Linking Patient-Centered Outcomes to Neuropsychological Practice: A Conceptual Framework and Opportunities for Research.

In the current healthcare climate, reimbursement for services is increasingly linked to the ability to demonstrate beneficial patient outcomes. Neuropsychology faces some unique challenges in outcomes research, namely, that neuropsychologists often do not follow patients over time and the effect of neuropsychological services on patient outcomes may not be fully realized until under another provider's care. Yet there is an urgent need for empirical evidence linking neuropsychological practice to positive patient outcomes. To provide a framework for this research, we define a core set of patient-centered outcomes and neuropsychological processes that apply across practice settings and patient populations. Within each area, we review the available existing literature on neuropsychological outcomes, identifying substantial gaps in the literature for future research. This work will be critical for the field to demonstrate the benefit of neuropsychological services, to continue to advocate effectively for reimbursement, and to ensure high-quality patient care.

Age-independent and dose-response effects of ethanol on spatial memory in rats.

Results of previous studies have shown that ethanol impairs the acquisition of spatial memory in adolescent rats at doses below those required to impair the acquisition in adults. However, the previous work did not identify doses of ethanol that failed to impair acquisition in adolescents or that impaired acquisition in both adolescent and adult animals. This was our aim in the present study. Male, Long-Evans hooded rats (adolescent and adult) were treated intraperitoneally with 0.0, 0.5, or 2.5 g/kg of ethanol 30 min before daily training on a spatial or nonspatial version of the Morris water maze task. Twenty-four hours after training on the spatial task the animals were given a 1-min probe trial. The low dose of ethanol (0.5 g/kg) failed to impair the performance of animals from either age group on any tasks. It did, however, enhance the initial rate of acquisition on the spatial task. The 2.5-g/kg dose eliminated acquisition of spatial learning in animals of both ages and significantly attenuated performance on a nonspatial task in both age groups. However, the treatment effect in the nonspatial task was eliminated with controlling for baseline performance. These results establish a low dose of ethanol (0.5 g/kg) that does not impair acquisition of spatial memory in adolescent or adult rats. Moreover, the study findings show that 2.5 g/kg of ethanol markedly impairs acquisition of spatial memory in both adolescent and adult animals.

Neurotoxicity of ethyl methacrylate in rats.

Ethyl methacrylate (ethyl 2-methyl-2-propenoate, EMA) has been implicated in the development of neurologic impairment following occupational exposure. The potential of EMA to produce neurotoxicity was investigated in adult male Sprague-Dawley rats in two experiments. In the first experiment, animals were administered 100, 200, 400, or 800 mg/kg by daily intraperitoneal (i.p.) injections for 60 d. Control rats received daily i.p. injections of 1 ml saline/kg. Clinical observations, spontaneous motor activity, and performance in the Morris water maze were assessed. Alterations in clinical parameters in the higher dose groups included lethargy, impaired breathing, decreased weight gain, and increased mortality. Alterations in motor activity were observed at 100 mg/kg, a dose that did not cause alterations in clinical parameters, body weight gain, or mortality. There was also a dose-dependent impairment in performance in the Morris water maze. In the second experiment, animals were administered EMA in drinking water at concentrations of 0.1, 0.2, or 0.5% for 60 d. Control rats were administered tap water. Animals were perfused at the termination of exposure and samples of brain, spinal cord, and sciatic nerve were prepared for histological examination. Spongiform alterations were observed in fiber tracts of the forebrain, brainstem, and spinal cord. Clusters of axonal swellings were scattered throughout the dorsal, ventral, and lateral columns of the spinal cord, and typically involved internodal segments of two or three neighboring axons. Shrunken axons with separated myelin lamellae and large axons with thinner than normal myelin sheaths were apparent in the sciatic nerve. The patterns of alterations in the white matter of the spinal cord and the sciatic nerve are consistent with myelinopathy, but additional experiments are necessary to confirm whether oligodendroglia and Schwann cells are the primary sites of injury. In addition to the alterations associated with myelin, there was a decrease in the density of neurons in the ventral horn of the spinal cord. While the observed effects of EMA on the nervous system of rats are consistent with neurologic symptoms of workers exposed to EMA, additional experiments are necessary to determine if the level and route of exposures associated with occupational use produce these impairments in experimental animals.

Developmental changes in seizure susceptibility during ethanol withdrawal.

It has recently been established that adolescence may represent a developmentally sensitive period with respect to the effects of ethanol, particularly within the NMDA neurotransmitter system. However, the same may also be true of the GABA system. There is evidence to suggest that the number of GABA receptors and their kinetics may change across development. The purpose of this study was to determine if GABA-mediated seizure susceptibility during ethanol withdrawal differed between adolescent and adult animals. Results indicate that adult animals pretreated with ethanol were more likely to achieve maximal tonic-clonic seizure activity and spent more time in stage 3 (or higher) seizure activity than all other groups. These data lend additional support to the contention that adolescent and adult animals differ in their susceptibility to the effects of ethanol and that this susceptibility is transmitter dependent.

