Exploring the Vitreoretinal Interface: A Key Instigator of Unique Retinal Hemorrhage Patterns in Pediatric Head Trauma.

PURPOSE: Various types of trauma can cause retinal hemorrhages in children, including accidental and nonaccidental head trauma. We used animal eyes and a finite element model of the eye to examine stress patterns produced during purely linear and angular accelerations, along with stresses attained during simulated repetitive shaking of an infant. METHODS: Using sheep and primate eyes, sclerotomy windows were created by removing the sclera, choroid, and retinal pigment epithelium to expose the retina. A nanofiber square was glued to a 5 mm2 area of retina. The square was pulled and separated from vitreous while force was measured. A finite element model of the pediatric eye was used to computationally measure tension stresses during shaking. RESULTS: In both sheep and primate eyes, tension stress required for separation of retina from vitreous range from 1 to 5 kPa. Tension stress generated at the vitreoretinal interface predicted by the computer simulation ranged from 3 to 16 kPa during a cycle of shaking. Linear acceleration generated lower tension stress than angular acceleration. Angular acceleration generated maximal tension stress along the retinal vasculature. Linear acceleration produced more diffuse force distribution centered at the poster pole. CONCLUSIONS: The finite element model predicted that tension stress attained at the retina during forcible shaking of an eye can exceed the minimum threshold needed to produce vitreoretinal separation as measured in animal eyes. Furthermore, the results show that movements that involve significant angular acceleration produce strong stresses localized along the vasculature, whereas linear acceleration produces weaker, more diffuse stress centered towards the posterior pole of the eye.

Determining the Tractional Forces on Vitreoretinal Interface Using a Computer Simulation Model in Abusive Head Trauma.

PURPOSE: Abusive head trauma (AHT) is the leading cause of infant death and long-term morbidity from injury. The ocular consequences of AHT are controversial, and the pathophysiology of retinal research findings is still not clearly understood. It has been postulated that vitreoretinal traction plays a major role in the retinal findings. A computer simulation model was developed to evaluate the vitreoretinal traction and determine whether the distribution of forces in different layers and locations of the retina can explain the patterns of retinal hemorrhage (RH) seen in AHT. DESIGN: Computer simulation model study. METHODS: A computer simulation model of the pediatric eye was developed to evaluate preretinal, intraretinal, and subretinal stresses during repetitive shaking. This model was also used to examine the forces applied to various segments along blood vessels. RESULTS: Calculated stress values from the computer simulation ranged from 3-16 kPa at the vitreoretinal interface through a cycle of shaking. Maximal stress was observed at the periphery of the retina, corresponding to areas of multiple vessel bifurcations, followed by the posterior pole of the retina. Stress values were similar throughout all 3 layers of the retina (preretinal, intraretinal, and subretinal layers). CONCLUSIONS: Ocular manifestations from AHT revealed unique retinal characteristics. The model predicted stress patterns consistent with the diffuse retinal hemorrhages (RH) typically found in the posterior pole and around the peripheral retina in AHT. This computer model demonstrated that similar stress forces were produced in different layers of the retina, consistent with the finding that retinal hemorrhages are often found in multiple layers of the retina. These data can help explain the RH patterns commonly found in AHT.

Retinopathy of prematurity: preferred practice patterns among pediatric ophthalmologists.

PURPOSE: The treatment of retinopathy of prematurity (ROP) is not standardized and can vary significantly between providers. This study aims to determine preferred practices in treating ROP by globally surveying pediatric ophthalmologists. METHODS: Between January and February 2017, an international pediatric ophthalmology interest group was invited to complete an anonymous survey of 18 questions. The main objectives were to determine the preferred first line of treatment for ROP, the preferred dosage of intravitreal bevacizumab (IVB) used, and the outcome and possible complications following bevacizumab injection. RESULTS: Out of 101 pediatric ophthalmologists, 72 (71.8%) stated that they had direct involvement in the treatment of ROP. When presented with type 1 ROP which requires treatment, 69 ophthalmologists (68.3%) stated that they prefer laser treatment over bevacizumab, and 33 ophthalmologists (32.7%) stated they would recommend bevacizumab as a first choice. Ninety-three ophthalmologists (92.1%) reported the success of 1 laser treatment between 75% and 100%, and 35 ophthalmologists (34.7%) perceive bevacizumab to be 75%-100% successful. Half dose of adult-prescribed bevacizumab at 0.625 mg/0.05 mL was preferred by 47 of the ophthalmologists (46.5%). No cases of endophthalmitis were reported with intravitreal injection. CONCLUSION: Laser photoablation remains the preferred mode of treatment for ROP among surveyed ophthalmologists across the world. Though bevacizumab is currently being used, this form of treatment is not as common, primarily due to the unknown safety profile and potential long-term ramifications of the drug.

