Bilirubin inhibits the activation of superoxide-producing NADPH oxidase in a neutrophil cell-free system.

We studied the effect of bilirubin on the NADPH-dependent superoxide production induced by sodium dodecyl sulfate in a cell-free system consisting of the membrane and cytosolic fractions of pig neutrophils. Preincubation of the cytosolic fraction with bilirubin before the addition of sodium dodecyl sulfate resulted in the time- and dose-dependent inhibition of the superoxide production while the preincubation of the membrane fraction with the tetrapyrrole did not result in the inhibition. When the pigment was added after the initiation of the reaction, the ongoing production was not affected by the addition. Other tetrapyrroles, such as hemin, protoporphyrin and biliverdin, also inhibited the production. The results indicate that bilirubin inhibits the activation process of the superoxide producing NADPH oxidase by decreasing the potency of the cytosolic fraction and its inhibitory effect seems to be due to the hydrophobic nature of the tetrapyrrole.

Investigation of anti-motion sickness drugs in the squirrel monkey.

Early attempts to develop an animal model for anti-motion sickness drugs, using dogs and cats; were unsuccessful. Dogs did not show a beneficial effect of scopolamine (probably the best single anti-motion sickness drug for humans thus far) and the findings in cats were not definitive. The authors have developed an animal model using the squirrel monkey (Saimiri sciureus) of the Bolivian phenotype. Unrestrained monkeys in a small lucite cage were tested in an apparatus that induces motion sickness by combining vertical oscillation and horizontal rotation in a visually unrestricted laboratory environment. Signs of motion sickness were scored using a rating scale. Ten susceptible monkeys (weighing 800-1000 g) were given a total of five tests each, to establish the baseline susceptibility level. Based on the anticholinergic activity of scopolamine, the sensitivity of squirrel monkey to scopolamine was investigated, and the appropriate dose of scopolamine for this species was determined. Then various anti-motion sickness preparations were administered in subsequent tests: 100 ug scopolamine per monkey; 140 ug dexedrine; 50 ug scopolamine plus 70 ug dexedrine; 100 ug scopolamine plus 140 ug dexedrine; 3 mg promethazine; 3 mg promethazine plus 3 mg ephedrine. All these preparations were significantly effective in preventing motion sickness in the monkeys. Ephedrine, by itself, which is marginally effective in humans, was ineffective in the monkeys at the doses tried (0.3-6.0 mg). The squirrel monkey appears to be a good animal model for antimotion sickness drugs. Peripherally acting antihistamines such as astemizole and terfenadine were found to be ineffective, whereas flunarizine, and an arginine vasopressin V1 antagonist, showed significant activity in preventing motion sickness.

Etiologic significance of arginine vasopressin in motion sickness.

There is abundant evidence implicating the role of arginine vasopressin in motion sickness. The effects of AVP analogs on motion sickness were investigated in squirrel monkeys. Two specific V1 antagonists (SK&F 100273 and SK&F 103561) and three mixed V1/V2 antagonists (SK&F 101926, SK&F 105494, and SK&F 104146-D) were tested on six highly susceptible monkeys. Intravenous injections of 200 ug of a V1 antagonist abolished emesis in all six monkeys, and few prodromal symptoms remained (latency to emesis > 120 minutes, P < .001). Mixed V1/V2 antagonists failed to abolish emesis in all monkeys. However, there was a slight increase in the latency to the first bout of emesis/retching with the mixed antagonists when compared with the baseline. The dose-response relationship and rate of onset of action of the V1 antagonists (SK&F 100273) were explored. Latency to the first bout of emesis/retching increased to about twice that of the baseline when half of the effective antiemetic dose was used. The efficacy demonstrated by the specific V1 antagonists indicates that V1 receptors may modulate emesis.

Lack of allelic imbalance in APOE epsilon3/4 brain mRNA expression in Alzheimer's disease.

Although the APOE epsilon4 allele is a strong risk factor for Alzheimer's disease (AD), it is not deterministic, as many APOE epsilon3/4 individuals do not develop AD. It has been hypothesized that this incomplete penetrance is due, in part, to an imbalance of allele expression in heterozygous individuals. In this regard, Lambert et al. (1998) reported that AD individuals have a higher APOE epsilon4/total APOE ratio than non-demented control subjects. We tested this hypothesis using radioactive RT-PCR to quantitate APOE epsilon3 and epsilon4 allele expression levels in AD and non-AD brain samples from APOE epsilon3/4 individuals. Quantitative analyses of amplified products within the linear range of amplification (18-20 cycles) revealed no difference from the expected 1:1 ratio in genomic DNA and in cDNA from AD and control brains. Using high PCR cycle numbers (approximately 30), we observed an artificial elevation of the APOE epsilon3/total APOE ratio in both DNA and cDNA samples, possibly due to DNA heteroduplex formation. Our results do not support the hypothesis that allelic imbalance contributes to the risk of developing AD among APOE epsilon3/4 heterozygote individuals.

