A Developmental Model of Infantile Nystagmus

The possibility that infantile nystagmus (IN) may reflect a failure in early sensorimotor integration has been proposed for more than a century, but is only recently being borne out in animal studies. The underlying neural and genetic substrate for this plasticity is complex. We propose that, in most cases, IN develops as a developmental response to reduced contrast sensitivity to high-spatial frequencies in an early "critical period," however caused, whether by structural malformations (e.g. foveal hypoplasia) or poor optics (e.g. cataract). As shown by psychophysics, contrast sensitivity to low spatial frequencies is enhanced by motion of the image across the retina. Based on our previous theoretical study (Harris & Berry, Nonlinear Dynamics, 2006), we argue that the best compromise between moving the image and maintaining the image near the fovea (or its remnant) is to oscillate the eyes with jerk nystagmus with increasing velocity waveforms, as seen empirically. The generation of jerk waveforms relies heavily on the saccadic system, which is immature in infancy. Pendular waveforms may therefore provide an alternative to jerk waveforms, and may explain why they are seen more often in young infants. We discuss the implications of this developmental model for the need to synchronize sensory and motor developments in normal development. Failure of this synchronization may also explain some idiopathic cases

A Distal Model of Congenital Nystagmus as Nonlinear Adaptive Oscillations

Congenital nystagmus (CN) is an incurable pathological spontaneous oscillation of the eyes with an onset in the first few months of life. The pathophysiology of CN is mysterious. There is no consistent neurological abnormality, but the majority of patients have a wide range of unrelated congenital visual abnormalities affecting either the cornea, lens, retina or optic nerve. In this theoretical study, we show that these eye oscillations could develop as an adaptive response to maximize visual contrast with poor foveal function in the infant visuomotor system, at a time of peak neural plasticity. We argue that in a visual system with abnormally poor high spatial frequency sensitivity, image contrast is not only maintained by keeping the image on the fovea (or its remnant) but also by some degree of image motion. Using the calculus of variations, we show that the optimal trade-off between these conflicting goals is to generate oscillatory eye movements with increasing velocity waveforms, as seen in real CN. When we include a stochastic component to the start of each epoch (quick-phase inaccuracy) various observed waveforms (including pseudo-cycloid) emerge as optimal strategies. Using the delay embedding technique, we find a low fractional dimension as reported in real data. We further show that, if a velocity command-based pre-motor circuitry (neural integrator) is harnessed to generate these waveforms, the emergence of a null region is inevitable. We conclude that CN could emerge paradoxically as an ‘optimal’ adaptive response in the infant visual system during an early critical period. This can explain why CN does not emerge later in life and why CN is so refractory to treatment. It also implies that any therapeutic intervention would need to be very early in life

Congenital Nystagmus as Non-Linear Adaptive Oscillations

Congenital Nystagmus (CN) is a pathological involuntary oscillation of the eyes with an onset within the first few months of life, with an incidence of about 1:3000. It is a life-long oculomotor disorder that cannot be explained by any underlying neurological abnormality which might compromise adaptive mechanisms. There is no cure, and CN has so far defied explanation in spite of numerous attempts to model the disorder. In this theoretical study we show that these eye oscillations could develop as an adaptive response to maximise visual contrast with poor foveal function in the infant visuomotor system, at a time of peak neural plasticity. We propose that CN is a normal developmental adaptive response to an abnormal congenital sensory input. This can explain why CN does not emerge later in life and why CN is so refractory to treatment. It also implies that any therapeutic intervention would need to be very early in life