Impairment of semantic and figural memory by acute ethanol: age-dependent effects.

Alcohol drinking is prevalent among young adults in the U.S. Moreover, heavy drinking is acknowledged by a substantial percentage of young adults in both college and military subpopulations, despite the known cognitive demands associated with these endeavors and the cognitive impairments associated with alcohol usage. We assessed the acute effects of ethanol (0.6 g/kg) on the acquisition of both semantic and figural memory in a sample of young adults from 21 to 29 years of age using a repeated-measures, placebo-controlled experimental design. Ethanol significantly impaired memory acquisition in both domains. In addition, the effect of ethanol on three of the four memory measures assessed was dependent on the age of the subjects. Subjects in a young subgroup (21 to 24 years of age) were significantly more impaired in memory measures than those in the subgroup that was 25 to 29 years of age. These results indicate a divergence of the potency of ethanol against memory acquisition across a narrow age range in early adulthood. Whereas these data are preliminary, and should be generalized cautiously, they are also consistent with a growing literature using animal models that indicates that acute ethanol is a more potent antagonist of memory and memory-related hippocampal activity in adolescent animals compared with adults.

Differential effects of ethanol on memory in adolescent and adult rats.

Previous studies have shown that ethanol inhibits memory-related synaptic activity and plasticity more potently in hippocampal slices from immature rats, compared with those taken from adults. We therefore hypothesized that ethanol would more potently attenuate the acquisition of spatial memory in adolescents, compared with adult rats. Adult (65 days of age) and adolescent (30 days of age) male rats were given five daily trials on a spatial memory task in a Morris Water Maze. The animals from each age group were subdivided into three subgroups. Each day, thirty minutes before training, the animals in each subgroup were given an intraperitoneal injection of 1.0 g/kg of ethanol, 2.0 g/kg of ethanol, or the saline vehicle. Training continued daily until the control animals had reached a performance criterion. Ethanol treatment significantly impaired spatial memory acquisition in the adolescent rats, but did not impair acquisition in adult rats. A separate experiment with identical treatment groups showed that ethanol did not impair acquisition of a nonspatial memory task in the water maze in animals from either age group. These experiments show that the acquisition of spatial, but not nonspatial, memory is more potently impaired by ethanol in adolescent animals, compared with adults.

A transition state in pieces: major contributions of entropic effects to ligand binding by adenosine deaminase.

Nebularine undergoes hydration at the active site of adenosine deaminase, in a reaction analogous to a partial reaction in the displacement of ammonia from adenosine by water, to generate an inhibitory complex that captures much of the binding affinity expected of an ideal transition-state analogue. Enzyme affinities of several compounds related to nebularine 1,6-hydrate, and to its stable analog 2'-deoxycoformycin, were compared in an effort to identify the structural origins of strong binding. Binding of the stable transition-state analog inhibitor 2'-deoxycoformycin was rendered 9.8 kcal/mol less favorable by removal of substituent ribose, 9.7 kcal/mol less favorable by inversion of the 8-hydroxyl substituent of the diazepine ring, and 10.0 kcal/mol less favorable by removal of atoms 4-6 of the diazepine ring. Binding of the unstable transition-state analog nebularine hydrate was rendered at least 9.9 kcal/mol less favorable by removal of the 6-hydroxyl group and 10.2 kcal/mol less favorable by removal of atoms 1-3 of the pyrimidine ring. In each case, the enzyme exhibited only modest affinity (Kd greater than or equal to 10(-2) M) for the "missing piece", indicating that incorporation of 2 binding determinants within a single molecule permits an additional 7-12 kcal/mol of intrinsic binding energy to be manifested as observed binding energy. These results are consistent with earlier indications that adenosine deaminase may use 10.5 kcal/mol of the intrinsic free energy of binding of the two substrates to place them in positions appropriate for reaction at the active site, overcoming the unfavorable entropy change of -35 eu for the equilibrium of 1,6-hydration of purine ribonucleoside and reducing the equilibrium constant for attainment of the transition state in deamination of adenosine. Thus, adenosine deaminase may achieve up to 8 orders of magnitude of its catalytic power by converting the nonenzymatic, bimolecular, hydration reaction to a monomolecular reaction at its active site. Several new 6-substituted 1,6-dihydropurine ribonucleosides, prepared by photoaddition of formate and by low-temperature addition of organolithium reagents to a derivative of purine ribonucleoside, exhibited Ki values of 9-1400 microM against adenosine deaminase, in accord with the active site's considerable tolerance of bulky leaving groups in substrates. Inhibition by one diastereomer of 6-carboxy-1,6-dihydropurine ribonucleoside was found to be time-dependent, progressing from a weakly bound to a more strongly bound complex.

Anatomy of acetylcholinesterase catalysis: reaction dynamics analogy for human erythrocyte and electric eel enzymes.

