Immune responses to human factor IX in haemophilia B mice of different genetic backgrounds are distinct and modified by TLR4.

Our laboratory develops protocols to prevent or reverse ongoing anti-hFIX IgG inhibitors in haemophilia B mice with a F9 gene deletion on BALB/c and C3H/HeJ backgrounds. C3H/HeJ F9(-/Y) mice develop high titre anti-hFIX IgG1 inhibitors and anaphylaxis, whereas most BALB/c F9(-/Y) mice have mild anti-hFIX IgG1 inhibitors and no anaphylaxis. Our aim was to determine if hFIX-specific B- and T-cell responses in BALB/c and C3H/HeJ F9(-/Y) mice trigger the difference in anti-hFIX immune responses. BALB/c and C3H/HeJ F9(-/Y) mice were challenged weekly with recombinant hFIX protein. Humoral immune responses were determined by IgG1 and IgG2a anti-hFIX ELISA, Bethesda assay for inhibitors and B-cell ELISpot on bone marrow and spleen cells. T-cell studies measured the TH 1 (IFN-γ) and TH 2 (IL-4) cytokine responses in splenocytes at the mRNA and protein level in response to hFIX protein. Antibody responses were also measured in C3H/HeJ/OuJ F9(-/Y) mice with restored toll-like receptor 4 (TLR4) function. BALB/c F9(-/Y) mice have a TH 2 skewed response and a reduction in anti-hFIX secreting plasma cells in the bone marrow. Independent antigen challenge revealed both strains generated equivalent IgG1 antibody titres to an intravenously delivered antigen. C3H/HeJ F9(-/Y) mice have a mixed TH 1 and TH 2 response (mainly TH 2). Importantly, TLR4 signalling has a modulatory role in the C3H background on the levels of anti-hFIX IgG1 and incidence of anaphylaxis. The background strain strongly impacts the immune response to hFIX, which can be significantly impacted by mutations in innate immune sensors.

Relationship among fMRI, contrast sensitivity and visual acuity.

The purpose of this study was to ascertain whether visual acuity or contrast sensitivity function (CSF) is proportional to visual cortical function based on fMRI volume and level of activation or Z-score. Forced choice procedures were utilized to measure the monocular log minimal angle of resolution (logMAR) visual acuity and CSF. The CSF data were collapsed into a single index by the use of weighted mean contrast sensitivity (WMCS), being defined as the mean of the products of each spatial frequency multiplied by its corresponding contrast sensitivity. fMRI data had been obtained with a 1.5 T GE Signa scanner with visual stimuli including 1.0 and 2.0 c/deg vertical sinusoidal gratings. Subjects consisted of eight normal adults and five amblyopic patients, with the amblyopic subjects added to gauge whether the outcome was due to a restricted range of scores or the small number of study participants. In normal subjects, the fMRI volume and level of activation exhibited no statistically significant correlation with visual acuity at P<0.05. Statistically significant correlations were obtained between WMCS and fMRI volume (R=0.765, P=0.027) and fMRI level of activation (R=0.645, P=0.007), with right eye stimulation using the 1.0 c/deg grating. On the whole, statistically significant correlations between WMCS and fMRI parameters were maintained when subject age was held constant and when data from the five amblyopic subjects were included to expand the range of values and increase the number of data sets for analysis. fMRI volume and Z-score were more closely associated with the CSF, as defined by WMCS, than visual acuity. The results suggest that the CSF reflects the underlying visual cortical cells responsible for fMRI volume and the level of activation.

Spectral model of a fluorescent ink halftone.

A model is presented of a fluorescent ink halftone. Unlike a nonfluorescent ink, which only absorbs, a fluorescent ink absorbs higher-energy photons and emits lower-energy photons. The amount of fluorescent light produced depends on the percent absorption of the incident light. For fluorescent ink printed on paper, both photon scattering within the paper substrate and multiple internal reflections between the ink layer and the paper substrate significantly increase the percent absorption, so a realistic model must include these effects. The model presented here utilizes the generalized Clapper-Yule theory, which accounts for photon diffusion that is due to both scatter and internal reflection. It is shown that while multiple internal reflections alone only marginally increase the percent absorption, when there are both scattering and internal reflection, the percent absorption is increased significantly. The current study is a theoretical model and does not present experimental results.

Pseudotumor cerebri in children receiving recombinant human growth hormone.

