Biotechnical development of genetic addiction risk score (GARS) and selective evidence for inclusion of polymorphic allelic risk in substance use disorder (SUD).

Research into the neurogenetic basis of addiction identified and characterized by Reward Deficiency Syndrome (RDS) includes all drug and non-drug addictive, obsessive and compulsive behaviors. We are proposing herein that a new model for the prevention and treatment of Substance Use Disorder (SUD) a subset of RDS behaviors, based on objective biologic evidence, should be given serious consideration in the face of a drug epidemic. The development of the Genetic Addiction Risk Score (GARS) followed seminal research in 1990, whereby, Blum's group identified the first genetic association with severe alcoholism published in JAMA. While it is true that no one to date has provided adequate RDS free controls there have been many studies using case -controls whereby SUD has been eliminated. We argue that this deficiency needs to be addressed in the field and if adopted appropriately many spurious results would be eliminated reducing confusion regarding the role of genetics in addiction. However, an estimation, based on these previous literature results provided herein, while not representative of all association studies known to date, this sampling of case- control studies displays significant associations between alcohol and drug risk. In fact, we present a total of 110,241 cases and 122,525 controls derived from the current literature. We strongly suggest that while we may take argument concerning many of these so-called controls (e.g. blood donors) it is quite remarkable that there are a plethora of case -control studies indicating selective association of these risk alleles ( measured in GARS) for the most part indicating a hypodopaminergia. The paper presents the detailed methodology of the GARS. Data collection procedures, instrumentation, and the analytical approach used to obtain GARS and subsequent research objectives are described. Can we combat SUD through early genetic risk screening in the addiction field enabling early intervention by the induction of dopamine homeostasis? It is envisaged that GARS type of screening will provide a novel opportunity to help identify causal pathways and associated mechanisms of genetic factors, psychological characteristics, and addictions awaiting additional scientific evidence including a future meta- analysis of all available data -a work in progress.

Ecologic and Paleoclimatic Implications of Morphologic Variation of Orbulina universa in the Indian Ocean.

Multivariate cluster analysis of various morphologic indices of Orbulina universa populations from the Indian Ocean indicate the existence of two major groups whose geographic distribution corresponds to the equatorial and central water masses. An abrupt change in shell porosity between populations of this planktonic foraminiferal species in plankton as well as sediment samples occurs within or near the 10 degrees S Hydrochemical Front. Orbulina universa is an excellent indicator of oceanographic conditions in the Indian Ocean today, and may be used as an independent check on shifts in water masses during the last glaciation.

Understanding the Scientific Basis of Post-traumatic Stress Disorder (PTSD): Precision Behavioral Management Overrides Stigmatization.

Post-traumatic stress disorder (PTSD) is a severe polygenic disorder triggered by environmental factors. Many polymorphic genes, particularly the genetic determinants of hypodopaminergia (low dopamine function), associate with a predisposition to PTSD as well as substance use disorder. Support from the National Institutes of Health for neuroimaging research and molecular, genetic applied technologies has improved understanding of brain reward circuitry functions that have inspired the development of new innovative approaches to their early diagnosis and treatment of some PTSD symptomatology and addiction. This review presents psychosocial and genetic evidence that vulnerability or resilience to PTSD can theoretically be impacted by dopamine regulation. From a neuroscience perspective, dopamine is widely accepted as a major neurotransmitter. Questions about how to modulate dopamine clinically in order to treat and prevent PTSD and other types of reward deficiency disorders remain. Identification of genetic variations associated with the relevant genotype-phenotype relationships can be characterized using the Genetic Addiction Risk Score (GARS®) and psychosocial tools. Development of an advanced genetic panel is under study and will be based on a new array of genes linked to PTSD. However, for now, the recommendation is that enlistees for military duty be given the opportunity to voluntarily pre-test for risk of PTSD with GARS, before exposure to environmental triggers or upon return from deployment as part of PTSD management. Dopamine homeostasis may be achieved via customization of neuronutrient supplementation "Precision Behavioral Management" (PBM™) based on GARS test values and other pro-dopamine regulation interventions like exercise, mindfulness, biosensor tracking, and meditation.

Would induction of dopamine homeostasis via coupling genetic addiction risk score (GARS®) and pro-dopamine regulation benefit benzodiazepine use disorder (BUD)?