Lack of independent associations of apolipoprotein E promoter and intron 1 polymorphisms with Alzheimer's disease.

Several studies have demonstrated genetic associations between Alzheimer's disease (AD) and polymorphisms in the promoter/enhancer regions of the apolipoprotein E (APOE) gene. These studies raise the possibility that APOE transcription control may be involved in altered risks for AD. We evaluated polymorphic sites in the intron-1 enhancer element (IE-1G/C) and in the APOE promoter (-219G/T). For the IE-1 polymorphism, we analyzed 433 individuals (183 AD and 250 controls), and found a strong linkage between the IE-1G allele and APOE-epsilon4. When we controlled for this linkage using log-linear model analysis, we found no independent association between the IE-1 polymorphism and AD. For the -219 polymorphism, we analyzed 475 individuals (168 AD cases, 234 controls, and 73 cases of cerebral amyloid angiopathy (CAA)). We found strong linkages between the -219G allele and APOE-epsilon2 and between the -219 T allele and APOE-epsilon4. Controlling for these linkages, we found no independent association between the -219 polymorphism and AD or CAA. Thus, our studies do not support independent associations between AD and either the IE-1 or the -219 polymorphisms.

Optokinetic torsion: dynamics and relation to circularvection.

Continuous records of optokinetic torsion to sinusoidal inputs were obtained using the electromagnetic scleral search-coil technique. We measured the gain and phase lag of optokinetic torsion in response to a spherical visual display rotating steadily at various angular velocities and sinusoidally at frequencies from 0.2 to 2.0 Hz and at amplitudes from 10 to 80 deg. Gain (peak slow-phase eye velocity over stimulus angular velocity) of up to 0.12 were obtained with stimulus frequencies of 0.2 Hz and declined to an average value of about 0.02 at a frequency of 2.0 Hz. Phase lag was virtually zero at a frequency of 0.2 Hz and increased to over 80 deg at 2.0 Hz. The records from the sinusoidal stimuli show very few quick phases. With increasing stimulus amplitudes, the amplitude of the response increased but its gain declined. We found no evidence of torsional after-nystagmus nor any relation between the torsional response and reports of vection or sensation of body tilt induced by the rotating display. Torsional optokinetic nystagmus is most suited to compensate for low-amplitude, low-frequency stimulus rotation and normally supplements torsion induced by head tilt.

An inexpensive surgical headholder for the rat.

In many surgical procedures, there is a need to secure the animal's skull in a particular orientation. Described here is a surgical headholder for the rat that is inexpensive and easily constructed. The main component of the headholder is a screw type tubing clamp that is modified to allow the hard palate of the rat to be rigidly secured to the base plate of the clamp. This headholder has proven to be a highly satisfactory alternative to commercially available devices.

Combined head and eye tracking system for dynamic testing of the vestibular system.

We present a combined head-eye tracking system suitable for use with free head movement during natural activities. This system provides an integrated head and eye position measurement while allowing for a large range of head movement (approx 1.8 m of head translation is tolerated). Six degrees of freedom of head motion and two degrees of freedom of eye motion are measured by the system. The system was designed to be useful for the evaluation of the vestibulo-ocular reflex (VOR). The VOR generates compensatory eye movements in order to stabilize gaze during linear or rotational motion of the head. Current clinical and basic research evaluation of the VOR has used a restricted range of head motion, mainly low-frequency, yaw rotation. An integrated eye-head tracking system such as the one presented here allows the VOR response to linear and angular head motion to be studied in a more physiologically relevant manner. Two examples of the utility of the integrated head and eye tracking system in evaluating the vestibular response to linear and angular motion are presented.

Circularvection about earth-horizontal axes in bilateral labyrinthine-defective subjects.

A stationary subject surrounded by a visual display rotating about an earth-horizontal axis typically experiences a sensation of continuous self-rotation (vection) coupled with a paradoxical sensation of a limited degree of body tilt, both opposite to the direction of the stimulus. The sensation of limited body tilt has been attributed to conflict between visually-induced vection, and otolithic and somatosensory graviceptive information which indicates that the body has not moved. We investigated circularvection and illusory body tilt about the horizontal axis in the pitch and roll planes in bilateral labyrinthine-defective (L-D) subjects. Results demonstrated that the bilateral group experienced complete unambiguous self-rotation through an upside-down orientation. The relative contributions of the otolithic and somatosensory graviceptors to visuall-induced tilt is discussed.

