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Accumulation of very long chain fatty acids (VLCFAs) due to defects in ATP binding cassette protein D1 (ABCD1) is thought to underlie the pathologies observed in adrenoleukodystrophy (ALD). Pursuing a substrate reduction approach based on the inhibition of elongation of very long chain fatty acid 1 enzyme (ELOVL1), we explored a series of thiazole amides that evolved into compound 27 ─a highly potent, central nervous system (CNS)-penetrant compound with favorable in vivo pharmacokinetics. Compound 27 selectively inhibits ELOVL1, reducing C26:0 VLCFA synthesis in ALD patient fibroblasts, lymphocytes, and microglia. In mouse models of ALD, compound 27 treatment reduced C26:0 VLCFA concentrations to near-wild-type levels in blood and up to 65% in the brain, a disease-relevant tissue. Preclinical safety findings in the skin, eye, and CNS precluded progression; the origin and relevance of these findings require further study. ELOVL1 inhibition is an effective approach for normalizing VLCFAs in models of ALD.

An experiment was conducted to assess the effects of a real-life stressor (public speaking) upon cardiovascular reactivity (CVR). Changes in blood pressure and heart rate from baseline to task were measured in a sample of 86 men and women. The purpose was to examine the effects of individual differences (Type A personality, hostility and gender) on CVR. Participants gave a 6-min oral presentation during which they were evaluated by their professor and with classmates as the audience. Results indicated that all participants had marked CVR during public speaking. There were differences in reactivity patterns between men and women, but personality did not play a role except for high hostile men. It is suggested that intense stressors may result in high levels of CVR independent of personality variables that moderate reactivity at lower levels of stress.

The human cannabinoid receptors, central cannabinoid receptor (CB1) and peripheral cannabinoid receptor (CB2), share only 44% amino acid identity overall, yet most ligands do not discriminate between receptor subtypes. Site-directed mutagenesis was employed as a means of mapping the ligand recognition site for the human CB2 cannabinoid receptor. A lysine residue in the third transmembrane domain of the CB2 receptor (K109), which is conserved between the CB1 and CB2 receptors, was mutated to alanine or arginine to determine the role of this charged amino acid in receptor function. The analogous mutation in the CB1 receptor (K192A) was found to be crucial for recognition of several cannabinoid compounds excluding (R)-(+)-[2, 3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrrolo[1,2,3-de]-1, 4-benzoxazin-6-yl](1-naphthalenyl)methanone (WIN 55,212-2). In contrast, in human embryonic kidney (HEK)-293 cells expressing the mutant or wild-type CB2 receptors, we found no significant differences in either the binding profile of several cannabinoid ligands nor in inhibition of cAMP accumulation. We identified a high-affinity site for (-)-3-[2-hydroxyl-4-(1, 1-dimethylheptyl)phenyl]-4-[3-hydroxyl propyl] cyclohexan-1-ol (CP-55,940) in the region of helices 3, 6, and 7, with S3.31(112), T3.35(116), and N7.49(295) in the K109A mutant using molecular modeling. The serine residue, unique to the CB2 receptor, was then mutated to glycine in the K109A mutant. This double mutant, K109AS112G, retains the ability to bind aminoalkylindoles but loses affinity for classical cannabinoids, as predicted by the molecular model. Distinct cellular localization of the mutant receptors observed with immunofluorescence also suggests differences in receptor function. In summary, we identified amino acid residues in the CB2 receptor that could lead to subtype specificity.

An experiment was conducted to investigate the relationships among Type A behavior, hostility and cardiovascular reactivity (CVR) in women. Changes in heart rate, blood pressure and skin conductance from baseline to task levels were used to assess reactivity. These measures were obtained from 96 women during a seated baseline period, a reaction time task and during an oral IQ quiz. Analyses indicated that Type A and high hostile women were more reactive to an oral IQ quiz and reaction time stressors than Type B and low hostile women. Specifically, Type As showed significantly greater increases in systolic blood pressure in the reaction time task and greater mean arterial pressure and systolic blood pressure increases in the IQ quiz. High hostiles evidenced significantly higher systolic blood pressure and diastolic blood pressure in the RT task and higher mean arterial pressure and diastolic blood pressure in the IQ quiz. It was concluded that Type A personality and hostility can predict greater reactivity in women to two different stressors. The oral quiz generated greater reactivity than the RT task and thus may be a more stressful task.