Prescriptions for Benzodiazepines (BZDs) have risen continually. According to national statistics, the combination of BZDs with opioids has increased since 1999. BZDs (sometimes called "benzos") work to calm or sedate a person by raising the level of the inhibitory neurotransmitter GABA in the brain. In terms of neurochemistry, BZDs act at the GABAA receptors to inhibit excitatory neurons, reducing VTA glutaminergic drive to reduce dopamine release at the Nucleus accumbens. Benzodiazepine Use Disorder (BUD) is very difficult to treat, partly because BZDs are used to reduce anxiety which paradoxically induces hypodopaminergia. Considering this, we are proposing a paradigm shift. Instead of simply targeting chloride channel direct GABAA receptors for replacement or substitution therapy, we propose the induction of dopamine homeostasis. Our rationale is supported by the well-established notion that the root cause of drug and non-drug addictions (i.e. Reward Deficiency Syndrome [RDS]), at least in adults, involve dopaminergic dysfunction and heightened stress. This proposition involves coupling the Genetic Addiction Risk Score (GARS) with a subsequent polymorphic matched genetic customized Pro-Dopamine Regulator known as KB220ZPBM (Precision Behavioral Management). Induction of dopamine homeostasis will be clinically beneficial in attempts to combat BUD for at least three reasons: 1) During detoxification of alcoholism, the potential induction of dopamine regulation reduces the need for BZDs; 2) A major reason for BZD abuse is because people want to achieve stress reduction and subsequently, the potential induction of dopamine regulation acts as an anti-stress factor; and 3) BUD and OUD are known to reduce resting state functional connectivity, and as such, potential induction of dopamine regulation enhances resting state functional connectivity. Future randomized placebo-controlled studies will investigate this forward thinking proposed novel modality.

Suppression of motion-produced smear during smooth pursuit eye movements.

Humans make smooth tracking eye movements to keep the image of a moving target on the foveal region of the retina and, thereby, maintain acute vision. Although the images of physically stationary background stimuli sweep across the retina during smooth pursuit eye movements, non-pursued targets are usually perceived to be neither moving nor smeared. The lack of perceived movement of background stimuli is generally attributed to a 'cancellation' of the retinal image motion by extraretinal information about the eye movement [1,2]; this information comes primarily from a neural facsimile of the efferent command to move the eyes, augmented by afferent signals from receptors in the extraocular muscles [3,4]. Here, we show that a physically stationary target presented during smooth tracking is perceived to have considerably less smear than a target that moves comparably across the retina, but when the eye is stationary. This result implies that extraretinal signals for pursuit eye movements also contribute to the alleviation of perceived smear for non-tracked, background targets.

Varicella in children with cancer: impact of antiviral therapy and prophylaxis.

To estimate the impact of antiviral therapy and prophylaxis on the natural course of the infection, 288 cases of varicella in children with cancer were reviewed. Among 127 patients with untreated infections, the overall mortality rate was 7%. Varicella-zoster virus pneumonitis developed in 28% of the untreated patients and was associated with a 25% mortality rate. Pneumonitis was much more likely to develop in patients with acute leukemia than in those with other malignancies (32% v 19%). Similarly, deaths due to pneumonitis were restricted to patients with acute leukemia. Lymphopenia (absolute lymphocyte count less than 500/microL) was significantly associated with varicella-zoster virus pneumonitis and a higher fatality rate among patients with this complication. Both acyclovir and adenine arabinoside, administered to 18 and 28 patients, respectively, stopped the progression of skin lesions; however, pneumonitis developed in none of the acyclovir recipients after two days of treatment, compared with 29% of the adenine arabinoside recipients (P = .03). Passive immunization in 45 children who subsequently had varicella was associated with an 11% incidence of varicella-zoster virus pneumonitis. Despite passive immunization of approximately 150 children, the attack rate of varicella at our institution remains unchanged. Results of this study demonstrate the efficacy of antiviral therapy and passive immunization in patients with childhood cancer and varicella, but prevention of the infection will require a universal vaccine.

Pseudomonas aeruginosa cellulitis and ecthyma gangrenosum in immunocompromised children.

Pseudomonas aeruginosa skin infections are generally considered to be secondary manifestations of disseminated disease. A retrospective analysis of all cases of P. aeruginosa skin infections seen at St. Jude Children's Research Hospital since 1962 revealed 16 episodes of the infection (ecthyma gangrenosum, 8 episodes, 7 patients; cellulitis, 8 episodes, 7 patients) in which blood cultures were uniformly negative for P. aeruginosa. All cases were identified while the patients were receiving ambulatory care. Five episodes developed while the patients' neutrophil counts were greater than 1 x 10(9) cells/liter. Eight patients had acute lymphoblastic leukemia, 2 had acute myeloid leukemia, 2 had aplastic anemia, 1 had transient agranulocytosis and 1 had cyclic neutropenia. There were no solid tumor patients. Although patients received different antibiotic combinations, all had resolutions of their lesions without fatal complications. Patients diagnosed as having cellulitis required a mean of 9.2 days of treatment with intravenous antibiotics, as compared with 17.8 days for those with ecthyma gangrenosum (P less than 0.05 by the Wilcoxon test). These observations show that P. aeruginosa skin infections can develop in the absence of bacteremia in immunocompromised children.

