Light induces peroxidation in retina by activating prostaglandin G/H synthase.

Prostaglandin G/H synthase (PGHS) has been shown to generate peroxides to a significant extent in the retina and absorbs light at the lower end of the visible spectrum. We postulated that PGHS could be an important initial source of peroxidation in the retina exposed to light, which would in turn alter retinal function. Exposure of pig eyes (in vivo) to light (350 fc/3770 lx) caused after 3 h a 50% increase and by 5 h a 30% decrease in a- and b-wave amplitudes of the electroretinogram (ERG) which were comparable at 380-650 nm and 380-440 nm but were not observed at wavelengths > 450 nm. These effects of light were prevented by free radical scavengers (dimethylthiourea and high-dose allopurinol) and PGHS inhibitors (naproxen and diclofenac), but stable analogs of prostaglandins did not affect the ERG. Both increases and subsequent decreases in ERG wave amplitudes following light exposure in vivo were associated with increases in retinal prostaglandin and malondialdehyde (peroxidation product) levels, which were inhibited by the nonselective PGHS blockers, naproxen and diclofenac. Similar observations were made in vitro on isolated porcine eyecups as well as on retinal membranes exposed to light (250 fc/ 2700 lx) 380-650 nm and 380-440 nm but not at > 500 nm. Both PGHS-1 and PGHS-2 contributed equivalently to light-induced prostaglandin synthesis, as shown after selective PGHS-2 blockers, but mRNA expression of PGHS-1 and 2 was not affected by light. Finally, light stimulated activities of pure PGHS-1 and PGHS-2 isozymes, and these were also shown to produce superoxide radical (detected with fluorogenic spin trap, proxyl fluorescamine). Taken together, data suggest that PGHS- (1 and 2) is activated by short wavelength visible light, and in the retina is an important source of reactive oxygen species which in turn alter retinal electrophysiological function. PGHS thus seems a likely chromophore in setting forth photic-induced retinal injury. Findings provide an explanation for increased sensitivity of the retina to visible light predominantly at the far blue range of its spectrum.

Reduced brain choline in homocystinuria due to remethylation defects.

OBJECTIVE: To investigate whether secondary impairment of the transmethylation pathway is a mechanism underlying the neurologic involvement in homocystinuria due to remethylation defects. METHODS: Twelve patients with neurologic disease due to remethylation defects were examined by brain magnetic resonance spectroscopic imaging ((1)H MRSI). Brain N-acetylaspartate, choline-containing compounds (Cho), and creatine (Cr) were quantified and compared to with controls. Metabolites of remethylation cycle and creatine biosynthesis pathway were measured in plasma and urine. RESULTS: MRSI revealed isolated Cho deficiency in all regions examined (mean concentration units +/- SD, patients vs controls): frontal white matter (0.051 +/- 0.010 vs 0.064 +/- 0.010; p = 0.001), lenticular nucleus (0.056 +/- 0.011 vs 0.069 +/- 0.009; p < 0.001), and thalamus (0.063 +/- 0.010 vs 0.071 +/- 0.007; p = 0.006). In contrast to controls, the Cho/Cr ratio decreased with age in patients in the three brain regions examined. Low creatine urinary excretion (p < 0.005), normal urine and plasma guanidinoacetate, and a paradoxical increase in plasma S-adenosylmethionine (p < 0.005) concentrations were observed. CONCLUSION: Patients with homocystinuria due to remethylation defects have an isolated brain choline deficiency, probably secondary to depletion of labile methyl groups produced by the transmethylation pathway. Although biochemical studies suggest mild peripheral creatine deficiency, brain creatine is in the reference range, indicating a possible compartmentation phenomenon. Paradoxical increase of S-adenosylmethionine suggests that secondary inhibition of methylases contributes to the transmethylation defect in these conditions.

Maturation of binocular pattern visual evoked potentials in normal full-term and preterm infants from 1 to 6 months of age.

The purpose of this study was to evaluate the visual development of preterm infants from 1 to 6 mo of age, using the pattern visual evoked potentials (VEP) in response to three check sizes: 60, 30, and 15 min of arc. Pattern VEP were recorded in 24 full-term and 24 preterm infants (26-36 wk of gestation). The results showed a rapid visual maturation between 1 and 3 mo, followed by a slower progression over the next 3 mo, in both groups. The implicit time of the P100 wave of the pattern VEP was also found to shorten with increasing check sizes. The maturation of pattern VEP in preterm infants was shown to be related to their gestational (or corrected) age rather than their postnatal age. The pattern VEP obtained in response to a 60-min check size in preterm infants aged between 1.5 and 2.5 mo (corrected age) showed a tendency for a faster maturation than those of full-term infants. Our results suggest that within the first 6 mo of age, pattern VEP response is useful to monitor visual development in full-term infants as well as in preterm infants using corrected age.

Alterations in the electroretinogram of newborn piglets by propionic acid-derivative nonsteroidal antiinflammatory drugs but not by indomethacin and diclofenac.

