'VOR' - an interactive iPad model of the combined angular and linear vestibulo-ocular reflex

The mammalian vestibular system consists of a series of sensory organs located in the labyrinths of the inner ear that are sensitive to angular and linear movements of the head. Afferent inputs from the vestibular end organs contribute to balance, proprioception and vision. The vestibulo-ocular reflex (VOR) driven by these sensory inputs produces oculomotor responses in a direction opposite to head movement which tend to stabilise visual images on the retina. We present a model, in the form of a software application called VOR, which represents a simplified view of this complex system. The basis for our model is the hypothesis that afferent vestibular signals are integrated to maintain a notional internal representation of the head position (RHP). The vestibulo-ocular reflex maintains gaze towards a world-fixed point relative to the RHP, regardless of the actual head position. The RHP will imperfectly match the real head position when end organ input imperfectly reports head movements, such as can occur in cases of organ dysfunction and even in healthy subjects due to adaptation to motion stimuli. We do not claim that any specific observable part of the real vestibulo-ocular system corresponds to the RHP, but it seems reasonable to suggest that it might exist as a literal "neural network", trained through evolution and experience to maintain gaze during head movement. We hypothesise that the real VOR is supported by this internal representation, continually updated by afferent signals from the vestibular end organs, and that VOR eye responses tend to direct the eyes towards a fixed point in the world. Human vestibulo-ocular research typically employs equipment to which a subject is securely attached and allows rotation around, and sometimes linear movement along, one or more axes ("rotating chair") while attempting to maintain gaze on a fixation point, fixed relative to the head or world. A series of consecutive movements are referred to as a "motion profile". Meanwhile eye movements are recorded, using scleral search coils (or, more recently, video cameras and image-processing software) which can detect the horizontal, vertical and torsional components of the direction of each eye. VOR allows the user to define motion profiles and predicts the eye movements that a researcher or clinician might expect to observe in a real subject during such motion profiles. For example, the "on-centre rotation" motion profile specifies that the subject's head is positioned upright and centred around the vertical axis of the rotating chair, with a chair-fixed fixation point 1m in front of the subject. The chair accelerates angularly to 200°/sec over 20 seconds, rotates at a constant 200°/sec for 60 seconds, then decelerates to stationary over 20 seconds. The model accurately predicts the transient nystagmus that would be expected: its direction, duration, phase velocity and even the brief secondary nystagmus which is characteristic of adaptation to constant velocity rotation. VOR also allows the user to define end organ condition configurations, e.g. "normal", "bilateral vestibular loss", "unilateral superior neuritis", which are represented as a series of response gains attached to the sensory inputs from each end organ, relative to a nominal perfect gain of 1, and various other parameters which are derived from the human vestibular system, including the rate of drift of gaze to fixation point in light and dark, the rate at which the end organs adapt to constant stimuli, and quick-phase trigger dependencies. The VOR is not the only source of eye movement while attempting to maintain gaze on a fixation point. In our model, eye position drifts towards the fixation point at a nominal fixed rate. If this slow drift is insufficient to maintain gaze on the fixation point, a saccade or quick phase is triggered. Hence the transduction of mechanical forces at the labyrinths into sensory signals, subject to end organ conditions and adaptation that reduce the strength of the neuronal signals, maintain the RHP. Eye movement is then determined entirely by (a) the direction from RHP to the (world-referenced) fixation point, and (b) the disparity between eye direction and actual fixation point (which may be head-referenced). To validate the model, we prepared 24 motion profile/end organ condition combinations, compared the outputs from our model with real world observations, and found the results to be similar. Similarities include a simple first approximation of the linear and angular VOR; nystagmus caused by a subject's attempts to maintain fixation on a head-referenced target during head movement; decay of nystagmus through adaptation to stimulus, including secondary nystagmus; indefinitely prolonged nystagmus during off-vertical axis rotation (OVAR); rapid decay of nystagmus during the "tilt dump" motion profile, and dynamic cyclovergence during vertical linear acceleration. VOR is programmed in Objective-C using Xcode and runs on the Apple iPad. Its screen displays a 3d graphical representation of the virtual subject's head and eyes, including imaginary lines of sight to clarify eye movements. The user may program an effectively unlimited series of linear and angular motions of the rotating chair, and of the virtual subject's head relative to the chair. They may also program the gain (roughly, the sensitivity) associated with each end organ and other variables relating to the subject. They may select a series of internal variables to chart during the motion profile such as head velocity, eye direction, neuron firing rates, etc., while simultaneously displaying the head and eyes. VOR can record a video screen capture of the virtual head, eyes and lines of sight during the execution of a motion profile, a CSV file containing the internal variables at each time interval, a PNG image of the labelled chart, PDF descriptions of the motion profile and end organ condition configurations, and data files defining the motion profiles and end organ conditions which can then be exchanged between researchers/clinicians. Predefined motion profiles include: lateral, LARP and RALP head impulses; lateral head impulse with close fixation point; sinusoidal yaw, on-centre rotation, linear heave along Y axis, linear oscillation along X, Y and Z axes; linear sled along Y axis; forward- and backward-facing centrifugation; off-vertical axis rotation; tilt dump; and head tilt. Predefined conditions include: normal; left unilateral vestibular loss; bilateral vestibular loss; left superior neuritis; and "perfect" (unrealistic gain of 1 in otoliths, producing perfect linear VOR). All of these motion profiles and conditions may easily be modified, created and shared

