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Jonathan M Holmes

Publications and source records attributed to Jonathan M Holmes.

At least 37 records · Page 2Linked to original sources
PubMed2005

Diabetes and hypertension in isolated sixth nerve palsy: a population-based study.

PURPOSE: Diabetes mellitus and systemic hypertension are frequently reported as ischemic causes of sixth nerve palsy/paresis, but there are few rigorous studies to support these associations. We conducted a population-based case-control study to determine the presence and magnitude of any association of preexisting diabetes mellitus and systemic hypertension with isolated sixth nerve palsy. DESIGN: Retrospective population-based case-control study. PARTICIPANTS AND CONTROLS: Participants were patients with new onset of neurologically isolated sixth nerve palsy or paresis (n = 76) in Olmsted County, Minnesota, from January 1, 1978, to December 31, 1992. Controls (n = 76) were selected from the same general population and were matched for age, gender, and length of medical follow-up. METHODS: Using the Rochester Epidemiology Project medical records linkage system, which captures virtually all medical care provided to residents of Olmsted County, Minnesota, we identified all incident cases of neurologically isolated sixth nerve palsy/paresis (n = 76) among county residents between the given dates. An equal number (n = 76) of controls were randomly selected from the general population. We reviewed the entire medical record of each case and control, using stringent predetermined criteria to define the presence of diabetes mellitus and systemic hypertension. We compared the prevalence of diabetes and systemic hypertension between cases and controls by use of chi-square tests, and we calculated odds ratios (OR) with 95% confidence intervals (CI). MAIN OUTCOME MEASURES: Presence or absence of diabetes mellitus and systemic hypertension. RESULTS: Diabetes mellitus occurred more frequently in cases (23.7%) than in controls (5.3%; P = 0.001; OR, 5.59; 95% CI, 1.79-17.42). Systemic hypertension occurred with similar frequency in cases (51.3%) and controls (39.5%; P = 0.14; OR, 1.62; 95% CI, 0.85-3.08). Coexistent diabetes mellitus and hypertension were more common in cases (18.4%) than in controls (2.6%; P = 0.002; OR, 8.36; 95% CI, 1.83-38.18). CONCLUSIONS: We conclude that there is a 6-fold increase in odds of having diabetes in cases of sixth nerve palsy over controls, whereas systemic hypertension does not seem to be associated with increased odds. In contrast, there is an 8-fold increased odds of having coexistent diabetes and hypertension in cases of sixth nerve palsy over controls. The much-cited association of systemic hypertension alone with sixth nerve palsy may be coincidental.

Abducens Nerve Diseases↗
PubMed2005

The effect of L-thyroxine supplementation on retinal vascular development in neonatal rats.

PURPOSE: Thyroxine (T4) plays a role in neuroretinal maturation, but little is known regarding its role in retinal vascularization. The neonatal rat retina is incompletely vascularized at birth, providing a model for the human premature infant retina and for retinopathy of prematurity (ROP). We hypothesized that T4 supplementation would accelerate vascular development of normal neonatal rat retina. METHODS: Two hundred twenty Sprague-Dawley rats were raised in litters of 10 in room air and received either 0.05 microg/g, 0.5 microg/g, or 1.0 microg/g of intraperitoneal T4 or saline control beginning on day 1 of life for 3 days, 7 days, or 3 days followed by 4 days recovery. Rats were sacrificed on either day 4 or day 8 of life. Left eyes were fixed, retinae dissected and ADPase-stained. Flat mounted retinae were digitized and total retinal areas and retinal vascular density were evaluated in a masked manner. Serum T4, thyroid stimulating hormone (TSH), and insulin-like growth factor-1 (IGF-1) were measured at each time point. RESULTS: Retinal vascular density was reduced in animals receiving daily 1 microg/g T4 compared with saline controls after 3 days of T4 (16.8 +/- 1.4 vessels/mm vs. 18.3 +/- 1.3 vessels/mm, p = 0.04) and 7 days of T4 (14.4 +/- 1.3 vessels/mm vs. 16.8 +/- 1.1 vessels/mm, p < 0.0006). However, retinal vascular density returned to normal after 3 days of treatment and 4 days of recovery. Vascularized retinal area was reduced in animals receiving 1 microg/g T4 for 3 days followed by 4 days recovery compared with saline controls (85 +/- 6% vs. 92 +/- 3%, p = 0.002). At lower doses of T4 (0.05 microg/g and 0.5 microg/g for 3 or 7 days) and at 1 microg/g T4 for 7 days, there was no effect on vascularized retinal area. Serum T4 levels were increased, with corresponding TSH suppression, after T4 treatment for 3 or 7 days. Serum IGF-1 levels were unaffected by T4 supplementation. CONCLUSIONS: Systemic T4 supplementation at 1 microg/g per day was detrimental to retinal vascular development in neonatal animals. If these effects are paralleled in human neonates, T4 supplementation might increase, rather than decrease, the risk of developing ROP. Further work on the role of T4 in the pathogenesis of ROP is warranted.

