Characterizing heterogeneity of disease incidence in a spatial hierarchy: a case study from a decade of observations of fusarium head blight of wheat.

A multilevel analysis of heterogeneity of disease incidence was conducted based on observations of Fusarium head blight (caused by Fusarium graminearum) in Ohio during the 2002-11 growing seasons. Sampling consisted of counting the number of diseased and healthy wheat spikes per 0.3 m of row at 10 sites (about 30 m apart) in a total of 67 to 159 sampled fields in 12 to 32 sampled counties per year. Incidence was then determined as the proportion of diseased spikes at each site. Spatial heterogeneity of incidence among counties, fields within counties, and sites within fields and counties was characterized by fitting a generalized linear mixed model to the data, using a complementary log-log link function, with the assumption that the disease status of spikes was binomially distributed conditional on the effects of county, field, and site. Based on the estimated variance terms, there was highly significant spatial heterogeneity among counties and among fields within counties each year; magnitude of the estimated variances was similar for counties and fields. The lowest level of heterogeneity was among sites within fields, and the site variance was either 0 or not significantly greater than 0 in 3 of the 10 years. Based on the variances, the intracluster correlation of disease status of spikes within sites indicated that spikes from the same site were somewhat more likely to share the same disease status relative to spikes from other sites, fields, or counties. The estimated best linear unbiased predictor (EBLUP) for each county was determined, showing large differences across the state in disease incidence (as represented by the link function of the estimated probability that a spike was diseased) but no consistency between years for the different counties. The effects of geographical location, corn and wheat acreage per county, and environmental conditions on the EBLUP for each county were not significant in the majority of years.

Variability in fusarium head blight epidemics in relation to global climate fluctuations as represented by the El Niño-Southern Oscillation and other atmospheric patterns.

Cross-spectral analysis was used to characterize the relationship between climate variability, represented by atmospheric patterns, and annual fluctuations of Fusarium head blight (FHB) disease intensity in wheat. Time series investigated were the Oceanic Niño Index (ONI), which is a measure of the El Niño-Southern Oscillation (ENSO), the Pacific-North American (PNA) pattern and the North Atlantic Oscillation (NAO), which are known to have strong influences on the Northern Hemisphere climate, and FHB disease intensity observations in Ohio from 1965 to 2010 and in Indiana from 1973 to 2008. For each climate variable, mean climate index values for the boreal winter (December to February) and spring (March to May) were utilized. The spectral density of each time series and the (squared) coherency of each pair of FHB-climate-index series were estimated. Significance for coherency was determined by a nonparametric permutation procedure. Results showed that winter and spring ONI were significantly coherent with FHB in Ohio, with a period of about 5.1 years (as well as for some adjacent periods). The estimated phase-shift distribution indicated that there was a generally negative relation between the two series, with high values of FHB (an indication of a major epidemic) estimated to occur about 1 year following low values of ONI (indication of a La Niña); equivalently, low values of FHB were estimated to occur about 1 year after high values of ONI (El Niño). There was also limited evidence that winter ONI had significant coherency with FHB in Indiana. At periods between 2 and 7 years, the PNA and NAO indices were coherent with FHB in both Ohio and Indiana, although results for phase shift and period depended on the specific location, climate index, and time span used in calculating the climate index. Differences in results for Ohio and Indiana were expected because the FHB disease series for the two states were not similar. Results suggest that global climate indices and models could be used to identify potential years with high (or low) risk for FHB development, although the most accurate risk predictions will need to be customized for a region and will also require use of local weather data during key time periods for sporulation and infection by the fungal pathogen.

Relationship between yearly fluctuations in Fusarium head blight intensity and environmental variables: a window-pane analysis.

Window-pane methodology was used to determine the length and starting time of temporal windows where environmental variables were associated with annual fluctuations of Fusarium head blight (FHB) intensity in wheat. Initial analysis involved FHB intensity observations for Ohio (44 years), with additional analyses for Indiana (36 years), Kansas (28 years), and North Dakota (23 years). Selected window lengths of 10 to 280 days were evaluated, with starting times from approximate crop maturity back to the approximate time of planting. Associations were quantified with Spearman rank correlation coefficients. Significance for a given variable (for any window starting time in a collection of starting times) was declared using the Simes' multiplicity adjustment; at individual time windows, significant correlations were declared when the individual (unadjusted) P values were <0.005. In all states, moisture- or wetness-related variables (e.g., daily average relative humidity [RH] and total daily precipitation) were found to be positively correlated with FHB intensity for multiple window lengths and starting times; however, the highest correlations were primarily for shorter-length windows (especially 15 and 30 days) at similar starting times during the final 60 days of the growing season, particularly near the time of anthesis. This period encompasses spore production, dispersal, and fungal colonization of wheat spikes. There was no evidence of significant correlations between FHB and temperature-only variables for any time window; however, variables that combined aspects of moisture or wetness with temperature (e.g., duration of temperature between 15 and 30 degrees C and RH > or = 80%) were positively correlated with FHB intensity. Results confirm that the intensity of FHB in a region depends, at least in part, on environmental conditions during relatively short, critical time periods for epidemic development.