PURPOSE: This article represents the first report in the ophthalmology literature of an association between pseudotumor cerebri (PTC) and recombinant human growth hormone (rhGH). DESIGN: Noncomparative case series. PARTICIPANTS: Three children receiving rhGH for short stature with Turner syndrome, Jeune syndrome, or Down syndrome. METHODS: Children underwent full ocular examination. After papilledema was identified, patients underwent lumbar puncture and imaging with either magnetic resonance imaging or computerized tomography. Treatment was under the guidance of the primary physician or neurosurgeon. The rhGH was discontinued in all children. MAIN OUTCOME MEASURES: Visual acuity and evaluation of the optic nerve for resolution of papilledema were followed at each examination. RESULTS: In all three cases, papilledema resolved with the cessation of rhGH, and treatment with acetazolamide or prednisone. Visual acuity was unchanged in case 1, decreased by two to three lines in case 2, and was inconsistent in case 3. One child (case 2) required a ventriculoperitoneal shunt for persistent elevation of intracranial pressure. CONCLUSION: There appears to be a causal relationship between the initiation of rhGH with the development of PTC. Children should have a complete ophthalmic evaluation if they report headache or visual disturbances. Baseline examination with routine follow-up should be instituted when children cannot adequately communicate.

Strabismus in premature infants in the first year of life. Cryotherapy for Retinopathy of Prematurity Cooperative Group.

OBJECTIVES: To present the 3- and 12-month strabismus data from 3030 premature infants with birth weights less than 1251 g enrolled in the Multicenter Trial of Cryotherapy for Retinopathy of Prematurity. DESIGN: Data from the 3- and 12-month examinations conducted at 23 regional study centers were tabulated for all infants. The main outcome measure, ocular motility, was compared with baseline demographic variables and retinopathy of prematurity severity for the worse eye. Findings at 3 months were compared with the incidence of strabismus at 12 months. RESULTS: At 3 months, 200 (6.6%) of the 3030 infants were strabismic. In the 2449 infants examined at both time points, 289 (11.8%) were found to have strabismus at 12 months. Retinopathy of prematurity was significant for strabismus at both 3 and 12 months (P<.001). The presence of strabismus at 3 months was found to be a highly significant predictor of strabismus at 12 months. Anisometropia, abnormal fixation, and unfavorable retinal structure also were significant predictors of strabismus at 1 year. The total prevalence of strabismus in the first year of life was 14.7%. CONCLUSION: The presence of acute-phase retinopathy of prematurity places the premature infant at increased risk for strabismus.

Occlusion and levodopa-carbidopa treatment for childhood amblyopia.

PURPOSE: The purpose of the current study was to compare the effects of levodopa-carbidopa with and without part-time occlusion on visual function in older amblyopic children. METHODS: Thirteen older amblyopic children were randomly assigned to receive or not receive part-time occlusion (3 h/day) combined with 7 weeks of oral dosing with levodopa-carbidopa (1.02 mg/0.25 mg/kg body weight three times daily). Visual acuity, contrast sensitivity, and fusion were measured at baseline; 1, 3, 5, and 7 weeks during the treatment regimen; and 4 weeks after termination of all treatment. At these same times health status was assessed with standard laboratory blood tests, physical examination, and subjective questionnaire. RESULTS: From baseline to the follow-up test trial, both groups improved in visual acuity in the amblyopic eyes (occlusion group 20/116 to 20/76, P < .001; no occlusion group 20/90 to 20/73, P < .01) and dominant eyes (occlusion group 20/18 to 20/15, P > .05; no occlusion group 20/20 to 20/16, P < .01). The occlusion group exhibited a significant decrease in the difference in acuity between the dominant and amblyopic eyes of 1.3 lines (P < .02), whereas the no occlusion group revealed no significant effect. A comparison between groups revealed a significantly greater improvement in visual acuity in the amblyopic eye in the occlusion group compared with the no occlusion group (P = .01). In contrast, there was no significant difference between groups in terms of the change in visual acuity in the dominant eye (P = .15). Mean log contrast sensitivity in the amblyopic eye significantly improved in the occlusion group and did not significantly change in the no occlusion group. Fusion changed similarly in both groups. The improvements in visual function were maintained 4 weeks after the termination of all treatment. Adverse side effects were minimal in both groups. CONCLUSION: The combination of levodopa-carbidopa and occlusion improves visual function more than levodopa-carbidopa alone in older amblyopic children.

