Linda M Pratt

Macular pigment optical density in a midwestern sample

OBJECTIVE To assess the distribution of the macular pigments (MPs) lutein (L) and zeaxanthin (Z) in a healthy sample more representative of the general population than past studies and to determine which dietary factors and personal characteristics might explain the large interindividual differences in the density of these MPs. DESIGN Prevalence study in a self-selected population. PARTICIPANTS Two hundred eighty healthy adult volunteers, consisting of 138 men and 142 women, between the ages of 18 and 50 years, recruited from the general population. METHODS MP optical density was measured psychophysically at 460 nm by use of a 1 degrees test field. Serum was analyzed for carotenoid and vitamin E content with reversed-phase high-performance liquid chromatography. Usual intakes of nutrients over the past year were determined by means of a food frequency questionnaire. MAIN OUTCOME MEASURES MP optical density. RESULTS Mean MP optical density measured 0.211 +/- 0.13, which is approximately 40% lower than the average reported in smaller, less representative studies. MP density was 44% lower in the bottom versus the top quintile of serum L and Z concentrations. Similarly, MP density was 33% lower in the bottom compared with the top quintile of L and Z intake. MP density was 19% lower in blue-grey-eyed subjects than in subjects with brown-black irises. When all variables were considered together in a general linear model of determinants of MP, statistically significant (P < 0.05) relationships were found between MP density and serum L and Z, dietary L and Z intake, fiber intake, and iris color. CONCLUSIONS These data suggest that MP values in this healthy adult population are lower than in smaller select samples. Moreover, these data indicate that MP is related to serum L and Z, dietary L and Z intake, fiber intake, and iris color.

Choroidal perfusion perturbations in non-neovascular age related macular degeneration.

Aim: Choroidal perfusion, affected in age related macular degeneration (AMD), is difficult to objectively assess given the overlying retinal circulation. This study more objectively compared choroidal perfusion parameters in a group with non-neovascular AMD to an unaffected age matched control group. Methods: 21 non-neovascular AMD subjects and 21 age matched control subjects without evidence of AMD underwent assessment of their choroidal blood flow in a case-control study. Scanning laser ophthalmoscope indocyanine green (ICG) angiograms were analysed by a new area dilution analysis technique. Four areas in the perifoveal region and two areas in the temporal peripapillary retina were evaluated by producing a graph of intensity of fluorescence of each area over time. The mean of the filling times and the heterogeneity of the filling times were assessed. Results: The means of the filling times within the perifoveal regions and the hetereogeneity of the filling times between regions within the same eyes were significantly greater in the AMD patients compared with the control subjects. Conclusions: Delayed and heterogeneous filling of the choroid was objectively demonstrated in eyes with non-neovascular AMD compared with age matched controls without evidence of AMD, using an area dilution analysis technique applied to ICG angiography.

Intravitreal triamcinolone for choroidal neovascularization in ocular histoplasmosis syndrome.

PURPOSE To report the effects of intravitreal triamcinolone acetonide injections for subfoveal and juxtafoveal choroidal neovascularization (CNV) in ocular histoplasmosis syndrome. METHODS In a retrospective analysis, the proportion of eyes that gained >or=5 or lost >or=5 and >or=15 Early Treatment of Diabetic Retinopathy Study (ETDRS) letters, best-corrected visual acuity using ETDRS letter score (VA), greatest linear dimension (GLD), and treatment side effects were assessed. RESULTS Ten patients (five subfoveal, five juxtafoveal CNV; median follow-up: 17 months; range, 6-41 months) were evaluated. Thirty percent gained >or=5 letters, 20% lost 5 to 14 letters, and 50% maintained stable VA. Overall, mean VA and GLD remained stable. Side effects were transient intraocular pressure elevation and mild cataract development. CONCLUSIONS Intravitreal triamcinolone acetonide for CNV resulting from OHS was found to be relatively safe and showed good visual outcome for both subfoveal and juxtafoveal CNV. Further studies are warranted to evaluate this treatment.

Proton therapy for exudative age-related macular degeneration: a randomized, sham-controlled clinical trial☆

PURPOSE To examine the effect of proton beam irradiation on subfoveal choroidal neovascular membranes (CNVM) associated with age-related macular degeneration (AMD).Randomized, prospective, sham-controlled, double-masked treatment trial. METHODS Thirty-seven subjects with subfoveal CNVM due to AMD were randomly assigned to 16-Gy proton irradiation delivered in two fractions 24 hours apart or to sham control treatment. Recruitment was halted at 37 subjects for ethical reasons regarding randomization to sham treatment when Food and Drug Administration approval of Visudyne was anticipated. RESULTS Proton irradiation was associated with a trend toward stabilization of visual acuity, but this association did not reach statistical significance. No correlations were found within the fluorescein angiography data, including greatest linear dimension of CNVM total size, area of active leakage, area of associated subretinal hemorrhage, and intensity. CONCLUSIONS With the acceptance of photodynamic therapy, future studies will require more complex design and larger sample size to determine whether radiation can play either a primary or adjunctive role in treating these lesions.