Benzodiazepine effects on flicker sensitivity: role of stimulus frequency and size.

1. Benzodiazepines (BZDs) impair sensitivity to temporally modulated visual stimuli (flicker). Critical flicker-fusion frequency (CFF) is commonly used as a measure of this effect, but it only measures sensitivity to a narrow range of frequencies, usually above 25 Hz. Are other frequencies more sensitive to the effects of BZDs? 2. Flicker sensitivity at 1, 2, 4, 8, 16, and 32 Hz was measured for 1 degrees and 5 degrees stimuli before and 50 to 100 minutes after triazolam (0.25 mg), lorazepam (1.0 mg) and placebo. Drug effects on CFF were also measured. 3. Both BZDs significantly impaired overall flicker sensitivity. Triazolam produced 50% more impairment than lorazepam. CFF was significantly impaired by triazolam. BZD effects did not vary with stimulus size. 4. Significantly greater BZD-induced impairment of flicker sensitivity occurred at 16 Hz than at 1, 2, 4, or 32 Hz. 5. The magnitude of BZD effects on flicker sensitivity vary with the temporal frequency of the stimulus. BZD effects are greatest for 8-16 Hz stimuli.

The relationship between vestibulo-ocular reflex plasticity and changes in apparent concomitant motion.

The vestibulo-ocular reflex (VOR) and the apparent motion of a spot stimulus fixated during head movement (apparent concomitant motion, ACM) were measured before and after an adaptation period during which subjects attempted fixation of a stimulus which moved either in the same or opposite direction as head oscillations. Movements of the head were voluntary and paced by a metronome at either 0.5 or 2.0 Hz during the 4 min adaptation period. Pre- and post-adaptation measures of VOR and ACM were obtained for both frequencies of head oscillation. VOR and ACM were altered similarly by the period of exposure to correlated head and stimulus motion. Viewing a stimulus moving in the same direction as head motion resulted in decreased VOR gain and increased ACM in the opposite direction as head motion. Viewing a stimulus moving opposite head motion resulted in increased VOR gain and increased ACM in the same direction as head movement. Differences between pre- and post-measures tended to be maximal at the adaptation frequency, but transferred to a lesser degree to the other frequency. The results indicate that changes in motor and perceptual systems are related, and are consistent with the proposal that VOR gain is a determinant of ACM.

The influence of subject instruction on horizontal and vertical vergence tracking.

Previously it has been reported that horizontal disparity vergence is strongly influenced by subject instructions to vary attention or tracking effort. This paper describes experiments which compared these instruction effects on horizontal and vertical disparity vergence. Within-trial comparisons were made possible by use of oblique (combined horizontal and vertical) disparity modulation. Subjects viewed a flat, fully correlated, dynamic random noise stereogram pattern through stationary circular apertures, with a small stationary fixation cross superimposed in the center. The disparity of the noise pattern was either modulated sinusoidally or changed abruptly. Subjects were instructed either to (1) hold fixation on the cross and ignore the disparity modulation of the noise pattern; or (2) follow the movement of the noise pattern as accurately as possible. Subjects showed clear effects of instruction on the horizontal component of tracking, but showed little or no effect on the vertical component. Horizontal and vertical components of oblique vergence tracking appear to be largely independent, and vertical vergence is affected minimally, if at all, by an effort to track.

Saccades reduce latency and increase velocity of ocular accommodation.

