Carolyn Drews-Botsch

Glutathione in Human Plasma: Decline in Association with Aging, Age-Related Macular Degeneration, and Diabetes

Blood samples were analyzed for GSH and GSH redox state in 40 age-related macular degeneration (ARMD) patients (> 60 y), 33 non-ARMD diabetic patients (> 60 years), 27 similarly aged non-ARMD and nondiabetic individuals (> 60 years), and 19 younger individuals (< 60 years) without ARMD or diabetes. Results showed a significantly lower plasma GSH in older individuals (ARMD, diabetes, and controls) than in younger individuals (p < .01). Total GSH (GSHt) obtained following treatment with dithiothreitol was significantly lower only in diabetic cases (p < .05) but also approached significance for ARMD cases (p = .089). Estimation of redox potential indicated that the plasma GSH pool is considerably more oxidized in all of the older groups. Analyses of whole blood GSH showed that GSH was significantly lower in diabetic cases compared to the other groups, but did not reveal any difference associated with age or ARMD. In contrast, GSSG in whole blood was significantly higher in the older groups compared to the younger controls. The results suggest that in studies of age-related pathologies, oxidation of GSH may be a more important parameter than a decline in pool size, while in specific pathologies such as diabetes, both oxidation and a decline in pool size may be important.

Karyotype versus Microarray Testing for Genetic Abnormalities after Stillbirth

BACKGROUND Genetic abnormalities have been associated with 6 to 13% of stillbirths, but the true prevalence may be higher. Unlike karyotype analysis, microarray analysis does not require live cells, and it detects small deletions and duplications called copy-number variants. METHODS The Stillbirth Collaborative Research Network conducted a population-based study of stillbirth in five geographic catchment areas. Standardized postmortem examinations and karyotype analyses were performed. A single-nucleotide polymorphism array was used to detect copy-number variants of at least 500 kb in placental or fetal tissue. Variants that were not identified in any of three databases of apparently unaffected persons were then classified into three groups: probably benign, clinical significance unknown, or pathogenic. We compared the results of karyotype and microarray analyses of samples obtained after delivery. RESULTS In our analysis of samples from 532 stillbirths, microarray analysis yielded results more often than did karyotype analysis (87.4% vs. 70.5%, P<0.001) and provided better detection of genetic abnormalities (aneuploidy or pathogenic copy-number variants, 8.3% vs. 5.8%; P=0.007). Microarray analysis also identified more genetic abnormalities among 443 antepartum stillbirths (8.8% vs. 6.5%, P=0.02) and 67 stillbirths with congenital anomalies (29.9% vs. 19.4%, P=0.008). As compared with karyotype analysis, microarray analysis provided a relative increase in the diagnosis of genetic abnormalities of 41.9% in all stillbirths, 34.5% in antepartum stillbirths, and 53.8% in stillbirths with anomalies. CONCLUSIONS Microarray analysis is more likely than karyotype analysis to provide a genetic diagnosis, primarily because of its success with nonviable tissue, and is especially valuable in analyses of stillbirths with congenital anomalies or in cases in which karyotype results cannot be obtained. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development.).

The Infant Aphakia Treatment Study: Design and Clinical Measures at Enrollment

OBJECTIVE To compare the use of contact lenses and intraocular lenses (IOLs) for the optical correction of unilateral aphakia during infancy. METHODS In a randomized, multicenter (12 sites) clinical trial, 114 infants with unilateral congenital cataracts were assigned to undergo cataract surgery with or without IOL implantation. Children randomized to IOL treatment had their residual refractive error corrected with spectacles. Children randomized to no IOL treatment had their aphakia treated with a contact lens. MAIN OUTCOME MEASURES Grating acuity at 12 months of age and HOTV visual acuity at 4 1/2 years of age. APPLICATION TO CLINICAL PRACTICE This study should determine whether either treatment for an infant with a visually significant unilateral congenital cataract results in a better visual outcome. RESULTS Enrollment began December 23, 2004, and was completed January 16, 2009. The median age at the time of cataract surgery was 1.8 months. Fifty patients were 4 to 6 weeks of age at the time of enrollment; 32, 7 weeks to 3 months of age; and the remaining 32, more than 3 to less than 7 months of age. Fifty-seven children were randomized to each treatment group. Eyes with cataracts had shorter axial lengths and steeper corneas on average than the fellow eyes. CONCLUSIONS The optimal optical treatment of aphakia in infants is unknown. However, the Infant Aphakia Treatment Study was designed to provide empirical evidence of whether optical treatment with an IOL or a contact lens after unilateral cataract surgery during infancy is associated with a better visual outcome.