Animals↗
PubMed2005

An abbreviated reading speed test.

PURPOSE: The Minnesota Low-Vision Reading Test (MNREAD) has been developed to measure reading speed. An abbreviated version of the MNREAD test was developed that presented only three large paragraphs and would be easier for children to complete. METHODS: Fifty children ages 8 to 18 years, with normal eye examinations or refractive error alone, underwent testing of reading speed using the MNREAD test. All the children read the standard MNREAD paragraphs starting at the 1.0 logarithm of the minimum angle of resolution (logMAR) level until they could no longer read the subsequent paragraph. Each eye was tested separately, using the second MNREAD card for the left eye. The standard MNREAD reading speed was calculated by plotting the speed for each paragraph, determining the critical print size, then taking the median value of all the paragraphs above the cutoff paragraph. The proposed abbreviated test reading speed was calculated from the median of three large paragraphs (logMAR, 1.0, 0.9, and 0.8). At a second site, 25 children with a variety of ocular conditions were similarly tested using an alternative abbreviated test (logMAR, 1.3, 1.2, and 1.1). The standard and abbreviated reading speeds were then compared between tests and between eyes using generalized estimating equation and intraclass correlation coefficients. RESULTS: The mean reading method speeds with the standard and abbreviated tests were almost identical [177 words per minute (wpm) +/- 46 wpm vs. 178 +/- 46 wpm, p = 0.43 for normal children and 140 +/- 29 wpm vs. 141 +/- 33 wpm, p = 0.35 in children with a variety of ocular conditions]. CONCLUSION.: The new abbreviated version of the MNREAD reading speed test yields similar results to the standard MNREAD test in children. The new abbreviated MNREAD test is faster to administer and appears to be particularly useful for children.

Adolescent↗
PubMed2004

Effect of bicarbonate on retinal vasculature and acidosis-induced retinopathy in the neonatal rat.

BACKGROUND: Systemic acidosis induces preretinal neovascularization (NV) analogous to retinopathy of prematurity (ROP) in the neonatal rat. Sodium bicarbonate is used in human neonates to treat acidosis. The effects of alkali administration on the developing retinal vasculature and on acidosis-induced retinopathy (AIR) are unknown. We investigated the effect of sodium bicarbonate gavage on the retinal vasculature of normal and acidotic neonatal rats to determine (1) whether bicarbonate treatment is associated with preretinal NV and (2) whether AIR can be prevented with systemic bicarbonate treatment. METHODS: The extent of acidosis and alkalosis were initially determined from carotid arterial blood samples. In the bicarbonate-alone study, newborn rats were randomized into litters of 25 and received bicarbonate doses of 15 mmol/kg twice daily and 20 mmol/kg once daily from days 2 to 7. Control animals received saline gavage. In the AIR treatment study, acidosis was induced in neonatal rats by intraperitoneal injection of acetazolamide 200 mg/kg from days 2 to 7. Acetazolamide-treated rats received either additional bicarbonate gavage or no additional treatment. Eyes were enucleated on day 13, and the retinal vasculature was assessed for NV using ADPase staining techniques and light microscopy. RESULTS: Systemic alkalosis (peak pH 7.55+/-0.02; mean +/- SD) was confirmed with bicarbonate gavage, and partial reversal of acidosis was confirmed when acetazolamide-treated rats received bicarbonate. Surviving rats receiving bicarbonate 15 mmol/kg twice daily (28% survival) and 20 mmol/kg bicarbonate once daily (45% survival) had an incidence of preretinal NV of 9% and 8%, respectively. No NV was seen in saline-control rats. In the acetazolamide-treated rats, the incidence of preretinal NV in surviving rats was numerically lower in bicarbonate-treated rats than acetazolamide-only controls (8% versus 24%, p=0.065) but with only 19% survival in the bicarbonate-treated rats. CONCLUSIONS: In the neonatal rat, alkalosis induced by bicarbonate gavage is associated with a low incidence of mild, preretinal NV similar to ROP. Although treating acidotic rats with bicarbonate may reduce the incidence of preretinal NV, treatment was associated with an unacceptable mortality rate.