Phenylethanolamine N-methyltransferase (PNMT), the final enzyme in the biosynthesis of epinephrine, has been detected in rat and human spleen with radioenzymatic assays, but the presence of PNMT has not been examined in other lymphoid tissues. Using the reverse transcription polymerase chain reaction (RT-PCR) and Southern blot analysis, we tested for PNMT mRNA in rat spleen and thymus. A single PCR fragment from spleen, thymus, adrenal and brainstem gave a strong hybridization signal with a PNMT cDNA probe, whereas a PCR fragment from liver was only faintly visible on Southern blots. These findings indicate that the PNMT gene is expressed in spleen and thymus and raise the possibility that lymphoid organs synthesize epinephrine as an intrinsic regulator.

Using the reverse transcription polymerase chain reaction, we detected a single form of phenylethanolamine N-methyltransferase (PNMT) mRNA in hypothalamus and medulla/pons and two forms in cerebellum. These findings indicate that the PNMT gene is expressed in these brain areas and suggest that tissue specific splicing of PNMT mRNA may occur.

Blood pressure and impedance cardiography derived measures of heart rate, stroke volume, cardiac output and total peripheral resistance were measured in 16 persons before and after participation in a comprehensive program of stress management that included home monitoring of blood pressure and feedback of finger skin temperature during relaxation. Ten of the subjects were hypertensive and six were normotensive. Baseline measures of systolic and diastolic blood pressure and heart rate decreased significantly after participation in the program. In addition, reactivity to a psychological stressor (oral quiz) was significantly lower as revealed in reduced systolic and diastolic pressure, heart rate and cardiac output at the second assessment. A reduction in sympathetic nervous system activity is postulated as a possible mechanism for the changes observed.

In the present study 36 police officers were exposed to a psychological stressor (IQ quiz) and to cold pressor stress while several cardiovascular variables were monitored. Impedance cardiography was used to provide measures of heart rate, stroke volume, cardiac output, myocardial contractility, and total peripheral resistance. In addition, measures of systolic and diastolic blood pressure and peripheral skin temperature were obtained. A multivariate analysis of variance (MANOVA) indicated that significant increases in diastolic and systolic blood pressure during the cold pressor test were mediated by large increases in total peripheral resistance, whereas blood pressure elevation during the IQ quiz were accompanied by significant increases in heart rate and, to a lesser extent, cardiac output. Peripheral skin temperature decreased in response to each stressor. Additional analysis indicated a degree of stimulus specificity for several variables. For example, diastolic blood pressure showed greater increases to cold pressor than quiz, whereas systolic blood pressure increased more with the psychological than the physical stressor. Directional fractionation occurred for both myocardial contractility and cardiac output.

A series of three experiments examined backward visual masking effects and visual evoked cortical potential correlates of such masking. In Experiment I, which was concerned with the effects of sequential sets of like stimuli (grids), it was found that when backward masking occurred, it was accompanied by decreased visual evoked potential (VEP) amplitudes. Experiment II replicated the first experiment using different stimuli (letter B's) and several new subjects. Again, backward masking was accompanied by decreased VEP amplitudes. In Experiment III, which examined the effects of sequential sets of unlike stimuli (B's and grids), it was found that when earlier stimuli differed in configuration from later stimuli, there was an absence of backward masking and VEP amplitude changes also failed to appear. Thus, when backward masking did not occur, no changes in the VEP were observed. The results are discussed in terms of interactions between excitatory and inhibitory activities produced at the visual cortex by the earlier and subsequently presented stimuli. Various concepts regarding the visual system mechanisms involved in backward masking, including integration and interruption hypotheses, may help to explain the complexity of findings obtained thus far in studies using VEP correlates of backward visual masking.

