The relationship of diabetic retinopathy severity scales with frequency and surface area of diabetic retinopathy lesions.

PURPOSE: To assess the relationship between qualitative diabetic retinopathy (DR) scales with the precise numbers and surface area of DR lesions within the Early Treatment Diabetic Retinopathy Study (ETDRS) standard seven field (S7F) region on ultrawide-field (UWF) color fundus images. METHODS: In this study, we collected UWF images from adult patients with diabetes. Poor-quality images and eyes with any pathology precluding assessment of DR severity were excluded. The DR lesions were manually segmented. DR severity was graded according to the International Clinical Diabetic Retinopathy (ICDR) and AA protocol by two masked graders within the ETDRS S7F. These lesions' numbers and surface area were computed and correlated against the DR scores using the Kruskal-Wallis H test. Cohen's Kappa was performed to determine the agreement between two graders. RESULTS: One thousand five hundred and twenty eyes of 869 patients (294 females, 756 right eyes) with a mean age of 58.7 years were included. 47.4% were graded as no DR, 2.2% as mild non-proliferative DR (NPDR), 24.0% as moderate NPDR, 6.3% as severe NPDR, and 20.1% as proliferative DR (PDR). The area and number of DR lesions generally increased as the ICDR level increased up to severe NPDR, but decreased from severe NPDR to PDR. There was perfect intergrader agreement on the DR severity. CONCLUSION: A quantitative approach reveals that DR lesions' number and area generally correlate with ICDR-based categorical DR severity levels with an increasing trend in the number and area of DR lesions from mild to severe NPDR and a decrease from severe NPDR to PDR.

Practical applications of vitreous imaging for the treatment of vitreous opacities with YAG vitreolysis.

PURPOSE: To demonstrate the methodology and efficacy of using scanning laser ophthalmoscopy (SLO) and dynamic optical coherence tomography (OCT) to identify and treat symptomatic vitreous floaters using yttrium-aluminum garnet laser vitreolysis (YLV). METHODS: This is a case series highlighted from a cross sectional retrospective study conducted at the Vitreous Retina Macula Specialists of Toronto. Forty eyes from thirty-five patients were treated with YLV between November 2018 and December 2020 for symptomatic floaters and imaged with SLO and dynamic OCT. Patients were re-treated with YLV if they reported ongoing significant vision symptoms during follow-up which correlated to visible opacities on exam and or imaging. Three cases will be highlighted to present the practical applications of SLO and dynamic OCT imaging for YLV treatment. RESULTS: Forty treated eyes were enrolled in this study, with twenty-six eyes (65%) requiring at least one repeat YLV treatment following the first treatment due to ongoing symptomatic floaters. Following the first YLV, there was a significant improvement in overall mean best corrected visual acuity compared to before treatment (0.11 ± 0.20 LogMAR units vs. 0.14 ± 0.20 LogMAR units, p = 0.02 (paired t test)). Case 1 demonstrates a dense, solitary vitreous opacity that has been localized with dynamic OCT imaging to track its movements and retinal shadowing with the patient's eye movements. Case 2 shows the utility of adjusting the fixation target to monitor the movement of vitreous opacities in real-time. Case 3 exhibits an association between decreased symptom burden and vitreous opacity density after YLV. CONCLUSION: Image-guided YLV facilitates the localization and confirmation of vitreous opacities. SLO and dynamic OCT of the vitreous can provide a real-time evaluation of floater size, movement, and morphology, to help clinicians target treatment and monitoring of symptomatic floaters.

Development and verification of a nomogram for prediction of recurrence-free survival in clear cell renal cell carcinoma.

