Alina V. Dumitrescu

Attachment disturbances in young children. II: Indiscriminate behavior and institutional care.

OBJECTIVE To assess convergence among three different measures of indiscriminate behavior and to assess the relationship of indiscriminate behavior to having an attachment figure and to aggressive behavior among young children living in a Romanian institution. METHOD Caregivers in the institution were interviewed with semistructured interviews regarding the behavior of 61 children with special emphasis on indiscriminate behavior. The study was conducted in Bucharest, Romania (1999). RESULTS Substantial convergence among measures of indiscriminate behavior was demonstrated. Indiscriminate behavior was common whether or not these children had a preferred attachment figure. Indiscriminate behavior was independent of aggressive behavior. CONCLUSIONS Differing explanations for indiscriminate behavior in young children derive from differing interpretations of similar findings rather than different findings with different measures. Indiscriminate behavior was largely independent of aggression in these institutionalized young children. Indiscriminate behavior may represent an independent problem rather than a type of reactive attachment disorder as suggested by DSM-IV criteria.

Automated Measurement of the Arteriolar-to-Venular Width Ratio in Digital Color Fundus Photographs

A decreased ratio of the width of retinal arteries to veins [arteriolar-to-venular diameter ratio (AVR)], is well established as predictive of cerebral atrophy, stroke and other cardiovascular events in adults. Tortuous and dilated arteries and veins, as well as decreased AVR are also markers for plus disease in retinopathy of prematurity. This work presents an automated method to estimate the AVR in retinal color images by detecting the location of the optic disc, determining an appropriate region of interest (ROI), classifying vessels as arteries or veins, estimating vessel widths, and calculating the AVR. After vessel segmentation and vessel width determination, the optic disc is located and the system eliminates all vessels outside the AVR measurement ROI. A skeletonization operation is applied to the remaining vessels after which vessel crossings and bifurcation points are removed, leaving a set of vessel segments consisting of only vessel centerline pixels. Features are extracted from each centerline pixel in order to assign these a soft label indicating the likelihood that the pixel is part of a vein. As all centerline pixels in a connected vessel segment should be the same type, the median soft label is assigned to each centerline pixel in the segment. Next, artery vein pairs are matched using an iterative algorithm, and the widths of the vessels are used to calculate the AVR. We trained and tested the algorithm on a set of 65 high resolution digital color fundus photographs using a reference standard that indicates for each major vessel in the image whether it is an artery or vein. We compared the AVR values produced by our system with those determined by a semi-automated reference system. We obtained a mean unsigned error of 0.06 (SD 0.04) in 40 images with a mean AVR of 0.67. A second observer using the semi-automated system obtained the same mean unsigned error of 0.06 (SD 0.05) on the set of images with a mean AVR of 0.66. The testing data and reference standard used in this study has been made publicly available.

TUDCA Slows Retinal Degeneration in Two Different Mouse Models of Retinitis Pigmentosa and Prevents Obesity in Bardet-Biedl Syndrome Type 1 Mice

PURPOSE To evaluate and compare the protective effect of tauroursodeoxycholic acid (TUDCA) on photoreceptor degeneration in different models of retinal degeneration (RD) in mice. METHODS Bbs(M390R/M390R) mice were injected subcutaneously twice a week, from P40 to P120, and rd10 mice were injected every 3 days from P6 to P38 with TUDCA or vehicle (0.15 M NaHCO(3)). Rd1 and rd16 mice were injected daily from P6 to P30 with TUDCA or vehicle. Retinal structure and function were determined at multiple time points by electroretinography (ERG), optical coherence tomography (OCT), and histology. RESULTS The amplitude of ERG b-waves was significantly higher in TUDCA-treated Bbs1 and rd10 animals than in controls. Retinal thickness on OCT was slightly greater in treated Bbs1 animals than in the controls. Histologically, outer segments were preserved, and the outer nuclear layer was significantly thicker in the treated Bbs1 and rd10 mice than in the controls. Bbs1(M390R/M390R) mice developed less obesity than the control Bbs1(M390R/M390R) while receiving TUDCA. The Rd1 and rd16 mice showed no improvement with TUDCA treatment, and the rd1 mice did not have normal weight gain during treatment. CONCLUSIONS TUDCA treatment preserved ERG b-waves and the outer nuclear layer in Bbs1(M390R/M390R) mice, and prevented obesity assessed at P120. TUDCA treatment preserved ERG b-waves and the outer nuclear layer in the rd10 mice to P30. TUDCA is a prime candidate for treatment of humans with retinal degeneration, especially those with Bardet-Biedl syndrome, whom it may help not only with the vision loss, but with the debilitating obesity as well.

Disruption of the complement cascade delays retinal ganglion cell death following retinal ischemia-reperfusion.