Insulin-Like Growth Factors I and II Peptide and Messenger RNA Levels in Macrosomic Infants of Diabetic Pregnancies

Objective: Fetal macrosomia is a common complication of maternal diabetes mellitus and is associated with substantial morbidity, but the precise cellular and molecular mechanisms that induce fetal macrosomia are not well understood. We hypothesized that the macrosomia or accelerated fetal growth seen in infants of diabetic mothers is due to a perturbation of a putative placental-fetal growth axis involving growth hormone and insulin-like growth factors. Insulin-like growth factors I and II (IGF-I and IGF-II) are ubiquitous peptides that share structural homology with insulin and have been implicated in processes that control fetal growth. Studies of IGF levels in pregnancies complicated by diabetes and macrosomia have shown conflicting results. We set out to resolve these inconsistencies using molecular techniques to measure the placental IGF-I and IGF-II messenger RNA levels in placentas and a specific radioimmunoassay to measure IGF-I and IGF-II peptide levels in cord serum of normal and diabetic pregnancies. Methods: Placentas and cord blood were collected immediately after delivery at term from patients from each of three study groups: 1) nonmacrosomic infants of nondiabetic mothers (controls), 2) macrosomic infants of diabetic mothers, and 3) nonmacrosomic infants of diabetic mothers. Both IGF-I and IGF-II levels were measured in cord serum and placental tissue by a specific radioimmunoassay. Total RNA was extracted and analyzed by Northern gels hybridized to IGF-I or IGF-II riboprobes. Results: Levels of IGF-I in cord serum from the macrosomic diabetic group (83 ± 4.2 ng/mL) were significantly higher than levels from either the nonmacrosomic nondiabetic group (38 ± 1.9 ng/mL) or the nonmacrosomic diabetic group (13 ± 3.5 ng/mL). There was a direct linear correlation between cord serum IGF-I and infant birth weight, independent of diabetes (r2 = 0.61, P < .01). On the other hand, IGF-II cord serum levels were elevated in diabetic pregnancies (337 ± 12.2 ng/mL) compared with nondiabetic women (172 ± 19.8 ng/mL), but there was no correlation with birth weight (r2 = 0.035, P = .52). In contrast to cord blood levels, IGF-II peptide levels were significantly decreased in the placentas from mothers with diabetes compared with nondiabetic controls (116 ± 3.2 versus 158 ± 5.3 ng/mL, respectively). Levels of IGF-I peptide in placentas from both nondiabetic controls and diabetic mothers were below the sensitivity of the assay. levels of IGF-I and IGF-II mRNA did not differ in placentas from diabetic mothers versus nondiabetic controls. Conclusion: Cord serum IGF-II levels are elevated in diabetic pregnancies without a concomitant increase in placental IGF-II levels. This novel finding, combined with the finding that IGF-I levels are correlated with macrosomia independent of the diabetic state, contributes to our understanding of the possible mechanisms involved in fetal growth in pregnancies complicated by diabetes.

Racial Differences in Sensitivity of Blood Pressure to Aldosterone

Blacks in comparison with whites are at risk for a more serious form of hypertension with high rates of complications. Greater sodium retention is thought to underlie the blood pressure (BP)-determining physiology of blacks, but specific mechanisms have not been identified. In a prospective observational study of BP, 226 black children and 314 white children (mean age, 10.6 years) were enrolled initially. Assessments were repeated in 85 blacks and 136 whites after reaching adulthood (mean age, 31 years). The relationship of BP to plasma aldosterone concentration in the context of the prevailing level of plasma renin activity was studied in blacks and whites. In a secondary interventional study, 9-&agr; fludrocortisone was administered for 2 weeks to healthy adult blacks and whites to simulate hyperaldosteronism. BP responses in the 2 race groups were then compared. Although black children had lower levels of plasma renin activity and plasma aldosterone, their BP was positively associated with the plasma aldosterone concentration, an effect that increased as plasma renin activity decreased (P=0.004). Data from black adults yielded similar results. No similar relationship was observed in whites. In the interventional study, 9-&agr; fludrocortisone increased BP in blacks but not in whites. In conclusion, aldosterone sensitivity is a significant determinant of BP in young blacks. Although its role in establishing the risk of hypertension is not known, it could be as relevant as the actual level of aldosterone.

Pharmacologic therapy for diabetic retinopathy.

Diabetic retinopathy remains one of the major causes of acquired blindness in developed nations. This is true despite the development of laser treatment, which can prevent blindness in the majority of those who develop macular oedema (ME) or proliferative diabetic retinopathy (PDR). ME is manifest by retinal vascular leakage and thickening of the retina. The hallmark of PDR is neovascularisation (NV) – abnormal angiogenesis that may ultimately cause severe vitreous cavity bleeding and/or retinal detachment. Pharmacologic therapy aimed specifically at preventing vascular leakage and NV would be a welcome addition to the armamentarium. PDR and ME could be prevented by improved metabolic control or by pharmacologically blunting the biochemical consequences of hyperglycaemia (e.g., with aldose reductase inhibitors, inhibitors of non-enzymatic glycation or by protein kinase C [PKC] inhibition). The angiogenesis in PDR could be treated via growth factor (e.g., vascular endothelial growth factor [VEGF], insulin like growth factor-1 [IGF-1]) blockade, integrin (e.g., alpha-v beta-3) blockade, extracellular matrix alteration (e.g., with steroid compounds) or interference with intracellular signal transduction pathways (e.g., PKC and mitogen activated protein kinase [MAPK] pathway proteins). Some of these antiangiogenic agents may also prove useful for treating or preventing ME. Numerous potentially useful antiangiogenic compounds are in development; two drugs are presently in clinical trials for treatment of the preproliferative stage of PDR, while two are in clinical trials for treatment of ME.