The effects of different levels of all-rac- and RRR-alpha-tocopheryl acetate (vitamin E) on visual function in rats.

OBJECTIVE: A rat model of vitamin E (alpha-tocopherol) deficiency with similar "clinical", electrophysiological and neuropathological abnormalities to that seen in man was used to investigate the effects of various dietary intakes of synthetic (all-rac-) and natural (RRR-) alpha-tocopheryl acetate (alphaTA) on visual function. METHODS: Longitudinal measurements of the electroretinogram (ERG) and visual evoked potentials (VEPs) were made monthly for 14 months in 9 groups of rats (n=12/group) receiving different amounts and types of alphaTA. The animals were then killed for biochemical analyses. RESULTS: (1) The first significant abnormalities of both the ERG and VEP were found after 8 months of deficiency. (2) A diet containing 1.25 mg/kg of alphaTA provided marginal protection. (3) The biological activity of all-rac- was approximately 75% of RRR-alphaTA. (4) The concentration of free malondialdehyde (a measure of lipid peroxidation) was significantly increased in all tissues, including the eye, from deficient compared to control rats. CONCLUSIONS: These results are consistent with alpha-tocopherol deficiency causing increased lipid peroxidation leading to abnormal visual function but could also be explained by more specific but undefined function(s) of alpha-tocopherol in the eye.

Diagnosing children presenting with asymmetric pendular nystagmus.

Horizontal asymmetric nystagmus usually occurs in one of three situations: secondary to an intracranial lesion, with monocular visual loss, or as part of the triad that constitutes the diagnosis of spasmus nutans (asymmetric nystagmus, abnormal head posture, head shake). Clinical records of 277 children, presenting with congenital nystagmus over an 8-year period were reviewed. Nystagmus was asymmetric in 24 of 277 cases. Seven of these patients were diagnosed with spasmus nutans. This is a rare condition that is only diagnosed retrospectively based on the absence of any abnormal neuroimaging or electrophysiological findings. Twelve of 24 patients had intracranial pathology and all had abnormal visual evoked potentials (VEPs). Five patients were diagnosed with congenital sensory defect nystagmus including one with albinism, three with congenital cone dysfunction, and one with cone-rod dystrophy. This paper stresses that although neuroimaging is necessary in all patients presenting with asymmetric nystagmus, such nystagmus can also occur with retinal disease or albinism and indicates the importance of non-invasive VEP/ERG testing in all forms of nystagmus.

A study of the effects of contrast change on pattern VEPS, and the transition between onset, reversal and offset modes of stimulation.

We studied the relationship between the visual evoked potential (VEP) components by tracing the transition from onset/offset mode of stimulation to the reversal mode by a series of contrast change steps. VEPs on the ipsilateral and contralateral side of the scalp with respect to the left half-field checkerboard stimulus (checksizes: 12', 50' and 80') were recorded in 15 subjects. Eight contrast steps for each checksize were recorded. Each test step consisted of the alternation of a constant high contrast checkerboard (A), with a second checkerboard (B) in which the contrast was changed. Checkerboard B was initially of identical spatial phase to A, but contrast was reduced systematically until B was a uniform grey field (i.e. onset/offset). In subsequent steps checkerboard B was of opposite spatial phase and contrast was increased until the final step when B was of equal high contrast (i.e. full reversal). All ipsilateral and contralateral onset components, ipsilateral offset components, and the reversal P100 component significantly enlarged with increasing contrast. The extent of amplitude change with contrast was greatest for offset, followed by onset and then reversal. A clear association could be discerned between all offset and reversal components. Onset CI and CII appeared to be related to the reversal P100 and N145, respectively. When small 12' checks were used, onset Co appeared to have common features with the reversal N80. The contralateral onset P105 component did not have a comparable component in the reversal mode.

In vivo, in utero microscopic magnetic resonance imaging: application in a rat model of diaphragmatic hernia.