The anatomy of catalysis (i.e., reaction dynamics, thermodynamics and transition state structures) is compared herein for acetylcholinesterases from human erythrocytes and Electrophorus electricus. The two enzymes have similar relative activities for the substrate o-nitrochloroacetanilide and o-nitrophenyl acetate. In addition, with each substrate K values and solvent deuterium kinetic isotope effects for kES and kE are similar for the two enzymes. Solvent isotope effects in mixed isotopic buffers indicate that the acylation stages of o-nitrochloroacetanilide turnover by the two enzymes are rate-limited by virtual transition states that are weighted averages of contributions from transition states of serial chemical and physical steps. Similar experiments show that the transition states for Vmax of o-nitrophenyl acetate turnover by the two enzymes are stabilized by simple general acid-base (i.e., one-proton) catalysis. These comparisons demonstrate that acetylcholinesterases from diverse sources display functional analogy in that reaction dynamics and transition state structures are closely similar.

Orotidine-5'-monophosphate decarboxylase catalysis: kinetic isotope effects and the state of hybridization of a bound transition-state analogue.

The enzymatic decarboxylation of orotidine 5'-monophosphate may proceed by an addition-elimination mechanism involving a covalently bound intermediate or by elimination of CO2 to generate a nitrogen ylide. In an attempt to distinguish between these two alternatives, 1-(phosphoribosyl)barbituric acid was synthesized with 13C at the 5-position. Interaction of this potential transition-state analogue inhibitor with yeast orotidine-5'-monophosphate decarboxylase resulted in a small (0.6 ppm) downfield displacement of the C-5 resonance, indicating no rehybridization of the kind that might have been expected to accompany 5,6-addition of an enzyme nucleophile. When the substrate orotidine 5'-monophosphate was synthesized with deuterium at C-5, no significant change in kcat (H/D = 0.99 +/- 0.06) or kcat/KM (H/D = 1.00 +/- 0.06) was found to result, suggesting that C-5 does not undergo significant changes in geometry before or during the step that determines the rate of the catalytic process. These results are consistent with a nitrogen ylide mechanism and offer no support for the intervention of covalently bound intermediates in the catalytic process.

An examination of the proconvulsant actions of pyrethroid insecticides using pentylenetetrazol and amygdala kindling seizure models.

Pyrethroid insecticides have recently been purported to possess strong proconvulsant potential. The seizure-inducing properties of two pyrethroids were assessed by pentylenetetrazol (PTZ) seizure models (repeated ip, suprathreshold ip, and iv), and electrical kindling of the amygdala. The efficacy of po versus ip routes of deltamethrin administration was compared using iv-PTZ administration and tests of locomotor activity in a figure-eight maze. Both po and ip deltamethrin produced comparable decreases in motor activity indicating the effectiveness of both of these exposure routes on biological activity. The Type I pyrethroid, cismethrin (15 mg/kg, po), produced a 17% reduction in the threshold dosage of ip-PTZ required to induce a seizure, while delaying the onset of generalized seizure activity. The Type II pyrethroid, deltamethrin (10 mg/kg, po), failed to alter threshold or latency to seizure onset, but did increase seizure duration. No differences were revealed between po (0, 10, 15 mg/kg) or ip (0, 1, 10 mg/kg) administered deltamethrin on seizure thresholds or durations following iv-PTZ. Seizure severity, however, was enhanced by pyrethroids administered po in the iv-PTZ and suprathreshold-ip PTZ tests, ip deltamethrin was without effect. Cismethrin (0, 8, 15 mg/kg) and deltamethrin (0, 6, 10 mg/kg) administered po daily, 2 hours prior to electrical kindling stimulation facilitated amygdala kindling to a minimal but equivalent degree at the highest dosage. This dosage also evoked strong behavioral signs of toxicity. Deltamethrin also induced spontaneous seizures in partially kindled animals in the absence of stimulation. Thus strong evidence of proconvulsant activity of pyrethroids was not evident. The primary effects were limited to an enhancement of seizure severity in response to PTZ (tonic seizures) and the provocation of spontaneous seizures in partially kindled animals.

Equilibrium of 5,6-hydration of NADH and mechanism of ATP-dependent dehydration.

At equilibrium, water addition to the 5,6 double bond of NADH was observed to favor the hydrate by a factor of approximately 100. Hydration generates two epimers of NADHX (beta-6-hydroxy-1,4,5,6-tetrahydronicotinamide adenine dinucleotide). Only the 6S epimer of the hydrate was found to serve as a true substrate for an ATP-dependent dehydratase from yeast that regenerates NADH. Yet enzymatic conversion of both epimers of the hydrate to NADH was found to proceed essentially to completion in the presence of ATP and dehydratase. This is explained by the observed ability of the epimers to undergo rapid spontaneous equilibration, so that it is unnecessary to postulate a lack of stereospecificity in the dehydratase.