Submacular Hemorrhage Removal

PURPOSE To determine whether pars plana vitrectomy combined with tissue plasminogen activator for evacuation of submacular hemorrhage results in improved visual acuity. METHODS Retrospective review of 18 patients who received a subretinal injection of tissue plasminogen activator during a pars plana vitrectomy to evacuate dense submacular hemorrhages. RESULTS Diagnoses included age-related macular degeneration (16 patients), ruptured macroaneurysm (1 patient), and penetrating ocular trauma (1 patient). Preoperative visual acuity ranged from 20/200 to counting fingers (median visual acuity, counting fingers). Follow-up ranged from 10 to 104 weeks (median, 33 weeks). Best postoperative visual acuity ranged from 20/30 to counting fingers (median, 20/300). Best postoperative visual acuity improved two or more lines in 11 (61%) of 18 eyes, remained unchanged in 4 (22%) of 18 eyes, and decreased two or more lines in 3 (17%) of 18 eyes (P = 0.10, Wilcoxon sign-rank test). Final visual acuity ranged from 20/40 to light perception (median, counting fingers). Final visual acuity improved two or more lines in 5 (28%) of 18 eyes, remained unchanged in 6 (33%) of 18 eyes, and decreased two or more lines in 7 (39%) of 18 eyes (P = 0.53, Wilcoxon sign-rank test). CONCLUSIONS Pars plana vitrectomy to evacuate massive subretinal hemorrhage can improve visual acuity, but final visual acuity is limited by the underlying disease.

Maternal alcohol abuse and neonatal infection

BACKGROUND Since chronic alcohol use suppresses the adult immune system, we tested the hypothesis that maternal alcohol ingestion increases the risk of infection in term newborns. METHODS Analysis of a large case-control study of birth weight for gestational age was performed focusing on maternal alcohol ingestion and the development of infection in term newborns > or =36 weeks gestation. After delivery, mothers were asked about alcohol and tobacco use in the 3 months prior to conception, the 1st, 2nd, and 3rd trimester of pregnancy. RESULTS Eight hundred and seventy-two singleton newborns (872) > or = 36 weeks gestation were identified for analysis. A total of 51 (5.8%) had newborn infections. Gestational age, sex, and small for gestational age (SGA) were similar in the newborns with and without infection (p = NS). Infants whose mothers reported alcohol use, excessive drinking or smoking in pregnancy were more likely to have a newborn diagnosed with an infection than were mothers who reported abstaining from alcohol or cigarettes (p < 0.05). When controlling for race and smoking, SGA infants whose mothers used any alcohol had a 2.5-fold increase risk of infection, while excessive alcohol use increased the risk 3-4-fold. In a multivariable logistic regression analysis controlling for low maternal income, smoking, and SGA, excessive alcohol use during the 2 trimester increased the risk of newborn infection (OR 3.7 [1.1,12.8], p < 0.05). CONCLUSIONS Excessive maternal alcohol use is associated with an increased risk of newborn infection in this patient sample. Increased awareness and further clinical investigations are warranted to address the detrimental effects of fetal alcohol exposure on the developing immune system.

Pregnancy outcomes in female childhood and adolescent cancer survivors: a linked cancer-birth registry analysis.