Nowadays, gene expression profiling has been widely used in screening out prognostic biomarkers in numerous kinds of carcinoma. Our studies attempt to construct a clinical nomogram which combines risk gene signature and clinical features for individual recurrent risk assessment and offer personalized managements for clear cell renal cell carcinoma. A total of 580 differentially expressed genes (DEGs) were identified via microarray. Functional analysis revealed that DEGs are of fundamental importance in ccRCC progression and metastasis. In our study, 338 ccRCC patients were retrospectively analysed and a risk gene signature which composed of 5 genes was obtained from a LASSO Cox regression model. Further analysis revealed that identified risk gene signature could usefully distinguish the patients with poor prognosis in training cohort (hazard ratio [HR] = 3.554, 95% confidence interval [CI] 2.261-7.472, P < .0001, n = 107). Moreover, the prognostic value of this gene-signature was independent of clinical features (P = .002). The efficacy of risk gene signature was verified in both internal and external cohorts. The area under receiver operating characteristic curve of this signature was 0.770, 0.765 and 0.774 in the training, testing and external validation cohorts, respectively. Finally, a nomogram was developed for clinicians and did well in the calibration plots. This nomogram based on risk gene signature and clinical features might provide a practical way for recurrence prediction and facilitating personalized managements of ccRCC patients after surgery.

Ag(I)-Hived Fullerene Microcube as an Enhanced Catalytic Substrate for the Reduction of 4-Nitrophenol and the Photodegradation of Orange G Dye.

We report a facile approach to fabricate an Ag-embedded fullerene (C60) catalyst by the chemical reduction of the AgNO3 complex encapsulated fullerene microcrystal, which showed an enhanced catalytic reduction of 4-nitrophenol because of the strong absorption and propagation of H2 along the fullerene surface. With the aid of visible-light radiation, photodegradation of orange G dye is achieved through the formation of an electron donor-acceptor dyad between plasmon Ag nanostructures and fullerene molecules, which effectively offsets the "electron-hole" recombination. Neither Ag nanoparticle nor fullerene crystal used in isolation could perform this chemical conversion, implying that the metal-fullerene hybrid structure is imperative for performing the catalytic reaction. The obtained Ag-embedded fullerene crystal is characterized by scanning electron microscopy (SEM), associated energy-dispersive X-ray spectroscopy (EDX) imaging, and X-ray photoelectron spectroscopy (XPS) and demonstrates that the present hybrid materials would add a supplemental member to a family of photocatalysts toward the organic synthesis and wastewater remediation.

Dual targeting of mTORC1 and mTORC2 by INK-128 potently inhibits human prostate cancer cell growth in vitro and in vivo.

Both mammalian target of rapamycin (mTOR) complexes 1 and 2 (mTORC1/2) are often over-activated in prostate cancer cells and are associated with cancer progression. In the current study, we evaluated the potential anti-prostate cancer activity of INK-128, an ATP-competitive mTORC1/2 dual inhibitor, both in vitro and in vivo. Our results showed that INK-128 exerted potent anti-proliferative activity in established (PC-3 and LNCaP lines) and primary (patient-derived) human prostate cancer cells by inducing cell apoptosis. The latter was evidenced by increase of annexin V percentage, formation of cytoplasmic histone-associated DNA fragments, and cleavage of caspase-3. INK-128-induced prostate cancer cell apoptosis and cytotoxicity were alleviated upon pretreatment of cells with the pan-caspase inhibitor z-VAD-FMK or the specific caspase-3 inhibitor z-DVED-FMK. At the molecular level, INK-18 blocked mTORC1/2 activation in PC-3 cells and LNCaP cells and downregulated mTOR-regulated genes including cyclin D1, hypoxia-inducible factor 1α (HIF-1α), and HIF-2α. ERK-MAPK activation and androgen receptor expression were, however, not affected by INK-128 treatment. In vivo, oral administration of INK-128 significantly inhibited growth of PC-3 xenografts in nude mice. The preclinical results of this study suggest that INK-128 could be further investigated as a promising anti-prostate cancer agent.

[Expression of dynamin-1 and phosphor-dynamin-1 in the hippocampus of children and rats with mesial temporal lobe epilepsy].