Acetazolamide↗
PubMed2004

Long-term retinal transgene expression with FIV versus adenoviral vectors.

PURPOSE: Gene therapy for chronic retinal diseases will require long-term expression of therapeutic transgenes. Lentiviral and adenoviral (Ad) vectors are gene delivery systems with markedly different properties. Lentiviral vectors require integration into the host genome, which facilitates long-term expression, while Ad vectors remain episomal. We compared time course, location, and extent of transgene expression from replication-deficient feline immunodeficiency virus (FIV) vectors and Ad vectors in neonatal rat retina. METHODS: A dose-response study was conducted to determine the optimal subretinal dose for comparison of FIV and Ad vectors with an internal cassette expressing beta-galactosidase under transcriptional control of the CMV immediate-early gene promoter/enhancer. Forty-two five-day old Sprague-Dawley rats received subretinal injections of 2 microl containing 2x10(3) transducing units (TU, n=14), 2x10(4) TU (n=14) or 2x10(5) TU (n=14) of FIV vector (right eye) and Ad vector (left eye). Expression was evaluated 48 h after transduction. In the subsequent long-term expression study, 60 five-day old rats received a subretinal injection of 2x10(5) TU FIV vector (right eye) and Ad vector (left eye). Ten pairs of eyes were analyzed at 1 week, 1 month, 3 months, 6 months, 12 months, and the remainder at 16 months. Eye cups were evaluated in a masked manner for extent of beta-galactosidase expression (graded 0-5) by whole mount microscopy and by cross sectional histology. RESULTS: In the dose-response study, 2x10(5) TU resulted in consistent, widespread retinal transduction with both vectors and was selected as the dose for the subsequent study. In the long-term expression study, FIV vector resulted in a higher grade of expression than Ad at multiple single time points and produced higher overall expression when data from all eyes across the entire 16 month study were analyzed (p=0.01). Retinal expression was present at 16 months with both vectors. beta-galactosidase expression was limited to the retinal pigment epithelium (RPE) until the first month, but later was also found to a lesser extent in neurosensory retina with each vector. In contrast to FIV, most Ad injected eyes showed signs of focal accumulation of macrophage-like cells with disrupted retinal architecture. CONCLUSIONS: Both FIV and Ad vectors result in long-term transgene expression in RPE after subretinal injection. FIV vectors show more promise than Ad as delivery systems for retinal diseases since they transduce greater areas of RPE, result in less cellular infiltrate, and cause less disruption of retinal architecture. The persistent expression at 16 months of follow-up suggests that these lentiviral vectors are useful for gene therapy of chronic retinal diseases.

Adenoviridae↗
PubMed2004

The role of VEGF and IGF-1 in a hypercarbic oxygen-induced retinopathy rat model of ROP.