The influence of age on susceptibility to motion sickness in monkeys.

A longitudinal study on the effects of age on the susceptibility to motion sickness in the squirrel monkey was carried out over a 10-year period (1982 to 1991). The typical life span of squirrel monkeys is 15 years. Ten mature male squirrel monkeys of the Bolivian subspecies were found to be susceptible to motion sickness induced by a combination of vertical oscillation at 0.5 Hz and rotation in the horizontal plane at 25 rotations per minute (RPM) in a visually unrestricted environment. Signs of motion sickness were quantified according to a rating scale based on Graybiel's diagnostic criteria. Latency to vomiting/retching and severity of sickness obtained from year 1 (baseline), 3, 5, 7 and 10 were subjected to repeated-measures design analysis. There were no significant differences in the susceptibility level (as measured by latency to vomiting/retching and cumulative sickness scores) in the monkeys throughout the 10-year period. The habituation to 7 consecutive daily exposures remained the same throughout the same period. We conclude that, in the squirrel monkeys from maturity to near the end of their life span, there is no change in susceptibility to motion sickness with aging.

Human gaze instability during brief exposure to reduced gravity.

The stability of gaze in three dimensions (horizontal, vertical and torsional) was investigated with the electromagnetic scleral search-coil technique during the microgravity phase of parabolic flights under two visual fixation conditions: fixation on a real target and on an imagined target. Subjects were secured upright with the head immobilized by a dental bite. There were torsional eye movements in response to the imposition of reduced gravitoinertial forces under both visual fixation conditions. The pattern of these movements was consistent with our previous findings on six other subjects. No significant horizontal eye movements were observed in either fixation condition. Under the condition of fixation on an imagined target, direction-specific vertical nystagmus was observed with slow phase directed upwards during transition from hypergravity to microgravity. The slow phase was directed downwards during transition from microgravity to hypergravity, although the nystagmus was of lower frequency and the magnitude of the slow phase velocity appeared to be smaller than during transition from hypergravity to microgravity. The vertical eye movements could be attributed to a change of otolithic stimulation along the subject's z axis since the rate of pitch rotation of the aircraft during parabolic flight was too slow to produce an effective canal input. These kinds of reflex eye movements could degrade vision during manoeuvres or turbulence in flight.

Control of isometric force in hypergravity.

BACKGROUND: Previous work suggests that proprioceptive signals are degraded in hypergravity (hyper-G). We therefore, expected that production of finely graded force is disturbed as well. METHODS: Subjects produced isometric force with their thumb and index finger upon verbal instruction, before, during and after exposure to +1.5 Gz and +3 Gz. Produced force was orthogonal to the direction of gravity. RESULTS: In hyper-G, responses to a given target value were significantly higher (by about 400 pond) than in normal gravity, while the modulation of produced force with target force didn't change. The results in +1.5 Gz and +3 Gz were quantitatively similar, and a positive aftereffect was found. CONCLUSIONS: Subjects underestimate by a constant amount the force they produce in hyper-G. Our results are reminiscent of similar findings with pointing and grasping movements in hyper-G.

Another function of the inner ear: facilitation of the emetic response to poisons.

If a foot were surgically removed and it was observed that walking was then impaired, it could be concluded that the foot is part of the normal mechanism for walking and that one of the physiological functions of the foot is to facilitate walking. In seven dogs, the vestibular apparatus of the inner ear was surgically removed and it was observed that the emetic response to certain poisons was impaired. It was concluded that the inner ear is part of the normal mechanism for vomiting in response to poisons, and that one of the physiological functions of the inner ear is to facilitate the emetic response to poisons. It seems likely that the mechanism, whereby the vestibular apparatus facilitates the emetic response to poisons, is the basis of motion sickness. In essence, motion sickness can be considered the result of activation, by motion, of a mechanism that normally functions to facilitate vomiting in response to poisons.

Motion sickness susceptibility and aerobic fitness: a longitudinal study.

A longitudinal study evaluated the susceptibility to motion sickness in initially unfit subjects before and after an endurance training program. Motion stimulation was provided by the Precision Angular Mover, in which the subject was tumbled head over heels about an Earth-horizontal axis at 20 cycles per minute in darkness. Maximal aerobic power and the blood lactate response to submaximal exercise were evaluated with cycle ergometry. The training program caused significant improvements in VO2max and endurance capacity, and a significant decrease in percent body fat. There was a significant (p less than 0.0125) increase in motion sickness susceptibility after the physical training, suggesting that increased physical fitness caused increased susceptibility to motion sickness in some individuals.