Anti-angiogenic therapy of proliferative diabetic retinopathy

Proliferative diabetic retinopathy (PDR) remains one of the major causes of acquired blindness in developed nations. This is true despite the development of laser treatment, which can prevent blindness in the majority of those who develop this complication. The hallmark of PDR is neovascularisation (NV), abnormal angiogenesis that may ultimately cause severe vitreous cavity bleeding and/or retinal detachment. Pharmacologic therapy aimed at preventing NV, as an adjunct to laser treatment, or as an alternative to laser treatment, would be a welcome addition to the armamentarium. PDR could be prevented by improved metabolic control or by pharmacologically blunting the biochemical consequences of hyperglycaemia (e.g., with aldose reductase inhibitors, inhibitors of non-enzymatic glycation or by protein kinase C (PKC) inhibition). The angiogenesis in PDR could be treated via growth factor (e.g., vascular endothelial growth factor (VEGF), insulin like growth factor-1) blockade, integrin (e.g., α-v β-3) blockade or extracellular matrix alteration (e.g., with steroid compounds), or interference with intracellular signal transduction pathways (e.g., PKC and mitogen activated protein kinase pathway proteins). Numerous potentially useful anti-angiogenic compounds are in development, but two drugs are presently in clinical trials for the treatment of the preproliferative stage of PDR.

The effects of dorzolamide on choroidal and retinal perfusion in non-exudative age related macular degeneration

Aim: To comprehensively evaluate the effects of dorzolamide on the choroidal and retinal circulation in patients with age related macular degeneration (AMD). Methods: In this randomised, double masked, parallel study, 36 non-exudative AMD patients were randomised in a 2 to 1 fashion to placebo versus topical dorzolamide and underwent assessment of their choroidal and retinal circulation. Scanning laser ophthalmoscope indocyanine green angiograms (ICGA) were analysed by a new area dilution analysis technique. Four areas in the perifoveal region and two areas in the temporal peripapillary region were evaluated by plotting intensity of fluorescence of each area over time. The means of the choroidal filling times and the heterogeneity of the filling times were assessed. Scanning laser ophthalmoscope fluorescein angiography (FA) was evaluated for retinal arteriovenous passage (AVP) times by plotting intensity of fluorescence of retinal vessels over time. Assessment was performed at baseline and at 4 months. Results: Compared to placebo, AMD patients treated with dorzolamide showed a significantly increased rapidity of choroidal filling in the superior and inferior peripapillary regions (p=0.007, p=0.02, respectively). No significant difference in choroidal filling times was found in any of the perifoveal areas (p=0.9). Also, on FA assessment, treatment with dorzolamide showed no statistical differences in AVP times (p=0.19). Conclusions: Dorzolamide may increase peripapillary choroidal perfusion in non-exudative AMD patients. Further studies are merited.

Temporal and histologic relationships of proliferating cell nuclear antigen and human papillomavirus type 11 in the mouse xenograft system

Proliferating cell nuclear antigen (PCNA) is an accessory protein of DNA polymerase delta. This protein is associated with cell cycle progression and can be detected in the replicating cells of normal tissues. Condylomata acuminata are benign epithelial tumors caused by infection with human papillomaviruses and are characterized by abnormal cell proliferation. The athymic mouse xenograft model of HPV 11 infection was used to test the hypothesis that PCNA is induced early in the course of HPV 11 infection and to study the temporal and histologic relationships between detection of PCNA and HPV DNA. Human foreskin tissue was infected with HPV 11 and implanted under the renal capsules of 10 athymic mice. Pairs of mice were sacrificed every week beginning four weeks after implantation. HPV DNA was detected in sections of foreskin implants by in situ hybridization. PCNA was as or more abundant in implants removed at earlier time points than at later time points, whereas HPV DNA became increasingly more abundant with time. PCNA was detected only in basal cells in areas of histologically normal epithelium that were also negative for HPV DNA. In contrast, PCNA was present throughout the epithelium in regions that were HPV DNA‐positive. HPV DNA was detected only in differentiated epithelial cells in implants removed at all five time points, but in HPV DNA‐positive regions, PCNA was detected with equal intensity in differentiated and undifferentiated cells. The foci of PCNA‐positive cells were well demarcated and were larger than, but included, the foci of HPV DNA‐positive cells. PCNA may be induced maximally in differentiated epithelium by HPV 11 prior to significant HPV DNA replication.