Visual evoked cortical potentials (VEPs) were recorded from an individual with a mature cataract in one eye. Stimulation was both monocular and binocular and VEPs were obtained from three occipital scalp sites. Comparisons of recordings taken prior to cataract removal and after removal showed a dramatic increase in amplitude of potentials derived through stimulation of the affected eye. Slight differences in hemispheric amplitude prior to surgery suggest a greater degree of opacity in one portion of the affected lens.

The first part of this study examined the relationship(s) between Type A behavior scores and heart rate, blood pressure and impedance derived cardiovascular measures in response to discrete stressors during a standardized psychophysiological assessment. Expts. 2A and 2B considered cardiovascular responses to dynamic exercise stress alone and in combination with psychological and cold pressor tests. Gender and stroke volume changes during the psychological stress correlated 0.45 (P less than 0.02) with Type A score. Subscale scores of Job Involvement correlated 0.78 (P less than 0.02) with stroke volume, total systemic resistance and heart rate during the psychological stressor, and systolic blood pressure during the cold pressor task. The combined effects of psychological stress and dynamic exercise on systolic and diastolic blood pressure were significantly greater than the individual effects of these stressors. The use of impedance cardiography in measuring cardiovascular variables that correlate with Type A behavior, during psychophysiological assessments, may further elucidate our understanding of Type A behavior in addition to providing information about how stress interacts with aerobic exercise.

Reaction time and signal detection performance were measured during a 78-min. vigilance task. 12 right-handed male subjects served in two experimental sessions. Subjects focused on a central fixation point and responded to signals presented at unpredictable times in one of three locations: 2.5 degrees to right of central fixation, central, and 2.5 degrees to the left of center. Subjects decided whether to press a response key with either the left or right hand with each presentation. Over-all vigilance performance (signal detections and response time) was similar for left and right visual-field presentations. Evidence from reaction times indicated that responses controlled by the left hemisphere were faster to a verbal stimulus (T) while reactions controlled by the right hemisphere were faster to an apparent non-verbal stimulus, an inverted T.

The purpose of the present study was to examine possible hemispheric differences in discriminations of line length and to determine whether the visual event related potential (ERP) recorded from over left and right hemispheres was related to performance. Twelve right-handed subjects participated on each of 2 separate days. The visual ERPs were derived from left occipital (O1) and right occipital (O2) placements. Eye blinks and vertical and lateral eye movements were also monitored. A single vertical 1.0 cm line (Standard) was displayed for 40 ms and was followed 2 s later by either a 0.9 cm, 1.0 cm or 1.1 cm (Comparison) line (also 40 ms). Subjects were asked to judge whether the second of the lines (Comparison) was "shorter" or "longer" than the first. Stimuli appeared at the center of a screen or at 1 degree 24' to the left and right of central fixation. Accuracy of line length judgements were similar in all 3 visual fields indicating a lack of hemispheric performance asymmetry for this type of discrimination task. In addition, there was no evidence of hemispheric asymmetry in the ERPs. The ambiguous discrimination involving the 1.0 cm standard and comparison lines seems to have influenced P3 latencies at both hemispheres. Namely, P3 latency was significantly longer in response to the 1.0 cm line than to the 0.9 cm or 1.1 cm lines. We propose that the ambiguous discrimination required a greater time for simulus evaluation and that this was reflected in the delayed P3 latencies.

Two experiments were conducted to determine whether the hypnotic suggestion of stimulus intensity change would affect the physical parameters (latencies, amplitudes) of the visual cortical evoked potential. Stimulus intensity was kept constant as visual cortical evoked potentials were measured under conditions in which it was suggested that stimuli were "bright" or "dim". The results of both experiments led to the conclusion that, under the present condition, hypnotic suggestion of stimulus intensity change did not result in changes in visual cortical evoked potentials.