OBJECTIVE: To observe the expression of dynamin-1 and phosphor-dynamin-1 in the hippocampus of children and rats with mesial temporal lobe epilepsy (MTLE) and to investigate the roles of dynamin-1 and phosphor-dynamin-1 in the development of MTLE. METHODS: Male Sprague-Dawley rats (aged 25 days) were randomly divided into acute control (AC), acute seizure (AS), latent control (LC), latent seizure (LS), chronic control (CC) and chronic spontaneous seizure (CS) groups. Lithium chloride-pilocarpine was used to induce a rat model of MTLE. The hippocampus samples of 5 children with a pathologically confirmed hippocampal sclerosis who received surgical operation were collected as a human model (HM) group, and the hippocampus samples of 4 dead children (without organic lesion of the hippocampus) were collected by autopsy as a human control (HC) group. The expression of dynamin-1 and phosphor-dynamin-1 in the hippocampus of children and rats with MTLE was measured by Western blot and immunohistochemistry. RESULTS: The Western blot showed that the expression of phosphor-dynamin-1 was significantly lower in the AS and CS groups than in the corresponding control groups (AC and CC groups) (P<0.05). The expression of phosphor-dynamin-1 was significantly lower in the HM group than in the HC group (P<0.05). There were no significant differences in the expression of dynamin-1 among the AS, LS and CS groups and between the HM and HC groups (P>0.05). The immunohistochemical results showed that phosphor-dynamin-1 was highly expressed in the cytoplasm of hippocampal neurons of AC, CC and HC groups, but its expression was significantly reduced in the AS, CS and HM groups (P<0.05). CONCLUSIONS: The expression of phosphor-dynamin-1, not dynamin-1, is downregulated in the hippocampus of children and rats with MTLE during seizures, which suggests that the phosphorylation/dephosphorylation of dynamin-1 may be involved in the development of MTLE.

Temporin-GHb-Derived Peptides Exhibit Potent Antibacterial and Antibiofilm Activities against Staphylococcus aureus In Vitro and Protect Mice from Acute Infectious Pneumonia.

With the continuous development of drug resistance in bacteria to traditional antibiotics, the demand for novel antibacterial agents is urgent. Antimicrobial peptides (AMPs) are promising candidates because of their unique mechanism of action and low tendency to induce drug resistance. Previously, we cloned temporin-GHb (hereafter referred to simply as "GHb") from Hylarana guentheri. In this study, a series of derived peptides were designed, namely, GHbR, GHbK, GHb3K, GHb11K, and GHbK4R. The five derived peptides had stronger antibacterial activities against Staphylococcus aureus than the parent peptide GHb and could effectively inhibit the formation of biofilms and eradicate mature biofilms in vitro. GHbR, GHbK, GHb3K, and GHbK4R exerted bactericidal effects by disrupting membrane integrity. However, GHb11K exhibited bacteriostatic efficacy with toroidal pore formation on the cell membrane. In comparison to GHbK4R, GHb3K showed much lower cytotoxicity against A549 alveolar epithelial cells, with an IC50 > 200 µM, which was much higher than its minimal inhibitory concentration (MIC = 3.1 µM) against S. aureus. The anti-infection potential of GHbK4R and GHb3K was investigated in vivo. Compared with vancomycin, the two peptides displayed significant efficacy in a mouse model of acute pneumonia infected with S. aureus. Both GHbK4R and GHb3K also had no obvious toxicity to normal mice after intraperitoneal administration (15 mg/kg) for 8 days. Our results indicate that GHb3K and GHbK4R might be promising candidates for the treatment of bacterial pneumonia infected with S. aureus.

Antimicrobial peptide temporin derivatives inhibit biofilm formation and virulence factor expression of Streptococcus mutans.