PURPOSE: We have previously described a severe form of oxygen-induced retinopathy (OIR) in the neonatal rat, analogous to human retinopathy of prematurity (ROP), where carbon dioxide is added to the inspired environment (hypercarbic OIR). We studied the time course of emergence and resolution of neovascularization (NV) in normocarbic OIR and hypercarbic OIR and the associated changes in VEGF and IGF-1 mRNA levels in hypercarbic OIR. METHODS: 550 newborn Sprague-Dawley rats were raised in 22 expanded litters of 25. Beginning at day 1 of life, rats were exposed to 7 daily cycles of hyperoxia (80% O2, 20.5 h) and hypoxia (10% O2, 0.5 h) with a gradual return to 80% O2 over 3 h. Inspired CO2 was maintained at 0.2% for 200 rats (normocarbic OIR) and 10% for 100 rats (hypercarbic OIR). Rats were sacrificed after a subsequent 5 day room air recovery period. An additional 250 rats raised in room air served as age matched controls. Retinae from left eyes were dissected and flatmounts were ADPase-stained. The presence and severity of NV was scored in a masked manner. Right eyes in hypercarbic OIR litters and room air controls were processed for analysis of VEGF and IGF-1 mRNA. RESULTS: In normocarbic OIR, NV started to emerge before room air recovery began at day 8. It was maximal at day 10 and resolved by day 20. In hypercarbic OIR, a similar pattern was seen, with emergence prior to day 8, peak at day 13 and resolution by day 20. In hypercarbic OIR, retinal VEGF mRNA was decreased at day 8 and increased at day 10 compared to room air controls, correlating with maximal NV. Retinal IGF-1 mRNA was not increased at any time in hypercarbic OIR compared to room air controls. CONCLUSIONS: Neovascularization resulting from normocarbic OIR or hypercarbic OIR occurs before room air recovery. Retinal VEGF mRNA was downregulated and subsequently upregulated prior to maximal NV in hypercarbic OIR. Neovascularization in the hypercarbic OIR model does not appear to be associated with increased retinal IGF-1 mRNA.

Animals↗
PubMed2004

Comparison of the amblyopia treatment study HOTV and electronic-early treatment of diabetic retinopathy study visual acuity protocols in children aged 5 to 12 years.

PURPOSE: To compare two established visual acuity protocols: the Amblyopia Treatment Study HOTV (ATS HOTV) visual acuity protocol and the Electronic-Early Treatment of Diabetic Retinopathy Study (E-ETDRS) protocol, in children aged 5 to 12 years. DESIGN: Prospective cohort study. METHODS: Crowded HOTV optotypes and crowded ETDRS optotypes were presented to 236 consecutive children aged 5 to 12 years using an electronic visual acuity tester (Palm handheld, personal computer, and monitor). Twenty-three percent of the children were classified as amblyopic, 35% as having uncorrected refractive error, 36% as normal, and 6% as other. Visual acuity test results were converted to logarithm of minimal angle of resolution (logMAR) units for analysis. RESULTS: In developmentally normal children (n = 230), testability was 100% for HOTV in 5- to 12-year-olds and 100% for E-ETDRS in 7- to 12-year-olds. The E-ETDRS testing could be completed in 52% of 5-year-olds and in 87% of 6-year-olds. Visual acuity performance was better when measured by HOTV compared with E-ETDRS (median difference 0.06 logMAR [three letters on a chart with five letters/line], P =.0001), and the difference was found in normal eyes, eyes with refractive error, and amblyopic eyes. CONCLUSIONS: The ATS HOTV protocol yields slightly better visual acuity performance compared with E-ETDRS in 5- to 12-year-olds, but on average by less than a logMAR level. This systematic difference is important when a physician changes testing modality as a child matures and should be considered when interpreting the results of recent and ongoing clinical trials in amblyopia.

Amblyopia↗
PubMed2004

Maximum angle of horizontal strabismus consistent with true stereopsis.

BACKGROUND: We prospectively evaluated the performance of three stereoacuity tests in patients with a wide range of strabismus angles to determine the maximum angle of horizontal strabismus consistent with true stereopsis as well as the extent of false-positive results. METHODS: Subjects age > or = 5 years old (n = 186) with constant horizontal strabismus were prospectively studied. Stereoacuity was measured using the Titmus Fly, Animals, and Circles tests; the original Preschool Randot test; and the Frisby test. We defined a false-positive result as any positive response to a stereoacuity test when a patient had > 20 prism diopters (PD) of deviation. Based on the results from our previous study of monocularly patched adults, we then defined a true-positive result as Titmus circles five to nine, at least 400" on the original Preschool Randot test, or a pass on the Frisby test. Data were then analyzed to determine a maximum deviation consistent with true stereopsis. RESULTS: False-positive results occurred with Titmus Fly (6%), Titmus Animals (10%), Titmus Circles (35%), and the 800 seconds of arc (") level of the original Preschool Randot test (10%). No false-positive results were seen with the Frisby test. Applying the criteria for a true-positive result, we found that no patient with > 10 PD of deviation had true stereopsis. The two patients with 10 PD and 6 PD deviations could not subsequently pass the Frisby test and were therefore deemed not to have true stereopsis. We concluded that the threshold for true stereopsis may be as low as 4 PD of horizontal deviation. CONCLUSION: In summary, the Titmus Fly, Titmus Animals, and Titmus Circles (the first four circles) tests possess monocular clues that limit their usefulness for clinical testing. The Frisby test is particularly useful for rapid assessment of whether stereopsis is present or absent. The new Preschool Randot test is valuable for quantifying stereopsis in both children and adults. True stereopsis may be rare when a patient has a horizontal deviation > 4 PD.