Levodopa-carbidopa and childhood retinal disease.

PURPOSE: Our purpose was to determine the influence of levodopa-carbidopa on visual function in children with retinal disease. METHOD: Two studies were undertaken, a single-dose study and a longitudinal dosing study. A double-masked, placebo controlled single-dose study was undertaken of levodopa-carbidopa (2.08 mg/kg of body weight levodopa with 25% carbidopa) on monocular visual acuity in 14 children with retinal disease. Subjects received two capsules approximately 2.5 hours apart, and monocular visual acuity was measured 2 hours after each capsule ingestion. The second study was a double-masked, placebo-controlled 12-week longitudinal dosing (0.62 mg/kg of body weight) crossover study in which subjects received levodopa-carbidopa for 6 weeks and placebo for 6 weeks. RESULTS: The single-dose study revealed a small but statistically significant improvement in monocular visual acuity after levodopa-carbidopa ingestion. The longitudinal study revealed a small but statistically significant improvement in binocular visual acuity after levodopa ingestion. In both studies placebo had no significant effect on visual acuity. Six subjects participated in both studies and demonstrated a significant correlation (r = 0.76, p < 0.05) between change in visual acuity in the single-dose study and the longitudinal dosing study. CONCLUSION: The results are consistent with the hypothesis that dopamine influences the receptive field characteristics of retinal cells. The results also suggest that there may be low retinal dopamine levels in some types of retinal disease, which may be amenable to treatment.

A comparison of cryotherapy versus diode laser retinopexy in 100 consecutive infants treated for threshold retinopathy of prematurity.

PURPOSE: The purpose of this paper is to present a series of patients who were treated for threshold retinopathy of prematurity with either cryotherapy or diode laser. Complications and unfavorable outcomes during the first year after treatment will be compared for the two procedures. METHODS: The clinical courses of a consecutive series of 100 infants (192 eyes) were reviewed. All infants had their threshold status confirmed by a second examiner. Infants were treated with cryotherapy through 1993 and with diode laser thereafter. One hundred two eyes of 54 patients were treated with cryotherapy. Ninety eyes of 46 patients were treated with laser retinopexy. Two of the patients who were treated with laser (4 eyes) did not survive to the 3-month follow-up visit, and their results are not included here. The two groups of infants were comparable in their birth weight, adjusted gestational age at treatment, and severity of disease as determined by zone and sectors of stage 3 retinopathy of prematurity. RESULTS: Unfavorable outcome (total retinal detachment) was seen in 25.4% of eyes treated with cryotherapy (26 of 102), as compared with 15% of eyes treated with laser (13 of 86). Two cataracts were seen in our patients: one patient 22 weeks after cryotherapy, and the other 7 months after diode laser. CONCLUSIONS: No statistically significant difference was found in the rate of retinal detachments in the two groups (X2 = 3.05; P = .08).

Measurement of the modulation transfer function of paper.

In recent years there has been a renewed interest in modeling the halftone microstructure to better control the colors produced in a halftone image. Diffusion of light within the paper has a significant effect on the halftone color; this effect is known as optical dot gain or the Yule-Neilsen effect. Because of diffusion, a photon may exit the paper from a different region of the halftone microstructure than that into which it entered the paper. To account rigorously for this effect requires knowledge of the paper's point-spread function or, equivalently, the paper's modulation transfer function (MTF). A new technique for measuring the MTF of paper-the series-expansion bar-target technique-is introduced. The method uses a bar target, but the analysis more closely resembles that of the edge-gradient technique. In the series-expansion method, bar-target image data are expanded into a Fourier series, and the paper's MTF is given by the series-expansion coefficients. It differs from the typical bar-target analysis in that the typical method plots the amplitude of the fundamental frequency component for several targets of varying frequency, whereas the series-expansion method plots the amplitude of the fundamental and its harmonics for a single target. Two possible techniques for measuring the MTF with the bar-target series-expansion method are considered. In the first, the image of the bar target is projected onto the paper, and in the second, the bar target is placed directly on the paper, in close contact.

Effect of somatic cell count and stage of lactation on the quality and storage life of ultra high temperature milk.