Introduction: Temporin-GHa obtained from the frog Hylarana guentheri showed bactericidal efficacy against Streptococcus mutans. To enhance its antibacterial activity, the derived peptides GHaR and GHa11R were designed, and their antibacterial performance, antibiofilm efficacy and potential in the inhibition of dental caries were evaluated. Methods: Bacterial survival assay, fluorescent staining assay and transmission electron microscopy observation were applied to explore how the peptides inhibited and killed S. mutans. The antibiofilm efficacy was assayed by examining exopolysaccharide (EPS) and lactic acid production, bacterial adhesion and cell surface hydrophobicity. The gene expression level of virulence factors of S. mutans was detected by qRT-PCR. Finally, the impact of the peptides on the caries induced ability of S. mutans was measured using a rat caries model. Results: It has been shown that the peptides inhibited biofilm rapid accumulation by weakening the initial adhesion of S. mutans and reducing the production of EPS. Meanwhile, they also decreased bacterial acidogenicity and aciduricity, and ultimately prevented caries development in vivo. Conclusion: GHaR and GHa11R might be promising candidates for controlling S. mutans infections.

Comparison of diabetic retinopathy severity grading on ETDRS 7-field versus ultrawide-field assessment.

OBJECTIVES: To compare the diabetic retinopathy (DR) severity level determined when considering only the ETDRS 7-field region versus the entire ultrawidefield (UWF) image. METHODS: In this retrospective, cross-sectional study, UWF pseudocolor images were graded on the Eyenuk image viewing, grading, and annotation platform for the severity of DR considering only the regions within the ETDRS 7-fields as well as the entire UWF image using two different protocols: 1) the simple International Classification of Diabetic Retinopathy (ICDR) scale and 2) the more complex DRCR.net Protocol AA grading scale. RESULTS: A total of 250 eyes from 157 patients were included in this analysis. Six eyes (2.4%) demonstrated a discrepancy in severity level between the ETDRS 7-field region and the entire UWF image when using the ICDR classification system. The discrepancies were due to the presence of lesions [intraretinal haemorrhage (n = 2), neovascular disease (n = 4)] in the peripheral fields which were not identified in the ETDRS 7-fields. Fourteen eyes (5.6%) had a discrepancy in severity level between the ETDRS 7-field region and the entire UWF image when using the ETDRS DRSS Protocol AA grading scale. The discrepancies were due to the presence of a higher level of disease [intraretinal haemorrhage (n = 4), neovascularization (n = 4), preretinal haemorrhage (n = 2), scatter laser scars (n = 4)] in the peripheral fields. CONCLUSION: Although considering regions outside of the ETDRS 7-fields altered the DR severity level assessment in <5% of cases in this cohort, significant and potentially vision-threatening lesions including neovascularization and preretinal haemorrhage were identified in these peripheral regions. This highlights the importance of evaluating the entire UWF region when assessing patients with diabetic retinopathy.

VASCULAR PERFUSION DENSITY MAPPING USING OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY COMPARING NORMAL AND OPTIC DISK PIT EYES.

PURPOSE: Optic disk pits (ODPs) are typically detected incidentally as small, gray, unilateral, oval-shaped excavation in the temporal optic disk on routine fundus examination. In this cross-sectional retrospective case series, we report optical coherence tomography angiography findings in patients with unilateral ODPs and describe changes in vessel perfusion associated with ODP. METHODS: A total of eight eyes (four with ODP and four normal contralateral) were included in this study. Patients were excluded if any other optic disk abnormalities were present. Spectral-domain optical coherence tomography angiography (AngioVue; Optovue, Fremont, CA) imaging was conducted to map the vascularization of three layers in the optic nerve over a 4.5-mm × 4.5-mm region. The radial peripapillary capillaries, the nerve head capillaries, and the choriocapillaris were automatically segmented based on the OCT system software, and the capillary perfusion density (CPD) was quantified for each layer. Kruskal-Wallis one-way analysis of variance was used to compare CPD in normal and ODP eyes of four patients with monocular ODP. RESULTS: Overall, CPD was lower in eyes with ODP compared with the contralateral normal eye in the radial peripapillary capillary (0.4521 ± 0.08 vs. 0.5505 ± 0.03, P = 0.08) and nerve head capillary layers (0.5461 ± 0.08 vs. 0.5989 ± 0.01, P = 0.08). Significantly lower CPD values were associated with ODP eyes in the radial peripapillary capillary layer within the disk (P = 0.04), inferior nasal (P = 0.04), and temporal (P = 0.02) regions and in the nerve head vessel layer within the disk region (P = 0.04). Significantly higher CPD values were associated with ODP eyes in the choriocapillaris layer within the nasal (P = 0.02), superior temporal (P = 0.02), and inferior temporal (P = 0.02) regions. Visual acuity was also decreased in ODP eyes at 0.4 ± 0.3 logarithm of the minimum angle of resolution units (20/50) compared with normal eyes at 0.1 ± 0.1 logarithm of the minimum angle of resolution units (20/25) (P = 0.12). CONCLUSION: This study demonstrated that the presence of an ODP is associated with decreased vascular density in some regions of the optic disk and reduced visual acuity.