This article presents a microscopic MR technique for imaging small mammalian fetuses in utero and in vivo which can be used as a tool for studying normal and abnormal development in small animal fetal models, for targeting in utero intervention in such models, and for following development serially. This new method is applied to a rat model of congenital diaphragmatic hernia (CDH). Pregnant Sprague-Dawley rats were fed nitrofen at 9.5 days postcoitus to induce CDH in the fetuses. The dams were imaged to identify fetuses with CDH for targeted in utero intervention, which consisted of fetal tracheal ligation. Following tracheal ligation, the fetuses were followed serially with our MR technique. For MR imaging, the dam was anesthetized with intramuscular ketamine and intraperitoneal pentobarbital. In utero imaging was performed on a 4 Tesla MRI system using a multislice, fast spin echo sequence with a long TR and short effective TE. These results were validated by examining individual fetuses postmortem using high-resolution MR and anatomic dissection. The in utero, in vivo MR technique is highly accurate for diagnosing CDH and following the effects of surgical intervention, and shows promise as a tool for the study of embryogenesis in small animal models. Magn Reson Med 44:331-335, 2000.

A study of EEG, electroretinogram, visual evoked potential, and eye movements in classical lissencephaly.

EEG, flash electroretinogram (ERG), and visual evoked potential (VEP) findings are described in eight children with classical lissencephaly (six girls, two boys), with a mean age of 17.6 months (range 2 to 60 months). The EEG shows typically high-voltage activity. Eye movements were formally recorded in two patients, and both showed features associated with oculomotor apraxia. The ERG and VEP to flash stimulation were normal in all cases. Two subjects had pattern reversal stimulation, and their pattern VEPs were within normal limits. Some patients with lissencephaly may appear to have delayed visual maturation on first presentation, and EEG and eye movement studies are valuable in indicating neurological deficiency at an early stage in these subjects.

Vertical or asymmetric nystagmus need not imply neurological disease.

AIM: To indicate that congenital idiopathic nystagmus (CIN) and sensory defect nystagmus (SDN) can be vertical or asymmetric in some children. METHODS: Of 276 children presenting with nystagmus for electrophysiological testing, 14 were identified as having CIN or SDN, yet had a nystagmus which was either vertical (n=11) or horizontal asymmetric (n=3). Flash electroretinograms and flash and pattern visual evoked potentials (VEPs) were recorded in all patients. Eye movement assessment, including horizontal optokinetic nystagmus (OKN) testing, was carried out in 11/14 patients. RESULTS: Eight patients (seven with vertical, one with asymmetric horizontal nystagmus) had congenital cone dysfunction. One patient with vertical and another with asymmetric nystagmus had cone-rod dystrophy. One patient with vertical upbeat had congenital stationary night blindness. Two patients (one downbeat, one upbeat nystagmus) had normal electrophysiological, clinical, and brain magnetic resonance imaging findings and were classified as having CIN. One patient with asymmetric nystagmus showed electrophysiological and clinical findings associated with albinism. Horizontal OKN was present in 80% of patients tested, including the three cases with horizontal asymmetric nystagmus. This is atypical in both CIN and SDN, where the OKN is usually absent. CONCLUSIONS: Vertical and asymmetric nystagmus are most commonly associated with serious intracranial pathology and its presence is an indication for neuroimaging studies. However, such nystagmus can occur in children with retinal disease, albinism, and in cases with CIN. These findings stress the importance of non-invasive VEP/ERG testing in all cases of typical and also atypical nystagmus.

Sodium visibility and quantitation in intact bovine articular cartilage using high field (23)Na MRI and MRS.

Noninvasive methods of detecting cartilage degeneration can have an impact on identifying the early stages of osteoarthritis. Accurate measurement of sodium concentrations within the cartilage matrix provides a means for analyzing tissue integrity. Here a method is described for quantitating sodium concentration and visibility in cartilage, with general applications to all tissue types. The sodium concentration in bovine patellar cartilage plugs was determined by three different methods: NMR spectroscopy of whole cartilage plugs, NMR spectroscopy of liquefied cartilage in concentrated HCl, and inductively coupled plasma emission spectroscopy. Whole bovine patellae were imaged with relaxation normalized calibration phantoms to ascertain sodium concentrations inside the articular cartilage. Sodium concentrations in intact articular cartilage were found to range from approximately 200 mM on the edges to approximately 390 mM in the center, with an average of approximately 320 mM in five separate bovine patellae studied. In essence, we have created sodium distribution maps of the cartilage, showing for the first time, spatial variations of sodium concentration in intact cartilage. This average concentration measurement correlates very well with the values obtained from the spectroscopic methods. Furthermore, sodium was found to be 100% NMR visible in cartilage plugs. Applications of this method in diagnosing and monitoring treatment of osteoarthritis are discussed.