The effects of bulk milk cell count (BMCC) and stage of lactation on the quality and storage characteristics of UHT milk were investigated. The UHT milk was manufactured in a pilot plant using milk of low BMCC from early and late lactation, and milk of high BMCC from early and late lactation. Upon storage at 20 degrees C, early lactation UHT milk gelled far ahead of late lactation milk. Within each stage of lactation, high BMCC milk tended to gel first. Few differences in the organoleptic properties of the UHT milks were observed. It was apparent that the onset of age gelation may not always be related directly to the level of proteolysis, and that other factors influencing milk composition and the reactions between milk components may play more important roles. At a particular stage of lactation, proteolysis induced by mastitis may hasten the onset of gelation.

Effects of somatic cell count and stage of lactation on raw milk composition and the yield and quality of Cheddar cheese.

The effects of somatic cell count and stage of lactation on the yield and quality of Cheddar cheese were investigated. Cheese was manufactured in a pilot scale factory using milk of low bulk milk cell count (BMCC) from herds in early (LE) and late (LL) lactation, and milk of high BMCC from herds in early (HE) and late (HL) lactation. The deleterious effect of an elevated BMCC on product yield and quality in late lactation was clear. Cheese made from LL milk was significantly superior to that made from HL milk for most yield and quality characteristics measured. Stage of lactation also affected cheese yield and quality, as evidenced by the lower recovery of fat and poorer flavour score for cheese from LL milk compared with that manufactured from LE milk. The observed differences could be explained largely by differences in raw milk composition. We conclude that the effect of stage of lactation was magnified by an elevated BMCC, and that many of the problems encountered when processing late season milk could be overcome by containing mastitis at this time.

Levodopa/carbidopa treatment for amblyopia in older children.

The purpose of the present study is to determine how long visual function improves during levodopa/carbidopa with part-time occlusion treatment in older amblyopic children. A 7-week open clinical trial of levodopa (0.55 mg/kg, three times daily) with 25% carbidopa combined with part-time occlusion (3 hours/day), was undertaken in 15 older (mean age, 8.87 years) amblyopic children. Visual acuity, fusion, and stereo acuity were measured at baseline, at weeks 1, 3, 5, and 7 during treatment, and 6 weeks following the end of all treatment. Health status was assessed by physical examination, questionnaire, and standard laboratory tests (CHEM 20, complete blood cell count [CBC], and differential). The results revealed that visual acuity in the amblyopic eye improved for 5 weeks, from 20/170 at baseline to 20/107, then stabilized for the last 2 weeks. Visual acuity also improved in the dominant eye by 0.6 lines, from 20/19 to 20/16. At the 6-week follow up, visual acuity in the amblyopic eye remained at 20/107 (paired t = 4.78, df = 14, P < .001), a 37% improvement. Thirty-three percent of the subjects demonstrated improved fusion from baseline to the 7-week trial that was maintained at follow up (chi 2 = 3.97, P < .05). Stereo acuity did not significantly change. Physical exam (blood pressure, body temperature, respiration, heart rate) and standard laboratory tests remained normal and side effects were minimal.(ABSTRACT TRUNCATED AT 250 WORDS)

Retinopathy of prematurity in discordant twins.

Discordant twins may be at increased risk for retinopathy of prematurity (ROP) because of factors related to their unequal growth. Discordancy is defined as a difference of 15% or more in the birth weights of the two infants. We examined the data in 26 sets of discordant twins from six NICUs, including birthweight, gestational age, sex, and highest grade of ROP. Thirty-eight percent (10) of the lower birthweight infants had higher grades of ROP than their twin. Twenty-three percent (6) of the heavier birthweight twins had higher grades of ROP than their smaller siblings. Three infants reached threshold, and five were prethreshold. In every case, their twin siblings had mild or no ROP. Thirty-eight percent of the twins (10) had the same ROP outcome.

Flash visual evoked response binocular summation in normal subjects and in patients with early-onset esotropia before and after surgery.

Flash visual evoked responses were recorded and visual evoked response binocular summation was assessed in normal children between the ages of 1 and 58 months, in normal adults and in children with early-onset esotropia before and longitudinally for 1 year after surgical binocular alignment. Normal flash visual evoked response binocular summation started in the range of facilitation (> 2.0) at 1 month of age and decreased to adult levels by 3.7 months of age. The shape of the flash visual evoked response binocular summation function obtained from the patients with early-onset esotropia, appeared similar to that of normal subjects; however, the rapid decrease in flash visual evoked response binocular summation from facilitation to normal adult levels occurred after surgical binocular alignment. In normal adults, flash visual evoked response binocular summation was significantly reduced by a 40-diopter base-in prism, suggesting that binocular misalignment was not the reason for the facilitation in flash visual evoked response binocular summation in either childhood population. It is proposed that this facilitation may reflect a process that leads to binocularity and that develops rapidly with binocular alignment.