Adolescent↗
PubMed2004

Incidence, associations, and evaluation of sixth nerve palsy using a population-based method.

PURPOSE: To determine the incidence of sixth nerve palsy in a population-based study, with particular emphasis on associated coexisting medical conditions and to use these data to develop a management algorithm. DESIGN: Retrospective, population-based case series. PARTICIPANTS: All residents of Olmsted County, Minnesota, USA, diagnosed with sixth nerve palsy between January 1, 1978 and December 31, 1992. METHODS: All cases were identified by using the Rochester Epidemiology Project medical records linkage system, which captures all patient-physician encounters in Olmsted County. The entire medical record of each patient was reviewed to confirm the diagnosis, document county residency, and to determine associated medical conditions. We used stringent predetermined criteria to define diabetes mellitus and hypertension as associations. Incidence rates were adjusted to the age and gender distribution of the 1990 white population in the United States. MAIN OUTCOME MEASURES: Etiology or systemic associations of the palsy. RESULTS: We identified 137 new cases of sixth nerve palsy over the 15-year period. The age- and gender-adjusted annual incidence of sixth nerve palsy was 11.3/100 000 (95% confidence interval, 9.3-13.2/100 000). Causes and associations were: undetermined (26%), hypertension alone (19%), coexistent hypertension and diabetes (12%), trauma (12%), multiple sclerosis (7%), neoplasm (5%), diabetes alone (4%), cerebrovascular accident (4%), postneurosurgery (3%), aneurysm (2%), and other (8%). When sixth nerve palsy was the presenting sign in cases of neoplasm (n = 1) and aneurysm (n = 3), history and examination revealed the presence of other neurologic symptoms or signs. CONCLUSIONS: We provide population-based data on the incidence of sixth nerve palsy with a notably lower incidence of neoplasm and higher incidence of diabetes and hypertension than previous institution-based series. We suggest that patients with nontraumatic neurologically isolated sixth nerve palsy may undergo a focused medical evaluation followed by close observation, whereas non-neurologically isolated cases warrant a full neurologic evaluation, including prompt neuroimaging.

Abducens Nerve Diseases↗
PubMed2004

A randomized trial of atropine regimens for treatment of moderate amblyopia in children.

OBJECTIVE: To compare daily atropine to weekend atropine as prescribed treatments for moderate amblyopia in children younger than 7 years. DESIGN: Prospective, randomized multicenter clinical trial (30 sites). PARTICIPANTS: One hundred sixty-eight children younger than 7 years with amblyopia in the range of 20/40 to 20/80 associated with strabismus, anisometropia, or both. INTERVENTION: Randomization either to daily atropine or to weekend atropine for 4 months. Partial responders were continued on the randomized treatment until no further improvement was noted. MAIN OUTCOME MEASURE: Visual acuity (VA) in the amblyopic eye after 4 months. RESULTS: The improvement in VA of the amblyopic eye from baseline to 4 months averaged 2.3 lines in each group. The VA of the amblyopic eye at study completion was either (1) at least 20/25 or (2) better than or equal to that of the sound eye in 39 children (47%) in the daily group and 45 children (53%) in the weekend group. The VA of the sound eye at the end of follow-up was reduced by 2 lines in one patient in each group. Stereoacuity outcomes were similar in the 2 groups. CONCLUSIONS: Weekend atropine provides an improvement in VA of a magnitude similar to that of the improvement provided by daily atropine in treating moderate amblyopia in children 3 to 7 years old. This article contains additional online-only material available at http://www.ophsource.com/periodicals/ophtha.

Amblyopia↗
PubMed2004

Risk of amblyopia recurrence after cessation of treatment.