Different nonsteroidal antiinflammatory drugs (NSAID), especially ibuprofen, are being considered as an alternative to indomethacin for use in the newborn and as antipyretics for infants. However, some of these NSAID have been shown to cause visual complications. We therefore studied the effects of different NSAID indomethacin 19.6 mumol/kg (7 mg/kg), diclofenac 15.7 mumol/kg (5 mg/kg), ibuprofen 48 and 194 mumol/kg (10 and 40 mg/kg), naproxen 79 mumol/kg (20 mg/kg), and flurbiprofen 41 mumol/kg (10 mg/kg) on photopic and scotopic electroretinograms (ERG) and retinal prostaglandin E2, prostaglandin F2 alpha, and 6-keto-prostaglandin F1 alpha levels in piglets 1-5 d old. All NSAID decreased retinal prostaglandin levels, but their effects on the ERG were not identical. Indomethacin and diclofenac did not alter the ERG. In contrast, the propionic acid derivatives ibuprofen (the two doses used), naproxen, and flurbiprofen affected the amplitude as well as the implicit time of the ERG under photopic and scotopic conditions. These changes are suggestive of generalized alterations in the function of rods and cones. Prior inhibition of prostaglandin synthesis by indomethacin did not modify the effects of ibuprofen on the ERG. These findings thus show a dissociation between the effects of NSAID on the ERG and prostaglandin synthesis. Because ERG changes are associated with visual alterations, these effects of propionic acid derivatives should be taken into account before considering their use in infants.

Effects of early reduced light exposure on central visual development in preterm infants.

The aim of this study was to determine, in infants born at < or =29 weeks postmenstrual age until 32 weeks postmenstrual age, whether reduction to light stimulation by occlusion of eyes affected central visual development. The pattern visual-evoked potential responses at 41 and 51 weeks postmenstrual age and 3 y of age did not differ between infants subjected or not to ocular occlusion. Hence, an early marked reduction in light stimulation in preterm infants does not seem deleterious to visual development.

Clinical heterogeneity in cobalamin C variant of combined homocystinuria and methylmalonic aciduria.

We describe two patients with methylmalonic aciduria and homocystinuria (Cbl C). The disorder was not diagnosed in patient 1 until 4 1/2 years of age; he had a history of fatigue, anorexia, delirium, and spasticity. Moderate megaloblastic bone marrow changes were observed, and there was hyperreflexia of the lower limbs. His condition improved clinically with hydroxycobalamin therapy. Patient 2 was hospitalized at 6 weeks of age because of lethargy and poor feeding. She was found to have macrocytosis. Despite an initial good clinical response to hydroxycobalamin, she developed a striking pigmentary retinopathy. Methylmalonic aciduria persisted in both patients, and homocystinuria persisted in patient 1 despite therapy. The diagnosis of Cbl C disease has been confirmed in both patients by biochemical studies of cultured fibroblasts, including complementation studies. The differences in age of onset and clinical findings together with the similar biochemical findings in these two patients demonstrate the heterogeneity of phenotypic expression in patients with apparently identical abnormalities of vitamin B12 metabolism.

Clinical evaluation of aminocaproic acid for managing traumatic hyphema in children.

PURPOSE: The purpose of this study is to determine the incidence of secondary hemorrhage after traumatic hyphema in children and to evaluate the efficacy of epsilon aminocaproic acid in reducing this incidence. METHODS: In a prospective, randomized, double-blind study performed between November 1987 and February 1994, 94 children admitted for traumatic hyphema were assigned to receive either aminocaproic acid (n = 48) (100 mg/kg every 4 hours; maximum, 30 g daily) or placebo (n = 46) for 5 days. Patients who had ingested aspirin in the week preceding admission were excluded from the study. RESULTS: Mean age of the patients was 9.4 years. Black patients comprised 4% of the study population. Secondary hemorrhage occurred in only three patients (3.2%), two from the placebo group and one from the aminocaproic acid group, none of whom had any complications. The duration of hospital stay and the clot resorption times were increased significantly in the aminocaproic acid group (P < 0.001). CONCLUSIONS: The authors report a very low incidence of secondary hemorrhage compared with most previous studies. This difference is likely related to the small proportion of black patients in our study and to the exclusion of patients having ingested aspirin, two factors that seem to be associated with higher rates of rebleeding. The efficacy of aminocaproic acid could not be determined due to the low incidence of hemorrhage. The results of this study, however, suggest that the incidence of secondary hemorrhage in white patients without prior ingestion of aspirin is insufficient to justify routine use of aminocaproic acid in managing traumatic hyphema. Rather, an individualized decision based on the risk factors of each patient would seem more appropriate to avoid a slower clot resorption time and possible side effects of this medication.

Malabsorption, hypocholesterolemia, and fat-filled enterocytes with increased intestinal apoprotein B. Chylomicron retention disease.

Eight infants presented with a malabsorption syndrome, normal fasting triglycerides, hypocholesterolemia (64.3 +/- 10.0 mg/dl), and deficiency of vitamins A and E. Plasma low-density lipoprotein, apolipoprotein B, and apolipoprotein A-I were decreased. After a fatty meal, plasma triglycerides did not increase and chylomicrons could not be identified. Lipoprotein composition was characterized by normal apoproteins, high phospholipids, and low cholesterol. Increased triglycerides were present in low-density lipoproteins. Immunoperoxidase localization of apolipoprotein B on fasting biopsy specimens showed increased staining of the lipid-laden intestinal epithelial cells compared to normals. On electron microscopy after a fat load, the enterocytes contained large numbers of fat particles vesiculating the endoplasmic reticulum. These particles, morphologically similar to chylomicrons, were also present as aggregates of well-individualized lipid droplets within dilated vesicles in the Golgi zone, but were not seen in the intercellular spaces and lacteals. This recessively transmitted condition differs from abetalipoproteinemia and from the homozygous form of hypobetalipoproteinemia and may be caused by a defect in the final assembly of chylomicrons or in the mechanism of their exocytosis.