h after in vivo exposure to DCVC at 20-100 mg kg-1 were incubated with GSH (6 mM). Preincubation of renal tubules with GSH (5-15 mM) made them more refractory to the DCVC-induced decreased PAH and TEA transport. The inhibition of active transport by DCVC is enhanced if the tubular non-protein sulfhydryl is first lowered by diethyl maleate or glycidol. Thus, the tubular GSH concentration appears to be an integral component in regulating the alterations in active transport caused by DCVC.

Correlation of the in vivo and in vitro renal toxicity of S-(1,2-dichlorovinyl)-L-cysteine.

The major site at which vinyl cysteine conjugates exert nephrotoxicity is the proximal tubule. Since this is the site of all active anion and cation transport, tubule transport integrity was used to assess nephrotoxicity. Tubules were isolated from young rabbits to study the in vivo and in vitro nephrotoxicity of the conjugate, dichlorovinyl cysteine (DCVC). In vivo exposure to DCVC caused necrosis in the pars recta region of the proximal tubules (20-100 mg/kg ip) and a dose-dependent decrease in tubular active transport. Addition of DCVC to the perfused kidney and tubule suspensions resulted in similar decreases in tubular organic ion transport. At 0.01 mM DCVC, transport was similar to controls while 1 mM DCVC completely inhibited active accumulation of the organic ions. Thus kidney tubule active transport is similarly inhibited in vivo and in vitro by DCVC indicating that bioactivation of DCVC and inhibition of active transport occur directly in the renal tubule.

Olestra, a nonabsorbed, noncaloric replacement for dietary fat: a review.

Olestra has been shown to be safe for its intended use by extensive testing in animals and in humans. It is not digested or absorbed and has no effect on the structure or physiology of the GI tract, the only organ of the body that it contacts. Olestra can interfere with the absorption of other lipophilic substances from the GI tract. The interference occurs because a portion of those molecules that are sufficiently lipophilic partition into the nonabsorbed olestra and is carried out of the body. Whether olestra will interfere with the absorption of a specific molecule can be predicted from the octanol-water partition coefficient of the molecule, a parameter that can be measured or calculated from a knowledge of the structure of the molecule. Olestra does not affect the absorption or efficacy of oral drugs because, in general, they are not sufficiently lipophilic to partition into the olestra. Olestra does not affect the absorption of water-soluble micronutrients or the absorption and utilization of macronutrients. Olestra can reduce the absorption of the fat-soluble vitamins when olestra foods and the vitamins are coingested. These effects can be offset by adding specific amounts of the vitamins to foods made with olestra. Other than the carotenoids and vitamins A and E, olestra does not affect the absorption of potentially beneficial components of fruits and vegetables. The effects on the vitamins can be offset by adding the vitamins to olestra foods. The reduction in the absorption of carotenoids will be less than 6-10% when olestra snacks are eaten under free-living dietary patterns. Any effect this reduction has on vitamin A status can be offset by addition of vitamin A to the foods. The absorption of flavonoids, polyphenols, and most other phytochemicals in fruits and vegetables, which have been shown to provide beneficial health effects, will not be affected by olestra because they are not sufficiently lipophilic. Individuals consuming large quantities of olestra may experience mild or moderate common GI symptoms such as loose or soft stools, gas, or nausea, symptoms similar to those experienced with certain other foods or changed dietary habits. When olestra snack foods are eaten under free-living dietary patterns, the symptoms are not different from those experienced when eating full-fat snack products, in either incidence or severity. When they are experienced, the symptoms resolve in 1-2 days, but may recur. They do not worsen with continued or increased olestra consumption and pose no health risk to the consumer. Olestra products will carry an information label alerting consumers to the possibility of GI symptoms. Olestra foods provide an additional option to those individuals who want or need to lower their total energy intake and body weight. These individuals will find it easier to change dietary habits and to maintain healthful nutritional practices when they use olestra foods. For those who want or need to reduce fat intake but not lose weight, olestra foods can reduce fat intake without affecting energy. Because olestra foods have taste and other organoleptic properties that are similar to those of full-fat foods, individuals will find it easier to switch to low-fat diets.

In vivo and in vitro nephrotoxicity of the cysteine conjugate of hexachlorobutadiene.

Hexachlorobutadiene (HCBD), a renal toxin and carcinogen, is thought to require bioactivation to exert toxicity. The chemically synthesized cysteine conjugate of structurally similar halogenated hydrocarbons, trichloroethylene, chlorotrifluoroethylene, and chlorodifluoroethylene, have been shown to be nephrotoxic. Hence the cysteine conjugate of HCBD, S-pentachlorobuta-1,3-dienyl cysteine (PCBC), was assessed for potential nephrotoxicity. Active acid and base transport in isolated rabbit renal tubules was used to screen nephrotoxicity. A dose-dependent decrease in acid and base transport was observed after incubation with PCBC. At 10(-5) M PCBC transport was similar to that in controls, while at 10(-3) M PCBC completely inhibited active transport. In addition, in vivo exposure of Swiss-Webster male mice caused dose-dependent damage in the pars recta region of the proximal tubules (5-25 mg/kg ip). Genotoxicity in renal tissue was studied by using alkaline elution to detect DNA single-strand breaks and total cross-links. No DNA single-strand breaks were observed in isolated rabbit renal tubules after exposure to 10(-3) to 10(-5) M PCBC. However, at 10(-3) M PCBC there was some evidence of DNA cross-links. Therefore if cysteine conjugates of HCBD are formed in vivo, they could account for the toxicity observed with exposure to HCBD.

Studies of the developmental toxicity of polycarboxylate dispersing agents.

Three linear polycarboxylate compounds, two linear polyacrylates (90,000 MW and 4,500 MW) and one linear polyacrylate-maleate copolymer (12,000 MW), were tested for their teratogenic potential in female Sprague Dawley rats. These polymers, which were tested as sodium salts, are used as dispersing agents in detergent formulations at levels of 1-5%. All compounds were administered by gavage during organogenesis (days 6-15 of pregnancy). No adverse effects on development were seen with any of the three compounds at any of the doses tested. The highest dose, and therefore the minimum no-effect dose, for the three linear polymers was 1125 mg/kg/day for the 90,000 MW polyacrylate, 3000 mg/kg/day for the 4,500 MW polyacrylate, and 6670 mg/kg/day for the polyacrylate-maleate copolymer. Based on these data, these compounds are not developmentally toxic, even at very high dose levels.