SKILL card results in amblyopic children.

Two experiments were undertaken to assess high contrast-high luminance (HCHL) and low contrast-low luminance (LCLL) visual acuity as measured with the Smith-Kettlewell Institute Low Luminance (SKILL) card, in childhood amblyopia. In experiment 1, HCHL and LCLL visual acuity was measured in 11 amblyopic children and in 12 normal children of similar age. The results revealed that HCHL visual acuity was similar in the normal eyes and in the amblyopes' dominant eyes, and was abnormal in 91% of the amblyopic eyes. LCLL visual acuity was significantly worse in normal eyes compared to the amblyopes' dominant eyes, and was abnormal in only 64% of the amblyopic eyes. In experiment 2, HCHL and LCLL visual acuity was measured in seven previously tested amblyopic children, after a 5-month interval, and in six additional amblyopic children. In the amblyopic children who were tested twice, significant test-retest reliability for HCHL and LCLL visual acuity was found and visual acuity varied by 3.6%. The results of experiment 2 corroborated the results of experiment 1 from the amblyopic children. It is concluded that visual acuity in the amblyopic eye tends to normalize under low contrast-low luminance conditions. In addition, the mechanism(s) underlying amblyopia appear also to influence the dominant eye, resulting in superior visual acuity under low contrast-low luminance conditions.

In-line soft-x-ray holography: the unwanted image.

Recent improvements in computer technology remove the limitations in the Bragg-Rogers method of eliminating the unwanted image from in-line holography.

Longitudinal study of levodopa/carbidopa for childhood amblyopia.

To determine the tolerability and efficacy of levodopa/carbidopa combined with occlusion therapy for childhood amblyopia, a double-masked placebo-controlled randomized longitudinal study was performed on 10 amblyopic children between 6 and 14 years of age. Subjects received, on average, 20/5 mg levodopa/carbidopa or 20 mg of placebo three times per day combined with part-time occlusion over a 3-week period. Visual function was assessed by Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity charts and by contrast sensitivity. Tolerability was assessed by questionnaire, SMAC (standard laboratory tests; consists of a chem 20 and complete blood count [CBC]) analysis, and physical examination. Compliance with occlusion and capsule consumption were assessed by questionnaire and by capsule count, respectively. At the end of the dosing regimen, the levodopa/carbidopa group significantly improved in visual acuity by 2.7 lines and in mean contrast sensitivity by 72% in the amblyopic eye. The placebo group improved in visual acuity by 1.6 lines in the amblyopic eye. Tolerability and occlusion compliance were similar between groups; however, capsule ingestion compliance was significantly lower in the levodopa/carbidopa group. One month after the termination of treatment, the levodopa/carbidopa group maintained a significant 1.2-line improvement in visual acuity and 74% improvement in contrast sensitivity in the amblyopic eye. The placebo group did not maintain an improvement in visual acuity between the eyes. It is concluded that levodopa/carbidopa, at an average of 0.48/0.12 mg/kg, is well tolerated and, when combined with part-time occlusion, is efficacious in improving visual function in amblyopic children.

Levodopa/carbidopa for childhood amblyopia.

PURPOSE: To evaluate the efficacy and tolerance of two low doses of levodopa/carbidopa (25/6.25 mg, 50/12.5 mg) and placebo (Tums) in 20 children with amblyopia between the ages of 4 and 14 years. METHODS: A double-masked placebo-controlled randomized 8-hour study was performed during which subjects received one of two doses of levodopa/carbidopa or placebo, combined with occlusion of the dominant eye. Visual acuity was measured at baseline and at 1 and 5 hours after capsule ingestion. Tolerance was assessed by questionnaire and physical examination. RESULTS: Visual acuity significantly improved by one line, from an overall average of 20/121 to 20/96, in the amblyopic eyes of both groups that received levodopa/carbidopa. Visual acuity did not significantly change in the placebo group. Tolerance was similar among all three groups. CONCLUSION: Average dose levels of 0.95/0.24 mg/kg and 1.94/0.49 mg/kg of levodopa/carbidopa were found to be well tolerated and efficacious at temporarily improving visual acuity in amblyopic eyes of children.