BACKGROUND: Although amblyopia can be successfully treated with patching or atropine, there have been few prospective studies of amblyopia recurrence once treatment is discontinued. METHODS: We enrolled 156 children with successfully treated anisometropic or strabismic amblyopia (145 completed follow-up), who were younger than 8 years of age and who received continuous amblyopia treatment for the previous 3 months (prescribed at least 2 hours of daily patching or prescribed at least one drop of atropine per week) and who had improved at least 3 logMAR levels during the period of continuous treatment. Patients were followed off treatment for 52 weeks to assess recurrence of amblyopia, defined as a 2 or more logMAR level reduction of visual acuity from enrollment, confirmed by a second examination. Recurrence was also considered to have occurred if treatment was restarted because of a nonreplicated 2 or more logMAR level reduction of visual acuity. RESULTS: Recurrence occurred in 35 (24%) of 145 cases (95% confidence interval 17% to 32%) and was similar in patients who stopped patching (25%) and in patients who stopped atropine (21%). In patients treated with moderately intense patching (6 to 8 hours per day), recurrence was more common (11 of 26; 42%) when treatment was not reduced prior to cessation than when treatment was reduced to 2 hours per day prior to cessation (3 of 22; 14%, odds ratio 4.4, 95% confidence interval 1.0 to 18.7). CONCLUSIONS: Approximately one fourth of successfully treated amblyopic children experience a recurrence within the first year off treatment. For patients treated with 6 or more hours of daily patching, our data suggest that the risk of recurrence is greater when patching is stopped abruptly rather than when it is reduced to 2 hours per day prior to cessation. A randomized clinical trial of no weaning versus weaning in successfully-treated amblyopia is warranted to confirm these observational findings.

Amblyopia↗
PubMed2004

Unintegrated lentivirus DNA persistence and accessibility to expression in nondividing cells: analysis with class I integrase mutants.

The circumstances under which unintegrated lentivirus DNA can persist and be a functional template for transcription and protein expression are not clear. We constructed and validated the first class I (nonpleiotropic) integrase (IN) mutants for a non-human lentivirus (feline immunodeficiency virus [FIV]) and analyzed both these and known class I human immunodeficiency virus type 1 IN mutants. The FIV IN mutants (D66V and D66V/D118A) had class I properties: Gag/Pol precursor expression, proteolytic processing, particle formation, and reverse transcriptase (RT) production were normal, while the transduction of dividing fibroblasts was prevented and integration was blocked. When injected into rat retinas, the wild-type (WT) vector produced extensive, persistent transgene expression, compared with only rare positive neuronal cells for the IN mutant vector. In contrast, both WT and mutant vectors produced entirely equivalent, effective transduction levels of primary rat neurons (retinal ganglion cells). By testing the hypothesis that the unexpected retinal neuron transduction was related to cell cycle status, we found that when fibroblasts were growth arrested, transduction and internally promoted transgene expression were not inhibited at all by the class I FIV or HIV-1 IN mutations. Cells were then transduced under aphidicolin arrest and were released from the block 48 h later. Vector expression was stable and durable during repeated passaging in WT vector-transduced cells, while the release of cells transduced with equivalent RT units of class I IN mutant FIV or HIV vector resulted in a steady decline of expression, from 97 to 0% of cells by day 10. Southern blot and PCR analyses showed a lack of integration, irrespective of cell cycle, for the class I mutants and an increase in one- and two-long terminal repeat circular and linear unintegrated DNAs in growth-arrested cells. We conclude that if cell division is prevented, unintegrated FIV and HIV-1 vector DNAs can produce high-level internally promoted transgene expression equivalent to WT vectors. The expression correlates with the unintegrated DNA levels. These observations may facilitate the study of the roles of IN and other preintegration complex components in preintegration phases of infection by (i) providing an alternative way to monitor unintegrated nuclear cDNA forms, (ii) restricting ascertainment to the transcriptionally functional subset of unintegrated DNA, (iii) enabling analysis in individual, nondividing cells, and (iv) uncoupling other potential functions of IN from integration.

Amino Acid Sequence↗
PubMed2004

The anti-thyroid drug methimazole induces neovascularization in the neonatal rat analogous to ROP.