Persistence of the bacterial pathogen Granulibacter bethesdensis in chronic granulomatous disease monocytes and macrophages lacking a functional NADPH oxidase.

Granulibacter bethesdensis is a Gram-negative pathogen in patients with chronic granulomatous disease (CGD), a deficiency in the phagocyte NADPH oxidase. Repeated isolation of genetically identical strains from the same patient over years, and prolonged waxing and waning seropositivity in some subjects, raises the possibility of long-term persistence. G. bethesdensis resists killing by serum, CGD polymorphonuclear leukocytes (PMN), and antimicrobial peptides, indicating resistance to nonoxidative killing mechanisms. Although G. bethesdensis extends the survival of PMN, persistent intracellular bacterial survival might rely on longer-lived macrophages and their precursor monocytes. Therefore, we examined phagocytic killing by primary human monocytes and monocyte-derived macrophages (MDM). Cells from both normal and CGD subjects internalized G. bethesdensis similarly. G. bethesdensis stimulated superoxide production in normal monocytes, but to a lesser degree than in normal PMN. Normal but not CGD monocytes and MDM killed G. bethesdensis and required in vitro treatment with IFN-γ to maintain this killing effect. Although in vitro IFN-γ did not enhance G. bethesdensis killing in CGD monocytes, it restricted growth in proportion to CGD PMN residual superoxide production, providing a potential method to identify patients responsive to IFN-γ therapy. In IFN-γ-treated CGD MDM, G. bethesdensis persisted for the duration of the study (7 d) without decreasing viability of the host cells. These results indicate that G. bethesdensis is highly resistant to oxygen-independent microbicides of myeloid cells, requires an intact NADPH oxidase for clearance, and can persist long-term in CGD mononuclear phagocytes, most likely relating to the persistence of this microorganism in infected CGD patients.

Innate immunity against Granulibacter bethesdensis, an emerging gram-negative bacterial pathogen.

Acetic acid bacteria were previously considered nonpathogenic in humans. However, over the past decade, five genera of Acetobacteraceae have been isolated from patients with inborn or iatrogenic immunodeficiencies. Here, we describe the first studies of the interactions of the human innate immune system with a member of this bacterial family, Granulibacter bethesdensis, an emerging pathogen in patients with chronic granulomatous disease (CGD). Efficient phagocytosis of G. bethesdensis by normal and CGD polymorphonuclear leukocytes (CGD PMN) required heat-labile serum components (e.g., C3), and binding of C3 and C9 to G. bethesdensis was detected by immunoblotting. However, this organism survived in human serum concentrations of ≥90%, indicating a high degree of serum resistance. Consistent with the clinical host tropism of G. bethesdensis, CGD PMN were unable to kill this organism, while normal PMN, in the presence of serum, reduced the number of CFU by about 50% after a 24-h coculture. This finding, together with the observations that G. bethesdensis was sensitive to H(2)O(2) but resistant to LL-37, a human cationic antimicrobial peptide, suggests an inherent resistance to O(2)-independent killing. Interestingly, 10 to 100 times greater numbers of G. bethesdensis were required to achieve the same level of reactive oxygen species (ROS) production induced by Escherichia coli in normal PMN. In addition to the relative inability of the organism to elicit production of PMN ROS, G. bethesdensis inhibited both constitutive and FAS-induced PMN apoptosis. These properties of reduced PMN activation and resistance to nonoxidative killing mechanisms likely play an important role in G. bethesdensis pathogenesis.