OBJECTIVE To compare birth outcomes among female survivors of childhood and adolescent cancer who subsequently bear children, relative to those of women without a history of cancer. DESIGN Retrospective cohort study. SETTING Four US regions. PARTICIPANTS Cancer registries identified girls younger than 20 years who were diagnosed as having cancer from 1973 through 2000. Linked birth records identified the first live births after diagnosis (n = 1898). Comparison subjects were selected from birth records (n = 14 278). Survivors of genital tract carcinomas underwent separate analysis. MAIN EXPOSURE Cancer diagnosis at younger than 20 years. MAIN OUTCOME MEASURES Infant low birth weight, preterm delivery, sex ratio, malformations, mortality, and delivery method, and maternal diabetes, anemia, and preeclampsia. RESULTS Infants born to childhood cancer survivors were more likely to be preterm (relative risk [RR], 1.54; 95% confidence interval [CI], 1.30-1.83) and to weigh less than 2500 g (1.31; 1.10-1.57). For the offspring of genital tract carcinoma survivors, RRs were 1.33 (95% CI, 1.13-1.56) and 1.29 (1.10-1.53), respectively. There were no increased risks of malformations, infant death, or altered sex ratio, suggesting no increased germ cell mutagenicity. In exploratory analysis, bone cancer survivors had an increased risk of diabetes (RR, 4.92; 95% CI, 1.60-15.13), and anemia was more common among brain tumor survivors (3.05; 1.16-7.98) and childhood cancer survivors whose initial treatment was chemotherapy only (2.45; 1.16-5.17). CONCLUSIONS Infants born to female survivors of childhood and adolescent cancer were not at increased risk of malformations or death. Increased occurrence of preterm delivery and low birth weight suggest that close monitoring is warranted. Increased diabetes and anemia among subgroups have not been reported, suggesting areas for study.

Metropolitan isolation segregation and Black–White disparities in very preterm birth: A test of mediating pathways and variance explained

Residential isolation segregation (a measure of residential inter-racial exposure) has been associated with rates of preterm birth (<37 weeks gestation) experienced by Black women. Epidemiologic differences between very preterm (<32 weeks gestation) and moderately preterm births (32-36 weeks) raise questions about whether this association is similar across gestational ages, and through what pathways it might be mediated. Hierarchical Bayesian models were fit to answer three questions: is the isolation-prematurity association similar for very and moderately preterm birth; is this association mediated by maternal chronic disease, socioeconomic status, or metropolitan area crime and poverty rates; and how much of the geographic variation in Black-White very preterm birth disparities is explained by isolation segregation? Singleton births to Black and White women in 231 U.S. metropolitan statistical areas in 2000-2002 were analyzed and isolation segregation was calculated for each. We found that among Black women, isolation is associated with very preterm birth and moderately preterm birth. The association may be partially mediated by individual level socioeconomic characteristics and metropolitan level violent crime rates. There is no association between segregation and prematurity among White women. Isolation segregation explains 28% of the geographic variation in Black-White very preterm birth disparities. Our findings highlight the importance of isolation segregation for the high-burden outcome of very preterm birth, but unexplained excess risk for prematurity among Black women is substantial.

Risk Markers of Juvenile Idiopathic Arthritis-associated Uveitis in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry

Objective. To characterize the epidemiology and clinical course of children with juvenile idiopathic arthritis-associated uveitis (JIA-U) in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry and explore differences between African American (AA) and non-Hispanic white (NHW) children. Methods. There were 4983 children with JIA enrolled in the CARRA Registry. Of those, 3967 NHW and AA children were included in this study. Demographic and disease-related data were collected from diagnosis to enrollment. Children with JIA were compared to those with JIA-U. Children with JIA-U were also compared by race. Results. There were 459/3967 children (11.6%) with JIA-U in our cohort with a mean age (SD) of 11.4 years (± 4.5) at enrollment. Compared to children with JIA, they were younger at arthritis onset, more likely to be female, had < 5 joints involved, had oligoarticular JIA, and were antinuclear antibody (ANA)-positive, rheumatoid factor (RF)-negative, and anticitrullinated protein antibody-negative. Predictors of uveitis development included female sex, early age of arthritis onset, and oligoarticular JIA. Polyarticular RF-positive JIA subtype was protective. Nearly 3% of children with JIA-U were AA. However, of the 220 AA children with JIA, 6% had uveitis; in contrast, 12% of the 3721 NHW children with JIA had uveitis. Conclusion. In the CARRA registry, the prevalence of JIA-U in AA and NHW children is 11.6%. We confirmed known uveitis risk markers (ANA positivity, younger age at arthritis onset, and oligoarticular JIA). We describe a decreased likelihood of uveitis in AA children and recommend further exploration of race as a risk factor in a larger population of AA children.

Reproductive outcomes in male childhood cancer survivors: a linked cancer-birth registry analysis

OBJECTIVE To compare the risk of reproductive and infant outcomes between male childhood cancer survivors and a population-based comparison group. DESIGN Retrospective cohort study. SETTING Four US regions. PARTICIPANTS Cancer registries identified males younger than 20 years diagnosed with cancer from 1973 to 2000. Linked birth certificates identified first subsequent live offspring (N = 470). Comparison subjects were identified from remaining birth certificates, frequency-matched on year and age at fatherhood, and race/ethnicity (N = 4150). MAIN EXPOSURE Cancer diagnosis before age 20 years. OUTCOME MEASURES Pregnancy and infant outcomes identified from birth certificates. RESULTS Compared with infants born to unaffected males, offspring of cancer survivors had a borderline risk of having a birth weight less than 2500 g (relative risk, 1.43 [95% confidence interval, 0.99-2.05]) that was associated most strongly with younger age at cancer diagnosis and exposure to any chemotherapy (1.96 [1.22-3.17]) or radiotherapy (1.95 [1.14-3.35]). However, they were not at risk of being born prematurely, being small for gestational age, having malformations, or having an altered male to female ratio. Overall, female partners of male survivors were not more likely to have maternal complications recorded on birth records vs the comparison group. However, preeclampsia was associated with some cancers, especially central nervous system tumors (relative risk, 3.36 [95% confidence interval, 1.63-6.90]). CONCLUSIONS Most pregnancies resulting in live births among partners of male childhood cancer survivors were not at significantly greater risk of complications vs comparison subjects. However, there remains the possibility that prior cancer therapy may affect male germ cells with some effects on progeny and on female partners.

Long-term visual outcome of penetrating keratoplasty in infants and children with Peters anomaly

PURPOSE To determine the long-term visual outcome of penetrating keratoplasty for Peters anomaly and to identify prognostic factors affecting final vision. METHODS The records of children 12 years of age or younger who underwent penetrating keratoplasty for Peters anomaly between January 1, 1971 and December 31, 1992 at Emory University were reviewed. Characteristics of the recipient, eye, donor, and surgical procedure were examined with the use of multivariate analyses. RESULTS One hundred forty-four keratoplasties in 72 eyes of 47 children who were followed for a minimum of 3 years from the date of first keratoplasty (median, 11.1 years) were reviewed. Visual acuities ranged from 20/25 to no light perception. Twenty-nine percent of eyes achieved 20/400 or better visual acuities, whereas 38% had light perception or no light perception. Stromal vessels (p < 0.001) and larger donor corneas (p < 0.001) were independent predictors of poor outcome. Postoperative complications included graft failure (n = 44), cataract (n = 15), glaucoma (n = 14), retinal detachment (n = 16), and phthisis (n = 22). More than half of the eyes (n = 18) without graft failure, retinal detachment and/or phthisis saw 20/400 or better. CONCLUSIONS Less than one-third of eyes with Peters anomaly undergoing keratoplasty achieved a visual acuity of 20/400 or better. Stromal vessels and large corneal grafts (>or=8 mm) were the only independent predictors of a poor visual outcome.