PURPOSE: To determine the effect of methimazole (MMI), an anti-thyroid drug known to reduce serum l-thyroxine (T4), and insulin-like growth factor (IGF)-1 concentrations, on retinal vascular development in neonatal rats. METHODS: Sprague-Dawley rats (n=175) were raised in expanded litters of 25 in room air and were exposed to MMI from birth (given as a 0.1% solution to nursing mothers for either 4 or 10 days). Experiments ended on day 4 (n=25) or 10 (n=50) of life. A third group was exposed to MMI for the initial 4 days of life and then allowed to recover for the next 6 days (n=50). Fifty control rats were analyzed on day 4 (n=25) or 10 (n=25) of life. Left eyes were fixed, and retinas were dissected and stained with adenosine diphosphatase (ADPase). Retinas were graded for presence and severity of neovascularization (NV) in a masked manner, and retinal vascular areas were quantified. In a subsequent study, serum IGF-1 and T4 levels were measured by radioimmunoassay in an additional 200 rats exposed to treatments identical to those described. RESULTS: Retinal NV occurred in 31% of rats exposed to 10 days of MMI and 4% (P=0.02) of rats exposed to 4 days of MMI, followed by 6 days of recovery. None of the rats exposed to 4 days of MMI alone and none of the control animals was graded positive for NV. Retinal vascular areas were significantly reduced in rats exposed to 4 days of MMI compared with 4-day control animals (36% +/- 6% vs. 50% +/- 6%, P=0.0001). Serum IGF-1 levels were markedly reduced in 4-day MMI rats compared with age-matched control animals (42 ng/mL vs. 133 ng/mL, P=0.0001) and in 10-day MMI rats compared with 10-day control animals (133 ng/mL vs. 206.5 ng/mL, P=0.005). Serum T4 levels were similarly suppressed in the MMI-exposed litters compared with control animals at day 10 (P=0.008). In contrast, rats exposed to 4 days of MMI followed by 6 days of recovery had normal serum IGF-1 and T4 levels by day 10. CONCLUSIONS: The anti-thyroid drug, MMI, induces NV in neonatal rats. This may be mediated by the initial suppression of serum IGF-1. Nevertheless, the lower incidence of NV when serum IGF-1 levels are initially suppressed followed by complete recovery, is contrary to a purely permissive role for serum IGF-1, as reported previously. The relationship between the temporal course of serum IGF-1 and NV in immature retinas needs further investigation.

Animals↗
PubMed2003

Impact of patching and atropine treatment on the child and family in the amblyopia treatment study.

OBJECTIVE: To assess the psychosocial impact on the child and family of patching and atropine as treatments for moderate amblyopia in children younger than 7 years. METHODS: In a randomized, controlled clinical trial, 419 children younger than 7 years with amblyopic eye visual acuity in the range of 20/40 to 20/100 were assigned to receive treatment with either patching or atropine at 47 clinical sites. After 5 weeks of treatment, a parental quality-of-life questionnaire was completed for 364 (87%) of the 419 patients. Main Outcome Measure Overall and subscale scores on the Amblyopia Treatment Index. RESULTS: High internal validity and reliability were demonstrated for the Amblyopia Treatment Index questionnaire. The overall Amblyopia Treatment Index scores and the 3 subscale scores were consistently higher (worse) in the patching group compared with the atropine-treated group (overall mean, 2.52 vs 2.02, P<.001; adverse effects of treatment: mean, 2.35 vs 2.11, P =.002; difficulty with compliance: mean, 2.46 vs 1.99, P<.001; and social stigma: mean, 3.09 vs 1.84, P<.001, respectively). CONCLUSION: Although the Amblyopia Treatment Index questionnaire results indicated that both atropine and patching treatments were well tolerated by the child and family, atropine received more favorable scores overall and on all 3 questionnaire subscales.

Adult↗
PubMed2003

A randomized trial of patching regimens for treatment of moderate amblyopia in children.