Recent reports have indicated that components of the complement cascade are synthesized during the degeneration of retinal ganglion cells (RGC) in glaucoma. While complement deposition in the retina may simply serve to aid phagocytosis of damaged RGC, activation of the complement cascade can also contribute to neuronal loss in neurodegenerative diseases. This study was designed to determine if disruption of the complement cascade affects RGC survival in a murine model of retinal ischemia-reperfusion (I/R) injury. We induced retinal ischemia in the eyes of normal mice and mice with a targeted disruption of the complement component 3 (C3) gene. Tissue was harvested 7 and 21 days after induction of I/R and retinal complement synthesis was determined by quantitative PCR and immunohistochemical methods. RGC death and associated axon loss was evaluated through histological examination of the optic nerve and retina. Our data show that retinal I/R induces the expression and deposition of complement components. C3 deficient mice clearly exhibited reduced optic nerve damage and substantial preservation of RGC 1 week after I/R when compared to normal animals (p=0.005). Three weeks after the ischemic event C3 deficient mice retained more RGC cell bodies although the degree of optic nerve damage was similar between both groups. These findings demonstrate that inhibition of the complement cascade delays optic nerve axonal and RGC degeneration in retinal I/R. It appears that injured RGC are targeted and actively destroyed through complement mediated processes. These results may have implications for the pathophysiology and clinical management of ischemic retinal conditions.

Evaluation of a computer-aided diagnosis system for diabetic retinopathy screening on public data.

PURPOSE To evaluate the performance of a comprehensive computer-aided diagnosis (CAD) system for diabetic retinopathy (DR) screening, using a publicly available database of retinal images, and to compare its performance with that of human experts. METHODS A previously developed, comprehensive DR CAD system was applied to 1200 digital color fundus photographs (nonmydriatic camera, single field) of 1200 eyes in the publicly available Messidor dataset (Methods to Evaluate Segmentation and Indexing Techniques in the Field of Retinal Ophthalmology (http://messidor.crihan.fr). The ability of the system to distinguish normal images from those with DR was determined by using receiver operator characteristic (ROC) analysis. Two experts also determined the presence of DR in each of the images. RESULTS The system achieved an area under the ROC curve of 0.876 for successfully distinguishing normal images from those with DR with a sensitivity of 92.2% at a specificity of 50%. These compare favorably with the two experts, who achieved sensitivities of 94.5% and 91.2% at a specificity of 50%. CONCLUSIONS This study shows, for the first time, the performance of a comprehensive DR screening system on an independent, publicly available dataset. The performance of the system on this dataset is comparable with that of human experts.

Subretinal Gene Therapy of Mice With Bardet-Biedl Syndrome Type 1

PURPOSE To study safety and efficacy of subretinal adeno-associated virus (AAV) vector AAV-Bbs1 injection for treatment of a mouse model of Bardet-Biedl syndrome type 1 (BBS1). METHODS Constructs containing a wild-type (WT) Bbs1 gene with and without a FLAG tag in AAV2/5 vectors were generated. Viral genomes were delivered by subretinal injection to right eyes and sham injections to left eyes at postnatal day 30 (P30) to P60. Transgene expression and BBSome reconstitution were evaluated by immunohistochemistry and Western blotting following sucrose gradient ultracentrifugation. Retinal function was analyzed by electroretinogram (ERG) and structure by optical coherence tomography (OCT). Histology and immunohistochemistry were performed on selected eyes. RESULTS Expression of FLAG-tagged Bbs1 was demonstrated in photoreceptor cells using antibody directed against the FLAG tag. Coinjection of AAV-GFP demonstrated transduction of 24% to 32% of the retina. Western blotting demonstrated BBS1 protein expression and reconstitution of the BBSome. ERG dark-adapted bright flash b-wave amplitudes were higher in AAV-Bbs1-injected eyes than in sham-injected fellow eyes in more than 50% of 19 animals. Anti-rhodopsin staining demonstrated improved localization of rhodopsin in AAV-Bbs1-treated eyes. WT retinas injected with AAV-Bbs1 with or without a FLAG tag showed outer retinal degeneration on ERG, OCT, and histology. CONCLUSIONS In a knock-in model of BBS1, subretinal delivery of AAV-Bbs1 rescues BBSome formation and rhodopsin localization, and shows a trend toward improved ERG. BBS is challenging to treat with gene therapy due to the stoichiometry of the BBSome protein complex and overexpression toxicity.