Visual-evoked potential evidence of chiasmal hypoplasia.

PURPOSE: To show that chiasmal hypoplasia or aplasia need not be an isolated developmental anomaly and to examine the spectrum of associated clinical findings to explore the possibility that these patients may represent a phenotypic manifestation of a developmental gene anomaly. DESIGN: An observational case series. PARTICIPANTS: Five infants, between several weeks and 7 months of age, in whom the electrophysiologic characteristic of chiasmal hypoplasia had been noted were included. METHODS: Flash electroretinography and flash and pattern visual-evoked potentials (VEPs) were elicited from all patients. Clinical ophthalmologic examinations, including funduscopy, were performed, and all patients had magnetic resonance imaging (MRI) brain scans. MAIN OUTCOME MEASURES: The occipital distribution of monocular VEP response peaks was studied. The symmetry of lateral channel responses was compared for monocular stimulation. RESULTS: All five patients had a crossed asymmetry in the monocular VEP occipital distribution, which is consistent with a paucity of fibers crossing at the chiasm. The MRI findings supported this electrophysiologic observation, illustrating degrees of chiasmal hypoplasia and variable coincidence of other midline abnormalities of the brain. Optic disc appearances varied from normal to hypoplastic and colobomatous. CONCLUSIONS: The ophthalmologic and MRI findings of five patients who showed a crossed asymmetry in monocular flash VEPs are consistent with a paucity of axons crossing at the chiasm. The similarities between achiasmia in humans and mice due to a Pax2 gene anomaly are discussed.

Visual evoked potential evidence of albino-like chiasmal misrouting in a patient with Angelman syndrome with no ocular features of albinism.

An 8-month-old boy with global developmental delay, including visual and hearing inattention, was examined in the ophthalmic clinic. Monocular flash visual evoked potentials demonstrated a crossed asymmetry in scalp distribution, a feature considered to be pathognomic of albinism. Remarkably a foveal reflex was noted in each eye and this patient did not have nystagmus, iris transillumination, nor conspicuously pale fundi. The optic discs appeared normal. He was noted to have very fair skin and hair, with a small head and flat occiput. Cytogenetic studies demonstrated a microdeletion of the maternal chromosome 15q11-q13, and he was diagnosed with Angelman syndrome.

Comparison of the effects of four anaesthetic agents on somatosensory evoked potentials in the rat.

Electrophysiological techniques provide an objective and non-invasive measure of neurological function. In order to undertake detailed evoked potential studies in rats on repeated occasions, it is necessary to find an appropriate anaesthetic agent which has minimal and reproducible effects on the parameters to be studied and also has a minimal effect on the general welfare of the animals. In this study we compared the effects of four common anaesthetic agents (ketamine-xylazine, medetomidine, isoflurane and fentanyl/fluanisone-midazolam) on somatosensory evoked potentials (SEPs) in rats following electrical stimulation of the fore- and hind-paw. Fentanyl/fluanisone-midazolam was found to be well tolerated by the animals and to have, in general, the least deleterious effect on SEPs. For example, the response recorded at the level of the somatosensory cortex (P1), following forelimb stimulation, appeared on average 1.80 ms earlier with fentanyl/fluanisone-midazolam than with the other agents and the peak-to-peak amplitude (CI to CII) of the response recorded at the cervical (C3) level was on average 5.86 microV greater with fentanyl/fluanisone-midazolam. Fentanyl/fluanisone-midazolam is, therefore, recommended as the anaesthetic of choice for longitudinal studies of SEPs in the rat.

Saccadic strategies in children with hemianopia.

Multiple hypometric (undershooting) saccades are generally reported as a compensatory strategy in adults with homonymous hemianopia. However, hypermetric (overshooting) saccades have been reported to develop spontaneously as a beneficial strategy in response to predictable targets. We examined the saccades of 10 children (aged 5 to 16 years) with homonymous hemianopia to determine the type of compensatory eye-movement strategies employed 6 months to 16 years after hemianopia onset. Homonymous hemianopia was identified using perimetry and/or pattern visual evoked potentials and supported with results of neuroimaging. Eye movements were recorded using bitemporal electrooculography. Saccades were elicited to a red light source in a semipredictable paradigm. We found that hypermetria was not a consistent compensatory strategy in our patients. In spite of the predictability of our paradigm and the long follow-up period, multiple hypometric saccades into the blind field appeared to be the preferred strategy.