TWo separate experiments were conducted to determinge the nature of the visual event related potential (ERP) at two different cortical areas under conditions of backward visual masking and to see the effects of varied inter-stimulus-intervals (ISIs) upon both masking and the ERP. The results of the first experiment clearly demonstrated visual ERP attenuation at a target-mask ISI of 40 ms, an ISI which consistently produced masking. Both experiments showed that this effect was specific for the occipital recording site since amplitude reductions were not observed at the vertex under this condition. The mask alone condition produced the largest amplitude ERPs in both experiments. Again, this was specific for Oz. In the second experiment target-mask ISIs which did not produce backward masking (i.e., 10 ms and 100 ms) were not accompanied by ERP amplitude reductions. The results may be explained by a cortical excitatory-inhibitory model. That is, when successive stimuli are presented to the visual system, the visual cortical excitation produced by the initial stimuli is inhibited by the presentation of subsequent stimuli when temporal and spatial intervals are appropriate.

This research was designed to determine whether visual event related potentials (ERPs) recorded from over the two occipital hemispheres would indicate differential processing of apparently moving and stationary stimuli. Previous findings in the literature led us to consider a male-female comparison as part of our experimental design. Nine male and nine female subjects were screened for right-handedness and visual abilities (acuity, depth and phoria). Each participated in three experimental sessions over a three day period in which ERPs were recorded from O1 and O2 in response to stimuli presented in left, central and right visual fields. The main finding was that, for female subjects, right hemispheric derived ERPs were larger in amplitude than left hemisphere recordings for apparently moving stimuli presented centrally. Males showed no hemispheric amplitude differences. However, for male subjects, the left hemisphere ERP latencies to motion were longer than those recorded from over O2 with central visual field presentations. It was speculated that different attentional strategies in the two sexes led to the observed result.

A total of 36 male individuals, 18 classified as Type A and 18 as Type B performed a cognitive (tonal memory) and a perceptual-motor (simulated race car driving) task along with a secondary reaction time (RT) task. Heart rate (HR), skin temperature, and skin conductance (SC) were measured. Multiple linear regression analysis revealed that tracking was related to Jenkins Activity Survey indicating superior performance for those scoring high in overall Type A behavior and low in the H sub-scale (hard driving, competitive behavior). Persons scoring high in the S scale (speed and impatience) and low in the H scale performed better in the short-term memory task. Type A subjects had higher HR and performed better (faster RTs and higher scores) than Type Bs, but only while engaged in the cognitive task. The Type As also had higher SCs than Bs, although they were not differentiated according to task. Sub-scale patterns may have important implications for refining the Type A behavior concept.

The present study examined possible hemispheric differences in discriminations of different sizes of geometric shapes (rectangles) and different meanings of words, and determined whether left and right hemisphere derived visual event related potentials (ERPs) were related to performance. Eighteen right-handed subjects (10 male and 8 female) participated in two separate sessions conducted on different days. The visual ERPs were recorded from over left parietal (P3) and right parietal (P4) scalp locations. Subjects were required to make discriminations of three words (PARE, PAIR, PEAR) and three sizes of rectangles (small, medium, large). Each word and rectangle was singly presented for 40 msec at 1 degree 24 minutes of arc to the left and right of central fixation (LVF and RVF respectively). The major findings were as follows: 1) there were no performance and ERP differences between hemispheres in the verbal task; 2) the left hemisphere excelled in the spatial task; however, ERPs derived from the two hemispheres were similar; 3) subjects experienced greater difficulty in their discriminations of geometric size, as compared to words, regardless of field of presentation. Discrimination of size seemed to have influenced P3 (P300) latency, i.e., it was longer (both hemispheres) when subjects made size discriminations as compared to words. It was proposed that the more difficult discriminations involved in size discrimination required a greater time for stimulus evaluation and that this was reflected in the delayed P3 response.

This experiment was undertaken to investigate the effects of different types and velocities of apparent motion on the Visual Evoked Potential (VEP). Central (Cz) recording site VEPs were obtained from four males and three females under seven conditions. Significant differences in terms of amplitude and latencies were found between continuous and discrete apparent motion at the Oz derivation only. Theoretical and cell system models describing separate cortical channels for processing continuous and discrete apparent motion were presented to account for the observed differences. The stationary condition produced a significantly shorter latency than all other conditions at Cz. In addition, discernable trends observed between central and occipital recording sites suggest the role of the occipital cortex as the primary processor of motion and for detecting differences in motion velocity.