Horizontal vergence can be stimulated binocularly with disparity (disparity vergence) or monocularly with accommodation (accommodative vergence). The latter results from a neural cross-coupling that causes both horizontal vergence and accommodation to respond when either one is stimulated [Alpern, M., & Ellen, P. (1956). American Journal of Ophthalmology, 42, 289-303]. The velocity of disparity and accommodative vergence is enhanced when accompanied by saccades [Enright, J. T. (1984). Journal of Physiology (London) 350, 9-31; Enright, J. T. (1986). Journal of Physiology (London) 371, 69-89]. Based upon the coupling between accommodation and vergence, we predicted that accommodation should also be facilitated by saccades. An SRI Dual Purkinje Eyetracker was used to measure left and right eye position, and the accommodation of the left eye, in response to stimulation. Horizontal saccades were stimulated by targets separated by 2-6 degrees and accommodation was stimulated monocularly over a range of +/- 2 diopters (D). When saccades occurred within 0-400 ms following a monocular step stimulus to accommodation, latency of accommodation decreased and the associated accommodative-vergence response was synchronized with the saccade. Saccades also enhanced the velocity of accommodation and accommodative-vergence, and this facilitation increased with saccade amplitude. Transient vergence responses that are normally associated with saccades [Erkelens, C. J., Steinman, R. M., & Collewijn, H. (1989). Proceedings of the Royal Society of London B. Biological Sciences, 236, 441-465; Maxwell, J. S., & King, W. M. (1992). Journal of Neurophysiology, 68 (4), 1248-1260] did not affect accommodation when it was not stimulated by defocus. Because saccades and accommodation utilize separate plants and final common pathways, the synchronization of saccades and accommodation and the enhanced velocity of accommodation and accommodative-vergence must occur at more central sites. Possibilities include the superior colliculus, which represents both accommodation and saccades [Nagasaka, Y., & Ohtsuka, K., (1998). Investigative Ophthalmology AVRO supplement], vestibular nuclei which project to regions near the oculomotor nuclei [Lang, W., Buttner-Ennever, J. A., & Buttner, U. (1979). Brain Research, 177, 3-17], and interactions between omni pause neurons and near response cells of the mesencephalic reticular formation (MRF) [Mays, L. E., & Gamlin, P. D. R. (1995a). Current Opinions in Neurobiology, 5, 763-768; Mays, L. E., & Gamlin, P. D. R. (1995b). Eye movement research: Mechanisms, processes and applications. New York: Elsevier] which represent both accommodation and vergence [Judge, S. J., & Cumming, B. G. (1986). Journal of Neurophysiology, 55, 915-930; Zhang, Y., Mays, L. E., & Gamli, P. D. R. (1992). Journal of Neurophysiology, 67, 944-960].

A method for repeated high-fidelity micromanometer measurement of intracardiac pressures.

Dial-tipped, high-fidelity micromanometers were inserted through polyurethane catheters to acutely measure blood pressures within the chambers of the heart and the great vessels of baboons, rhesus monkeys, and goats. Repeated measurements of atrial, ventricular, aortic, and pulmonary artery pressure were possible with this method, with calibration of micromanometers accomplished immediately prior to and after pressure recordings to assure data accuracy. All attempts to pass micromanometers into the atria in all species were successful. Passage of micromanometers from the left ventricle across the aortic valve and into the aorta was successful in 97% of the attempts in baboons, 100% for rhesus monkeys, and 75% for goats; while insertions into the pulmonary artery from the right ventricle were successful in 64% of the baboons, 40% of the rhesus monkeys, and 75% of the goats. Advantages of this technique are that a permanent conduit for cardiac vascular access is available and that high-fidelity pressure signals may be acquired.

An effect of alcohol on the distribution of spatial attention.

OBJECTIVE: Previous research on the effects of alcohol on visual performance led us to the prediction that alcohol should interfere with the distribution of visual spatial attention. This prediction was examined in two experiments that measured the effect of alcohol on reaction time (RT) for tasks that differed in visual spatial attention requirements. METHOD: In the first experiment, 48 adult volunteers (33 female) responded to either the onset or offset of one of five potential targets without alcohol to determine the relative demands on attention of stimulus onset and offset. The spatial extent of the five-target display was also varied. In the second experiment, the effect of alcohol was determined for both the onset and the offset tasks in 12 adult volunteers (nine female). RESULTS: The offset task was found to place greater demands on spatial attention as the increase in display area result in relatively greater increases in RT. Alcohol increased RT in the offset task for the larger, but not the smaller, display, and there were no significant effects of alcohol for the onset task. CONCLUSIONS: The results indicate that alcohol impairs performance on tasks that place greater demands on visual spatial attention and likely disrupts the ability to shift attention from one spatial locus to another during serial search.

Effects of lorazepam on the distribution of spatial attention.