Early VEP and ERG evidence of visual dysfunction in autosomal recessive osteopetrosis.

Autosomal recessive (AR) osteopetrosis has a rapid course and manifests in the first months of life. Visual loss occurs because of optic nerve compromise, and more rarely retinal dysfunction (which may be a part of a primary neurodegeneration). The only curative treatment currently available is bone marrow transplantation (BMT). It has been suggested that BMT is contraindicated if AR osteopetrosis is associated with a primary neurodegeneration. Visual impairment tends to be irreversible after BMT. The young age of the patients makes reliable, objective tests of visual function especially important. We have reviewed the flash electroretinograms (ERGs) and flash and pattern visual evoked potentials (VEPs) recorded without sedation from 15 patients with AR osteopetrosis, 11 of whom were recorded longitudinally. The most frequent, early indication of visual dysfunction was a delay in the pattern or flash VEP latency. This first affects the pattern reversal VEP to small checks. Importantly this often preceded fundal changes of optic disc pallor, and evidence of optic nerve compression on neuroimaging. Only two patients had ERG evidence of retinal dysfunction affecting both rods and cones. One of these patients had a distinctive fundal appearance, but did not have evidence of associated neuronal degenerative disease. The other patient was lost to follow-up. In the patients reviewed in this study successful BMT and optic nerve decompression did not result in VEP improvement. Fundoscopy, VEP and ERG testing are indicated when the diagnosis of AR osteopetrosis is suspected and provide a useful means of monitoring visual involvement.

Alström syndrome. Report of 22 cases and literature review.

OBJECTIVE: The authors report 22 cases of Alström syndrome (AS), which is the largest series to date. Only 37 cases have been reported in the world literature since 1959. The authors review the clinical features and compare these with the overlapping condition of Bardet-Biedl syndrome. Their aim is to clarify the AS phenotype and to increase awareness of the early features. DESIGN: A retrospective case series. PARTICIPANTS: All patients (22) with a diagnosis of AS admitted to the authors' hospital in the past 10 years were included in this review. INTERVENTION: This is principally a review of ocular features, but other features are recorded and discussed. MAIN OUTCOME MEASURES: Features noted included age at onset of visual symptoms, presence of photophobia, visual acuity, and electroretinogram findings. Nonocular features recorded included cardiac status, weight and height, hearing, and presence of diabetes mellitus. RESULTS: Cardiomyopathy presenting in infancy has only been recognized recently to be a feature of AS. Of the authors' cases, 18 of 22 had infantile cardiomyopathy. In the authors' tertiary referral institution, there is an ascertainment bias toward younger patients and especially those with pathology that is other than ocular pathology. In addition, AS is difficult to recognize in childhood without the development of infantile cardiomyopathy. Alström syndrome often is not recognized until diabetes mellitus develops in the second or third decade. Initially, a diagnosis of cone-rod dystrophy, achromatopsia, Leber's congenital amaurosis, or Bardet-Biedl syndrome may be made. In AS, there is a severe infantile retinal dystrophy. The electroretinogram is absent or attenuated with better preserved rod than cone function. The retinal dystrophy is progressive with the patient's visual acuity of 6/60 or less by 10 years of age and no light perception by 20 years of age. CONCLUSIONS: A diagnosis of AS should be considered in infantile cone and rod retinal dystrophy, particularly if the weight is above the 90th percentile (16 of 18 cases) or if there is an infantile cardiomyopathy (18 of 22 cases).

The nanophthalmic macula.

AIMS: To define an unusual macular appearance found in association with nanophthalmos. METHODS: A case review. RESULTS: Seven children (aged 8 months to 17 years) with nanophthalmos were examined. They all exhibited the same clinical findings of an unusual yellow macula appearance with retinal folds and crowded optic discs. Visual electrophysiology performed in four cases was normal. CONCLUSION: A distinctive yellow macular pigmentation with associated chorioretinal folds and crowded optic discs is present in nanophthalmos. It is proposed that the retinal folds are due to a disparity between scleral and retinal growth while the macula discoloration is due to a congenital abnormality in arrangement or position of the luteal pigment and is not degenerative. Included in this case series is the second case in the literature of nanophthalmos associated with Kenny's syndrome. Inheritance of nanophthalmos appears to be autosomal recessive.