Ophthalmic findings in marginally housed women in a Canadian city.

OBJECTIVE: To assess the prevalence and common causes of ocular pathology experienced by vulnerable women with marginalized housing and/or a history of abuse, violence, and trafficking. METHODS: Using a stratified random sampling technique, we recruited 93 women living in 10 randomly selected women's shelters in Toronto, Canada between May and November of 2018. All English-speaking females older than the age of 18 were eligible to participate. Data on demographics, medical or ocular history, subjective visual acuity, and access to eye care were obtained. Comprehensive visual screening and dilated fundoscopy were performed for each participant. RESULTS: The median age was 40 years (interquartile range, 30.5-54 years) and the median duration of homelessness was 8 months (interquartile range, 2.25-20.5 months); 63.4% of participants reported a history of abuse, 44.9% experienced head trauma, 15.9% experienced eye trauma, 22.5% identified as refugees, and 2.17% (2 of 92) had been victims of human trafficking. The above variables were not significantly related to vision problem severity on univariate analysis. Based on the presenting visual acuity, 27.8% of participants (95% CI [18.9-38.2]) were found to have visual impairment. Visual impairment was mainly related to refractive error (54.8% [51 of 93]), however, nonrefractive pathology was also observed. Of all the participants, 64.5% had one or more abnormal findings during the vision screening, and 40.9% needed follow-up by an ophthalmologist. Most participants (96.7%) expressed interest in accessing free eye examinations. CONCLUSIONS: Visual impairment is highly prevalent among homeless women living in Toronto. Routine vision-screening programs present an opportunity to improve the ocular health of this vulnerable population.

NOVEL APPROACH TO SCLERAL FIXATION OF A REPER INTRAOCULAR LENS AND ARTIFICIAL IRIS COMPLEX FOLLOWING PARS PLANA LENSECTOMY AND VITRECTOMY FOR ECTOPIA LENTIS AND CATARACT IN A PATIENT WITH ANIRIDIA AND NYSTAGMUS.

PURPOSE: Prosthetic iris devices have recently been used to improve cosmesis and reduce glare in aniridia. There is currently no consensus on which prosthetic iris device or which surgical approach is preferred for managing large iris defects. METHODS: A novel surgical approach with Gore-Tex polytetrafluoroethylene sutures was used to achieve scleral fixation of an intraocular lens and artificial iris complex in a 19-year-old Caucasian female patient with aniridia, nystagmus, cataracts, and ectopia lentis. RESULTS: Six weeks postoperatively, the intraocular lens-artificial iris complex remained well centered, and the vision in the left eye improved from 20/400 to 20/70. Two years after prosthetic iris device implantation, there have been no complications. CONCLUSION: This case demonstrates a promising proof-of-concept for long-term management of complicated aniridia cases using an intraocular lens and artificial iris complex prosthetic iris devices. Gore-Tex sutures may be preferable to conventional polypropylene sutures because of their improved durability.

Prevalence and impact of eye disease in an urban homeless and marginally housed population.