Contextual computer-aided detection: Improving bright lesion detection in retinal images and coronary calcification identification in CT scans

Contextual information plays an important role in medical image understanding. Medical experts make use of context to detect and differentiate pathologies in medical images, especially when interpreting difficult cases. The majority of computer-aided diagnosis (CAD) systems, however, employ only local information to classify candidates, without taking into account global image information or the relation of a candidate with neighboring structures. In this paper, we present a generic system for including contextual information in a CAD system. Context is described by means of high-level features based on the spatial relation between lesion candidates and surrounding anatomical landmarks and lesions of different classes (static contextual features) and lesions of the same type (dynamic contextual features). We demonstrate the added value of contextual CAD for two real-world CAD tasks: the identification of exudates and drusen in 2D retinal images and coronary calcifications in 3D computed tomography scans. Results show that in both applications contextual CAD is superior to a local CAD approach with a significant increase of the figure of merit of the Free Receiver Operating Characteristic curve from 0.84 to 0.92 and from 0.88 to 0.98 for exudates and drusen, respectively, and from 0.87 to 0.93 for coronary calcifications.

Prevalence and Characteristics of Abnormal Head Posture in Children with Down Syndrome: A 20-Year Retrospective, Descriptive Review

PURPOSE To characterize the abnormal head posture (AHP) in children with Down syndrome (DS). The study had 3 aims: to estimate the prevalence of AHP, to describe the distribution of different causes for AHP, and to evaluate the long-term outcomes of AHP in children with DS evaluated at the University of Iowa Hospitals and Clinics between 1989 and 2009. DESIGN Retrospective chart review. PARTICIPANTS Two hundred fifty-nine patient records. METHODS The study data were analyzed using chi-square tests (the Fisher exact test when appropriate) to describe the relationship between the outcome of interest and each study covariate. A predictive logistic regression model for AHP was constructed including all the significant covariates. MAIN OUTCOME MEASURES Abnormal head posture. RESULTS Over the study period, 259 records of patients with DS were identified. Of these, 64 (24.7%) patients had AHP. The most frequent cause of AHP was incomitant strabismus in 17 (26.6%) of 64 patients. The second most frequent cause of AHP was nystagmus, in 14 (21.8%) of 64 patients. For a substantial number of patients with AHP, the cause could not be determined. They represented 12 (18.8%) of all the patients with AHP in this study and 12 (4.6%) of all patients with DS examined. When compared with patients with AHP from a determined cause, this subgroup has a statistically significantly (P = 0.027, Fisher exact test) higher percentage of atlantoaxial instability. In the study population, 9 (14.1%) of 64 patients with AHP had more than 1 cause for AHP. Refractive errors, ptosis, unilateral hearing loss, and neck and spine musculoskeletal abnormalities were responsible for AHP in a small percentage of patients. Of all the patients with AHP, 23 (35.9%) improved their head posture with treatment (glasses or surgery). An additional 6 (9.4%) patients improved their posture spontaneously, over time and without treatment. CONCLUSIONS The prevalence of AHP in the children with DS evaluated was 24.7%. From this analysis, having strabismus of any kind and particularly incomitant strabismus, nystagmus, or both is highly correlated with the development of an AHP. Almost 19% of DS patients with AHP had no definitive cause that could be determined.

A family with branchio-oculo-facial syndrome with primarily ocular involvement associated with mutation of the TFAP2A gene

Background: Branchio-Oculo-Facial syndrome (BOFS) is a rare, autosomal dominant developmental disorder that has a distinct phenotype with characteristic craniofacial abnormalities. We report a family with extensive ocular manifestations of BOFS caused by a novel mutation in the transcription factor AP-2 alpha (TFAP2A) gene. Materials and methods: Case report of phenotypic and genotypic characterization of a family with BOFS. Results: An infant presenting with anophththalmia/coloboma and subtle craniofacial symptoms was found to have a family history of congenital cataracts and colobomas in her mother. A mutation in the TFAP2A gene associated with BOFS (heterozygous H384Y in exon 7) was found in both the proband and her mother. This mutation had not been reported previously. Compared with other molecularly confirmed cases in the literature, this family has primarily ocular features, which are severe. Conclusions: BOFS can have profound ocular involvement without prominent extraocular features. When the syndrome presents in this way, it may be confused with isolated autosomal dominant chorioretinal coloboma. Testing for mutations in the TFAP2A gene is recommended to establish an accurate diagnosis for the family.

Juvenile xanthogranulomatosis with bilateral and multifocal ocular lesions of the iris, cornealscleral limbus, and choroid

A 14-month-old boy with juvenile xanthogranuloma skin lesions presented with increased intraocular pressure, hyphema, anterior uveitis, iris mass, and a subconjunctival limbal mass of the right eye. He subsequently developed a subretinal mass in the left eye. The anterior uveitis resolved after 2 periocular injections of triamcinolone in addition to the administration of topical prednisolone and oral prednisone and methotrexate. The subretinal mass in the left eye also resolved during the course of 1 year. He developed a cataract in the right eye and underwent lensectomy with anterior vitrectomy. This is the first published case in which methotrexate was used as an adjunctive treatment of juvenile xanthogranuloma in a child.