Performance of a simple aiming task in hypergravity: I. overall accuracy.

BACKGROUND: Visuo-motor performance is known to be affected by exposure to hyper-gravity (hyper-G), but the underlying mechanisms remain to be determined; the present study investigated the role of target mislocalization. METHOD: Subjects pointed before, during and after exposure to hyper-G at targets without seeing their hand. Target positions were displayed: a) throughout each pointing response; b) before response onset; or c) in normal gravity prior to a set of movements. RESULTS AND CONCLUSIONS: For all display conditions, subjects pointed higher in hyper-G than in normal gravity from the first movement on. We attribute the discrepancy between this finding and previous results (8, 12) to different movement strategies. The effects of hyper-G on pointing performance were small, but sustained when targets were displayed before or throughout each movement, but they were large and transient when targets were memorized in normal-G. We conclude that too-high pointing in hyper-G cannot be simply explained by the "elevator illusion," and propose a tentative interpretation based on known perceptual deficits.

Performance of a simple aiming task in hypergravity: II. detailed response characteristics.

BACKGROUND: Literature proposes three hypotheses for impaired movement execution in hyper-G. The present study attempted to discriminate between these hypotheses by comparing kinematic characteristics and final accuracy of pointing movements in different gravity levels. METHOD: Subjects pointed without seeing their hand at targets presented before, during and after exposure to hyper-G. RESULTS: After factoring out movement amplitude, peak vertical velocity and the skewness of velocity profiles tended to increase, while movement duration tended to decrease with increasing G-level. Further, final response position was slightly less modulated by target position in hyper-G than in normal-G. CONCLUSION: Although not all findings reached statistical significance, the observed pattern of results corroborates the hypothesis (2) that the motor system re-interprets hyper-G as increased arm weight.

Visually-induced sickness in normal and bilaterally labyrinthine-defective subjects.

A group of nine normal subjects (with no overt vestibular dysfunction) and a group of 6 bilaterally labyrinthine-defective subjects were exposed to a visual field rotating about an Earth-horizontal axis (orthogonal to the gravity axis). The visual stimulus was provided by a 3-m diameter sphere with random dots rotating at 30, 45, and 60 degrees per second (degree/s) about the stationary subject's roll, pitch and yaw axes. The subject's head was positioned at the center of the sphere such that it experienced apparent motion in all three axes. Results indicated that in the normal group, symptoms of motion sickness were reported in 21 of 27 test-trials. When labyrinthine-defective subjects were exposed to the roll and pitch stimulus, no sickness symptoms were reported or observed. These results strongly suggest that the vestibular system is necessary for sickness induced by moving visual fields.

An illusion of reversed direction in hyperopes.

If a subject who is sufficiently farsighted removes his corrective, positive, lenses and looks with one eye from a distance of one or a few meters, at a small lighted area such as the (continuously "on") indicator light of an electric toothbrush, razor, or smoke detector, and if a small object such as a pin is then moved slowly from above to below the subject's eyes (in a plane close to the eye), the subject will perceive the object moving normally from above to below until it encroaches on his view of the lighted area. The object will then be seen to encroach first on the bottom of the lighted area, and as the object continues to move down it will be seen to be moving up across the lighted area, exiting the lighted area at the top. Similarly, an object moved in front of the eye from the subject's left to his right will be seen by the subject to traverse the lighted area in the reverse direction, right to left, even though the subject moves the object himself. Also, while the object is in front of the lighted area, it is perceived as an upside down silhouette having surprisingly clear and sharp edges, and it appears to be located on the lighted area rather than close to the eye where it really is.

Visually-induced tilt during parabolic flights.

A helmet-mounted visual display system was used to study visually induced sensations of self-motion (vection) about the roll, pitch and yaw axes under normal gravity condition (1g) and during the microgravity and hypergravity phases of parabolic flights aboard the NASA KC-135 aircraft. Under each gravity condition, the following parameters were investigated: (1) the subject's perceived body vertical with eyes closed and with eyes open gazing at a stationary random dot display; (2) the magnitude of sensations of body tilt with respect to the subjective vertical, while the subject viewed displays rotating about the roll, pitch and yaw axes; (3) the magnitude of vection; (4) latency of vection. All eleven subjects perceived a definite "up and down" orientation throughout the course of the flight. During the microgravity phase, the average magnitudes of perceived body tilt and self-motion increased significantly, and there was no significant difference in vection latency. These results show that there is a rapid onset of increased dependence on visual inputs for perception of self-orientation and self-motion in weightlessness, and a decreased dependence on otolithic and somatosensory graviceptive information. Anti-motion sickness drugs appear not to affect the parameters measured.