OBJECTIVE: Homeless and marginally housed (HMH) populations have a higher prevalence of visual impairment than the general population. This study is the first to conduct a comprehensive ophthalmic examination using portable equipment at various homeless shelter locations in an urban population to identify objective ocular pathologies in a randomly selected sample. METHODS: Ten adult shelters were randomly selected in Toronto, Ontario, Canada, and 143 individuals were randomly selected based on their shelter bed numbers at each shelter, in proportion to the shelter's bed capacity. Participants completed a sociodemographic survey and clinical eye examination. Finally, a dilated ocular examination was performed using a portable slit lamp, autorefractor, tonometer, indirect ophthalmoscope, and fundus camera. RESULTS: The median age of participants was 53.3 years; 82.5% were male and 17.5% female. The age-standardized prevalence of visual impairment was 27.4% (95% confidence interval [CI], 20.6-35.1) for study participants. Refractive error was present in 48% of participants, 34% with myopia and 11% with hyperopia, and 37.8% (95% CI, 32.2-45.9) of this study population were diagnosed with at least one nonrefractive ocular pathology. Low income and low educational attainment were associated with increased odds of being diagnosed with nonrefractive ocular pathologies. CONCLUSIONS: A clear health care gap exists between the ophthalmological disease burden of the HMH population and the amount of resources allocated directed toward their needs. Addressing risk factors such as low income and education, as well as increasing access to free eye examinations and visual aids, may be an effective method of attending to this lack of health equity.

Multimodal Analysis of Hyperautofluorescent Ring Size in Retinitis Pigmentosa.

BACKGROUND AND OBJECTIVE: To determine if a correlation exists between hyperautofluorescent ring size with visual acuity (VA), foveal avascular zone (FAZ) size, and retinal capillary perfusion density (CPD) in retinitis pigmentosa (RP). PATIENTS AND METHODS: Eighteen eyes from nine patients with RP were imaged using fundus autofluorescence (AF) to identify autofluorescence defects, and hyperautofluorescent ring size was measured with an image-processing program. Spectral-domain optical coherence tomography angiography was used to measure FAZ area and calculate parafoveal CPD in the superficial capillary plexus (SCP) and the deep capillary plexus (DCP) using both a 3 mm × 3 mm and 6 mm × 6 mm strategy. RESULTS: The area of hyperautofluorescence was not strongly correlated with SCP perfusion density (P = .74), DCP perfusion density (P = .25), FAZ area (P = .14), or VA (P = .33). CONCLUSION: The area of the hyperautofluorescent ring does not correlate with VA, retinal CPD, or FAZ area. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:492-496.].

OCTA: A Practical Method of Image Averaging Using Adobe Photoshop Software.

BACKGROUND AND OBJECTIVE: To describe a method for averaging ocular coherence tomography angiography (OCTA) images using a commercially available photo editing software: Adobe Photoshop CC 2017. PATIENTS AND METHODS: This single-center study assessed the feasibility of using Adobe Photoshop as an OCTA image averaging tool. Three 3.0 mm × 3.0 mm OCTA images from each eye were obtained using commercially available OCTA devices. Captured OCTA images were exported in high-resolution TIFF format, imported as an image stack, aligned using an automated function, and averaged by creating a Smart Object using Photoshop CC 2017 software. In conjunction with qualitative assessment, the main outcome of the study was image grader preferences with respect to clarity of the foveal avascular zone (FAZ), blood vessel delineation, and the ability to identify abnormal vasculature. RESULTS: After removing OCTA scans with significant image distortion, 25 sets of images were included in the analysis. Adobe Photoshop CC 2017 successfully aligned and averaged all images of the superficial and deep retinal plexuses that contained a minimum 40% overlap. Three independent retinal specialists found the averaged images to be slightly or definitely preferable to the original 87%, 89%, and 69% of the time with respect to clarity of the FAZ, clarity of blood vessel delineation, and the ability to identify abnormal vasculature, respectively. CONCLUSIONS: Adobe Photoshop CC 2017 is an excellent tool for image averaging, producing high-quality resulting OCTA images. As an easily accessible software, Photoshop has the potential for use in a diversity of pathological conditions. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:802-807.].

Swept-Source OCT Angiography of the Anomalous Foveal Avascular Zone.