A Developmental Model of Congenital Nystagmus

Purpose: Congenital nystagmus (CN) is a spontaneous oscillation of the eyes with an onset in the first few months of life. In 90% of affected children there is an associated underlying sensory defect (foveal hypoplasia, cone dysfunction, cataracts, etc.). In 10% no underlying visual defect can be found, and the nystagmus is labelled as ‘idiopathic’. CN appears to be a developmental anomaly of sensorimotor integration, as it is not have an onset later in infancy or beyond, but why such a wide variety of early onset visual defects should lead to life-long oscillation of the eyes is a mystery. Previous models have focussed on a systems level approach to explain how CN might be generated by known oculomotor circuits. We ask, instead, why CN might occur. Model: Our basic tenet is that infant visuomotor development is highly plastic during some early ‘critical’ period. A defect of foveal vision occurring during (and only during) this period leads to an anomalous connectivity in the oculomotor circuitry, which becomes permanent thereafter. We propose that circuitry normally used for precise foveal registration of a visual object (gaze holding, fixation, and smooth pursuit) develops to maintain some degree of image motion, as this would maximise contrast for a low spatial frequency system. However, this motion is in conflict with maintaining the image on the fovea (or its remnant). We explore the best oculomotor strategy to cope with this conflict. Results: The optimal strategy (in the least squares sense) is to oscillate the eyes in one meridian with alternating slow and quick (saccade) phases. Remarkably, the optimal waveform profile has an increasing-velocity profile. Many of the unique waveforms seen empirically in CN are also optimal strategies given realistic uncertainty in the initial position of a slow phase. Using non-linear dynamical systems analysis, we show that these ‘optimal’ oscillations have similar fractional correlation dimensions to observed data. We also show that a ‘null region’, as commonly observed in CN, would be an inevitable consequence of a velocity driven oculomotor system. Conclusions: We have developed a new approach to understanding oculomotor development, in which we examine the best strategy to maximise visual contrast. In a normal foveate visual system with fine oculomotor control, the best strategy is to develop good foveal registration, which we call ‘fixation’, and ‘smooth pursuit’. If, however, the fovea is absent or not being stimulated (eg. cataracts), the best strategy would be to develop oscillations of the type seen in CN. It implies that the chaotic oscillations are the result of a physiological developmental adaptive process. This is in contrast to the prevailing view that CN is a disease that can be ‘cured’. It is not surprising that CN has proven remarkably refractory to therapeutic intervention with only minimal (if any) long-term successes using drugs, surgery, or even biofeedback. We argue that CN is as adaptive and permanent as normal eye movements are in a normally sighted individual

IL-1 regulates the IL-23 response to wheat gliadin, the etiologic agent of Celiac Disease

Celiac disease (CD) is an autoimmune disease prevalent in ~1% of the general population. CD is unique because both the major genetic (Human Leukocyte Antigen-DQ2/DQ8 alleles) and etiologic factors (dietary glutens) for susceptibility are known. While these alleles are responsible for the inappropriate T cell response that characterizes CD, they are not sufficient since most HLA-DQ2+/DQ8+ individuals exposed to glutens never develop disease. The reasons for this have not been explained; however our novel findings strongly advocate a role for interleukin-23 (IL-23) in the immunopathogenesis of CD. We demonstrate that wheat gliadin stimulates monocytes to produce significantly higher amounts of inflammatory cytokines IL-1b, IL-23, and tumor necrosis factor-a (TNFa) in CD patients compared to HLA-DQ2+ healthy individuals. Furthermore, we determine that IL-1 signalling is obligatory for production of IL-23, since IL-1b triggers IL-23 secretion in a dose-dependent manner and IL-1 receptor antagonist (IL-1ra) blocks IL-23 responses to gliadin. Our results suggest that gliadin activation of monocytes and the subsequent robust secretion of IL-1b and IL-23 initiate the immune response cascade that is manifest as CD, and reveal for the first time that the IL-1 system regulates production of IL-23. The discovery of IL-23 has highlighted the critical role of the innate immune response in autoimmunity and other inflammatory conditions. We anticipate that our novel findings will lead to the discovery of therapeutic targets for this disease and other inflammatory diseases mediated by IL-23

Potential Deficit Reduction Efforts and WTO Cotton Ruling Adding to Policy Uncertainty

Agricultural and Food Policy, Crop Production/Industries, International Relations/Trade,

Electron Energy Distributions at Relativistic Shock Sites: Observational Constraints from the Cygnus A Hotspots

We report new detections of the hotspots in Cygnus A at 4.5 and 8.0 microns with the Spitzer Space Telescope. Together with detailed published radio observations and synchrotron self-Compton modeling of previous X-ray detections, we reconstruct the underlying electron energy spectra of the two brightest hotspots (A and D). The low-energy portion of the electron distributions have flat power-law slopes (s~1.5) up to the break energy which corresponds almost exactly to the mass ratio between protons and electrons; we argue that these features are most likely intrinsic rather than due to absorption effects. Beyond the break, the electron spectra continue to higher energies with very steep slopes s>3. Thus, there is no evidence for the `canonical' s=2 slope expected in 1st order Fermi-type shocks within the whole observable electron energy range. We discuss the significance of these observations and the insight offered into high-energy particle acceleration processes in mildly relativistic shocks.Comment: 5 pages, 3 figures, in Extragalactic Jets: Theory and Observation from Radio to Gamma Ray, Eds. T. A. Rector and D. S. De Youn

Recent Developments in Osteogenesis Imperfecta

Osteogenesis imperfecta (OI) is an uncommon genetic bone disease associated with brittle bones and fractures in children and adults. Although OI is most commonly associated with mutations of the genes for type I collagen, many other genes (some associated with type I collagen processing) have now been identified. The genetics of OI and advances in our understanding of the biomechanical properties of OI bone are reviewed in this article. Treatment includes physiotherapy, fall prevention, and sometimes orthopedic procedures. In this brief review, we will also discuss current understanding of pharmacologic therapies for treatment of OI