ADVANCE AUSTRALIA FAIR? (IN)EQUALITY, PROSPERITY AND SUSTAINABILITY IN SHAPING AUSTRALIA’S FUTURE

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Indinavir/Low-dose Ritonavir Containing HAART in HIV-1 Infected Children has Potent Antiretroviral Activity, but is Associated with Side Effects and Frequent Discontinuation of Treatment

We here present the study results of 21 HIV-1 infected children who were treated with indinavir plus low-dose ritonavir and two nucleoside reverse transcriptase inhibitors (NRTIs) for 48 weeks. Although this q12h HAART regimen had potent antiretroviral activity, it was frequently associated with side effects and discontinuation of therapy

Efficacy of highly active antiretroviral therapy in HIV-1 infected children.

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Influenza bij kinderen.

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Therapieontrouw HIV-geinfecteerde kinderen.

Contains fulltext : 59267.pdf (publisher's version ) (Open Access

Pharmacokinetics of nelfinavir in children: influencing factors and dose implications.

Item does not contain fulltextOBJECTIVES: The study describes the pharmacokinetics (PK) of the protease inhibitor nelfinavir and its active metabolite M8 in children and evaluates the influence of patient-related factors on nelfinavir plasma levels. METHODS: HIV-1-infected children treated with nelfinavir every 8 h (q8h) were eligible for inclusion in this retrospective study. 0-8 h intensive plasma pharmacokinetics (PK) sampling was performed at steady state. Nelfinavir maximum concentration (Cmax), area under the plasma concentration-time curve in 0-8 h (AUC0-8), trough level at the 8 h time point (C8) and relative apparent oral clearance (CI*F/kg) were calculated. RESULTS: Twenty-four children (median age: 4.5 years, median nelfinavir dose: 28 mg/kg q8h) were included. Nelfinavir PK were highly variable: 10/24 children had an AUC0-8 below the value of 12.5 mg/l x h, which has previously been associated with an increased virological failure rate in children. With children aged 0.69 mg/l predicted an AUC0-8 > 12.5 mg/l x h with 71% sensitivity and 80% specificity. Dose of nelfinavir per body surface area was a better predictor of AUC0-8 than dose per body weight. CONCLUSION: Nelfinavir PK show high interindividual variability in children. Children < 2 years old tend to be at increased risk for low nelfinavir levels. These data show that the nelfinavir dose of 20 mg/kg q8h is inadequate in most children. Also, these data suggest that paediatric dosing of nelfinavir based on body surface area should be considered. Therapeutic drug monitoring (TDM) can detect abnormal plasma levels and is therefore useful in optimizing nelfinavir therapy in HIV-infected children. However, further research is needed to more firmly establish a therapeutic range for nelfinavir in children

A new method for analysis of AZT-triphosphate and nucleotide-triphosphates.

Contains fulltext : 57236.pdf (publisher's version ) (Closed access

Plasma levels of zidovudine twice daily compared with three times daily in six HIV-1-infected children.

Contains fulltext : 57984.pdf (publisher's version ) (Closed access)OBJECTIVES: Zidovudine is often administered every 12 h in HIV-infected children, but so far no pharmacokinetic data are available for the administration of this agent every 12 h. We have evaluated the plasma pharmacokinetics of zidovudine administered every 8 h versus every 12 h in HIV-1-infected children. METHODS: In HIV-1-infected children who switched from zidovudine every 8 h to every 12 h, a pharmacokinetic curve was recorded both before and after the switch. Zidovudine plasma levels were measured by HPLC. Pharmacokinetic parameters were calculated by non-compartmental methods. RESULTS: Six HIV-1-infected children [median age (range) 7.8 (2.5-13.4) years] were included. In these patients, geometric mean ratios of AUC(0-24) and C(max) for zidovudine every 12 h versus every 8 h were not significantly different from 1.0. CONCLUSIONS: The plasma pharmacokinetic parameters of zidovudine taken every 8 h and every 12 h were not significantly different and therefore suggest bioequivalence of these two dose frequencies