OBJECTIVE: To compare 2 hours vs 6 hours of daily patching as treatments for moderate amblyopia in children younger than 7 years. METHODS: In a randomized multicenter (35 sites) clinical trial, 189 children younger than 7 years with amblyopia in the range of 20/40 to 20/80 were assigned to receive either 2 hours or 6 hours of daily patching combined with at least 1 hour per day of near visual activities during patching.Main Outcome Measure Visual acuity in the amblyopic eye after 4 months. RESULTS: Visual acuity in the amblyopic eye improved a similar amount in both groups. The improvement in the visual acuity of the amblyopic eye from baseline to 4 months averaged 2.40 lines in each group (P =.98). The 4-month visual acuity was at least 20/32 and/or improved from baseline by 3 or more lines in 62% of patients in each group (P>.99). CONCLUSION: When combined with prescribing 1 hour of near visual activities, 2 hours of daily patching produces an improvement in visual acuity that is of similar magnitude to the improvement produced by 6 hours of daily patching in treating moderate amblyopia in children aged 3 to 7 years.

Amblyopia↗
PubMed2003

Comparison of wild-type and class I integrase mutant-FIV vectors in retina demonstrates sustained expression of integrated transgenes in retinal pigment epithelium.

BACKGROUND: In neonatal and adult rodent retina, substantial lentiviral vector expression has been detected primarily in retinal pigment epithelium (RPE), except in very young animals (2-5 days post-natal). In non-retinal tissues, studies of lentiviral vectors have utilized various controls. Among the most stringent are class I integrase mutants, which selectively block the integration reaction while leaving all other gag/pol-encoded functions intact. For HIV-1 vectors injected into brain, these have been used to simultaneously control for pseudotransduction and verify that long-term expression requires integration. Such experiments compare particles that differ only in a single amino acid within a single enzyme that forms a very small molar fraction of the virion. Class I integrase mutants have not been described for feline immunodeficiency virus (FIV) integrase, or tested in the eye for any lentiviral vector. METHODS: We compared subretinally and intravitreally injected FIV vectors and followed animals for up to 7 months, a duration that exceeds prior studies. We also compared the wild-type (WT) vector with one incorporating a single class I amino acid mutation in FIV integrase (D66V). A mock vector (packaging construct absent) was an alternative control. All vectors were vesicular stomatitis virus glycoprotein G (VSV-G)-pseudotyped and were injected on day 7 of life. One group of animals received either subretinal or intravitreal injections of WT vector in the right eyes. Control left eyes were injected with mock vector. These animals were sacrificed at 2 or 7 days post-injection. A second group received subretinal injections of either WT vector or equivalent D66V vector (reverse transcriptase-normalized to WT), and were analyzed after 2, 3 and 7 months. All eyes were scored for marker gene (beta-galactosidase) expression by an observer blinded to vector assignments. RESULTS: Subretinal FIV vector injections were much more effective than intravitreal injections. The RPE was the principal retinal layer transduced by the WT vector, and at least 50% of the area of the retina expressed the marker gene at 3 and 7 months. Occasional cells in inner retinal layers also expressed beta-galactosidase at these time points. The sustained retinal expression produced by subretinally injected vector was blocked by the D66V mutation. CONCLUSIONS: These results show that class I integrase mutant FIV vectors are useful control vectors, and that VSV-G-pseudotyped FIV vectors produce extensive retinal expression for at least 215 days, the longest duration yet reported for lentiviral vectors in retina. Transgene expression is mostly restricted to RPE after post-natal day 7 in rats, suggesting that FIV vectors could be used to target RPE for gene therapy.

Age Factors↗
PubMed2003

A randomized trial of prescribed patching regimens for treatment of severe amblyopia in children.

OBJECTIVE: To compare full-time patching (all hours or all but 1 hour per day) to 6 hours of patching per day, as prescribed treatments for severe amblyopia in children younger than 7 years. DESIGN: Prospective, randomized multicenter clinical trial (32 sites). PARTICIPANTS: One hundred seventy-five children younger than 7 years with amblyopia in the range of 20/100 to 20/400. INTERVENTION: Randomization either to full-time patching or to 6 hours of patching per day, each combined with at least 1 hour of near-visual activities during patching. MAIN OUTCOME MEASURE: Visual acuity in the amblyopic eye after 4 months. RESULTS: Visual acuity in the amblyopic eye improved a similar amount in both groups. The improvement in the amblyopic eye acuity from baseline to 4 months averaged 4.8 lines in the 6-hour group and 4.7 lines in the full-time group (P = 0.45). CONCLUSION: Six hours of prescribed daily patching produces an improvement in visual acuity that is of similar magnitude to the improvement produced by prescribed full-time patching in treating severe amblyopia in children 3 to less than 7 years of age.

Amblyopia↗