BACKGROUND AND OBJECTIVE: To gain insight into clinical presentations associated with anomalous foveal avascular zone (FAZ) architecture and foveal pit morphology. PATIENTS AND METHODS: Twenty-two eyes with anomalous (vascularized) FAZs were identified from 14 patients using optical coherence tomography angiography (OCTA). The FAZ was evaluated in three vascular layers of the retina: the superficial capillary plexus (SCP), the deep capillary plexus (DCP), and the degree of foveal pit hypoplasia was graded. RESULTS: The FAZ was absent in 21 out of 22 eyes at the SCP and in eight out of 22 eyes at the DCP. Foveal pit hypoplasia was more severe in patients where the FAZ was fully vascularized in both the SCP and DCP. The absence of the FAZ did not affect visual acuity. CONCLUSION: Anomalies of the FAZ and foveal pit can present with varying degrees of severity in patients with a wide range of ages and diagnoses. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:852-858.].

OCT Angiographic Findings in Glucose-6-Phosphate Dehydrogenase Deficiency.

Fovea plana (FP) describes the abnormal absence of the foveal pit in the retina. It is a sign that is associated with prematurity, albinism, and other ophthalmic disorders. The authors present the optical coherence tomography angiographic findings in a case of a 19-year-old male with FP and glucose-6-phosphate dehydrogenase (G6PD) deficiency. G6PD deficiency is a very common condition that typically presents with hemolytic anemia and jaundice. G6PD deficiency is also known to affect vision, but these pathologies have been less well-characterized. To the authors' knowledge, this is the first report of G6PD deficiency in FP. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:664-667.].

The extent of intrauterine growth restriction determines the severity of cerebral injury and neurobehavioural deficits in rodents.

BACKGROUND: Cerebral Palsy (CP) is the most common physical pediatric neurodevelopmental disorder and spastic diplegic injury is its most frequent subtype. CP results in substantial neuromotor and cognitive impairments that have significant socioeconomic impact. Despite this, its underlying pathophysiological mechanisms and etiology remain incompletely understood. Furthermore, there is a need for clinically relevant injury models, which a) reflect the heterogeneity of the condition and b) can be used to evaluate new translational therapies. To address these key knowledge gaps, we characterized a chronic placental insufficiency (PI) model, using bilateral uterine artery ligation (BUAL) of dams. This injury model results in intrauterine growth restriction (IUGR) in pups, and animals recapitulate the human phenotype both in terms of neurobehavioural and anatomical deficits. METHODS: Effects of BUAL were studied using luxol fast blue (LFB)/hematoxylin & eosin (H&E) staining, immunohistochemistry, quantitative Magnetic Resonance Imaging (MRI), and Catwalk neurobehavioural tests. RESULTS: Neuroanatomical analysis revealed regional ventricular enlargement and corpus callosum thinning in IUGR animals, which was correlated with the extent of growth restriction. Olig2 staining revealed reductions in oligodendrocyte density in white and grey matter structures, including the corpus callosum, optic chiasm, and nucleus accumbens. The caudate nucleus, along with other brain structures such as the optic chiasm, internal capsule, septofimbrial and lateral septal nuclei, exhibited reduced size in animals with IUGR. The size of the pretectal nucleus was reduced only in moderately injured animals. MAG/NF200 staining demonstrated reduced myelination and axonal counts in the corpus callosum of IUGR animals. NeuN staining revealed changes in neuronal density in the hippocampus and in the thickness of hippocampal CA2 and CA3 regions. Diffusion weighted imaging (DWI) revealed regional white and grey matter changes at 3 weeks of age. Furthermore, neurobehavioural testing demonstrated neuromotor impairments in animals with IUGR in paw intensities, swing speed, relative print positions, and phase dispersions. CONCLUSIONS: We have characterized a rodent model of IUGR and have demonstrated that the neuroanatomical and neurobehavioural deficits mirror the severity of the IUGR injury. This model has the potential to be applied to examine the pathobiology of and potential therapeutic strategies for IUGR-related brain injury. Thus, this work has potential translational relevance for the study of CP.