Reaction time (RT) to stimulus events was assessed for 2 tasks with different spatial attention demands before and after receiving either a placebo or lorazepam (1 mg). In 1 task (onset), 12 participants responded to the onset of 1 of 5 potential dot targets contained within either a small or large area. In the other task (offset), all 5 targets were illuminated and 12 participants responded to the offset of 1 of them. In the onset task, lorazepam slowed RT equally for both the large and small display areas. In the offset task, substantial impairment was found with the large but not the small display area. Results are consistent with the hypothesis that lorazepam interferes with the processes involved in the movement of spatial attention. The possibility that lorazepam selectively impairs the disengage component of attentional movement is discussed.

The effect of alcohol on the vestibulo-ocular reflex and apparent concomitant motion.

Measures of the vestibulo-ocular reflex (VOR) and apparent concomitant motion (ACM), the apparent motion of stationary visual stimuli during head motion, were obtained during sessions in which subjects consumed either alcoholic or placebo beverages. Both VOR and ACM remained constant throughout the placebo sessions. During sessions in which alcohol was consumed, the gain of the VOR was reduced and there was an increased tendency to see ACM in the direction opposite head motion. The effects of alcohol on ACM were greatest 50 min following cessation of drinking, near the maximum of the blood alcohol concentration (BAC). ACM measures then returned towards baseline, whereas the BAC measures remained elevated. VOR gain alterations paralleled the BAC measures. Therefore, reduction of VOR gain with alcohol produces an increase of ACM, but the ACM changes are relatively transient when compared with the altered VOR gain.

The conundrum of patient records.

Examines issues and concerns surrounding the management of patient information in the form of health records, such as accessibility, privacy, security, confidentiality, ownership and eventual disposal. Discusses the effects of health reform on the management of patient information, especially regionalization in Saskatchewan, and advances in technology. Concludes that it is incumbent on health-care professionals to show leadership and set guidelines since technology will outstrip legislation.

Sensitivity to full-field visual movement compatible with head rotation: variations among axes of rotation.

Movement detection thresholds for full-field visual motion about various axes were measured in three subjects using a two-alternative forced-choice staircase method. Thresholds for 1-s exposures to rotation about different rotation axes varied significantly over the range 0.139 +/- 0.05 deg/s to 0.463 +/- 0.166 deg/s. The highest thresholds were found in response to rotation about axes closely aligned to the line of sight. Variations among the thresholds for different axes could not be explained by different movement patterns in the fovea or variations in motion sensitivity with eccentricity. The variations can be well simulated by a three-channel model for coding the axis and velocity of full-field visual motion. A three-channel visual coding system would be well suited for extracting information about self-rotation from a complex pattern of retinal image motion containing components due to both rotation and translation. A three-channel visual motion system would also be readily compatible with vestibular information concerning self-rotation arising from the semicircular canals.

Observations on the adaptation of induced motion.

Induced motion (IM) was measured before and after a 10-min adaptation period during which subjects viewed the IM display without judging IM magnitude. The inducing stimulus was a rectangle, which contains both horizontal and vertical reference detail. The magnitude of IM was significantly lower following the adaptation period. This result is inconsistent with the hypothesis that adaptation of IM represents an instance of perceptual learning wherein the contribution of relative motion to motion perception is reduced. In a separate study, similar results were obtained when the inducing stimulus was a single vertical bar presented either to the left or to the right of the fixation stimulus. In addition, adaptation was obtained when the location of the inducing bar was changed during test measures, demonstrating that this effect is not specific to the retinal locus of the adaptation stimulus.

Up-down asymmetry in vertical induced motion.

Induced motion (IM) is the illusory movement of an object in the direction opposite to the real motion of adjacent detail. One theory of IM suggests that it results, in part, from suppression of optokinetic nystagmus (OKN) by fixational (smooth-pursuit) effort. In several studies an asymmetry in human vertical OKN has been reported, with upward optokinetic stimulation eliciting higher OKN gain than downward motion. This provides a test of the nystagmus-suppression theory of IM. If suppression of OKN contributes significantly to IM, upward inducing stimuli should result in a greater magnitude of the illusion than should downward stimulus motion. Additionally, the asymmetry of vertical OKN should become more pronounced at higher stimulus velocities. Therefore, the asymmetry of vertical IM should be greater at higher inducing-stimulus velocities. Twelve subjects viewed a large, random-dot stimulus, which moved either upward or downward at a velocity of 10, 40, or 70 deg s-1. Subjects fixated a horizontally moving laser spot and adjusted a rod to match the apparent slope of the motion path of the spot. IM magnitude was derived from these measures. Mean IM velocity was significantly higher with upward than with downward stimulation, and the difference was maximal at velocities of 40 and 70 deg s-1. The results are discussed within the context of the nystagmus-suppression theory and other theories of IM.