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Browsing by Author "Department of Ophthalmology, IU School of Medicine"
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Item ACE2 Deficiency Worsens Epicardial Adipose Tissue Inflammation and Cardiac Dysfunction in Response to Diet-Induced Obesity(American Diabetes Association, 2016-01) Patel, Vaibhav B.; Mori, Jun; McLean, Brent A.; Basu, Ratnadeep; Das, Subhash K.; Ramprasath, Tharmarajan; Parajuli, Nirmal; Penninger, Josef M.; Grant, Maria B.; Lopaschuk, Gary D.; Oudit, Gavin Y.; Department of Ophthalmology, IU School of MedicineObesity is increasing in prevalence and is strongly associated with metabolic and cardiovascular disorders. The renin-angiotensin system (RAS) has emerged as a key pathogenic mechanism for these disorders; angiotensin (Ang)-converting enzyme 2 (ACE2) negatively regulates RAS by metabolizing Ang II into Ang 1-7. We studied the role of ACE2 in obesity-mediated cardiac dysfunction. ACE2 null (ACE2KO) and wild-type (WT) mice were fed a high-fat diet (HFD) or a control diet and studied at 6 months of age. Loss of ACE2 resulted in decreased weight gain but increased glucose intolerance, epicardial adipose tissue (EAT) inflammation, and polarization of macrophages into a proinflammatory phenotype in response to HFD. Similarly, human EAT in patients with obesity and heart failure displayed a proinflammatory macrophage phenotype. Exacerbated EAT inflammation in ACE2KO-HFD mice was associated with decreased myocardial adiponectin, decreased phosphorylation of AMPK, increased cardiac steatosis and lipotoxicity, and myocardial insulin resistance, which worsened heart function. Ang 1-7 (24 µg/kg/h) administered to ACE2KO-HFD mice resulted in ameliorated EAT inflammation and reduced cardiac steatosis and lipotoxicity, resulting in normalization of heart failure. In conclusion, ACE2 plays a novel role in heart disease associated with obesity wherein ACE2 negatively regulates obesity-induced EAT inflammation and cardiac insulin resistance.Item Ataxia Telangiectasia Mutated Dysregulation Results in Diabetic Retinopathy(Wiley Blackwell (John Wiley & Sons), 2016-02) Bhatwadekar, Ashay D.; Duan, Yaqian; Chakravarthy, Harshini; Korah, Maria; Caballero, Sergio; Busik, Julia V.; Grant, Maria B.; Department of Ophthalmology, IU School of MedicineAtaxia telangiectasia mutated (ATM) acts as a defense against a variety of bone marrow (BM) stressors. We hypothesized that ATM loss in BM-hematopoietic stem cells (HSCs) would be detrimental to both HSC function and microvascular repair while sustained ATM would be beneficial in disease models of diabetes. Chronic diabetes represents a condition associated with HSC depletion and inadequate vascular repair. Gender mismatched chimeras of ATM(-/-) on wild type background were generated and a cohort were made diabetic using streptozotocin (STZ). HSCs from the STZ-ATM(-/-) chimeras showed (a) reduced self-renewal; (b) decreased long-term repopulation; (c) depletion from the primitive endosteal niche; (d) myeloid bias; and (e) accelerated diabetic retinopathy (DR). To further test the significance of ATM in hematopoiesis and diabetes, we performed microarrays on circulating angiogenic cells, CD34(+) cells, obtained from a unique cohort of human subjects with long-standing (>40 years duration) poorly controlled diabetes that were free of DR. Pathway analysis of microarrays in these individuals revealed DNA repair and cell-cycle regulation as the top networks with marked upregulation of ATM mRNA compared with CD34(+) cells from diabetics with DR. In conclusion, our study highlights using rodent models and human subjects, the critical role of ATM in microvascular repair in DR.Item Cancer Genetics Education in a Low- to Middle-Income Country: Evaluation of an Interactive Workshop for Clinicians in Kenya(PLoS, 2015-06) Hill, Jessica A.; Lee, Su Yeon; Corson, Timothy W.; Dimaras, Helen; Department of Ophthalmology, IU School of MedicineBackground Clinical genetic testing is becoming an integral part of medical care for inherited disorders. While genetic testing and counseling are readily available in high-income countries, in low- and middle-income countries like Kenya genetic testing is limited and genetic counseling is virtually non-existent. Genetic testing is likely to become widespread in Kenya within the next decade, yet there has not been a concomitant increase in genetic counseling resources. To address this gap, we designed an interactive workshop for clinicians in Kenya focused on the genetics of the childhood eye cancer retinoblastoma. The objectives were to increase retinoblastoma genetics knowledge, build genetic counseling skills and increase confidence in those skills. Methods The workshop was conducted at the 2013 Kenyan National Retinoblastoma Strategy meeting. It included a retinoblastoma genetics presentation, small group discussion of case studies and genetic counseling role-play. Knowledge was assessed by standardized test, and genetic counseling skills and confidence by questionnaire. Results Knowledge increased significantly post-workshop, driven by increased knowledge of retinoblastoma causative genetics. One-year post-workshop, participant knowledge had returned to baseline, indicating that knowledge retention requires more frequent reinforcement. Participants reported feeling more confident discussing genetics with patients, and had integrated more genetic counseling into patient interactions. Conclusion A comprehensive retinoblastoma genetics workshop can increase the knowledge and skills necessary for effective retinoblastoma genetic counseling.Item Central neural activation following contact sensitivity peripheral immune challenge: evidence of brain–immune regulation through C fibres.(Wiley, 2015-10) Thinschmidt, Jeffrey S.; King, Michael A.; Korah, Maria; Perez, Pablo D.; Febo, Marcelo; Miyan, Jaleel; Grant, Maria B.; Department of Ophthalmology, IU School of MedicineThis study tested the hypothesis that peripheral immune challenges will produce predictable activation patterns in the rat brain consistent with sympathetic excitation. As part of examining this hypothesis, this study asked whether central activation is dependent on capsaicin-sensitive C-fibres. We induced skin contact sensitivity immune responses with 2,4-dinitrochlorobenzene (DNCB), in the presence or absence of the acute C-fibre toxin capsaicin (8-methyl-N-vanillyl-6-nonenamide) to trigger immune responses with and without diminished activity of C-fibres. Innovative blood-oxygen-level-dependent functional magnetic resonance imaging data revealed that the skin contact sensitivity immune responses induced with DNCB were associated with localized increases in brain neuronal activity in treated rats. This response was diminished by pre-treatment with capsaicin 1 week before scans. In the same animals, we found expression of the immediate early gene c-Fos in sub-regions of the amygdala and hypothalamic sympathetic brain nuclei. Significant increases in c-Fos expression were found in the supraoptic nucleus, central amygdala and medial habenula following immune challenges. Our results support the idea that selective brain regions, some of which are associated with sympathetic function, process or modulate immune function through pathways that are partially dependent on C-fibres. Together with previous studies demonstrating the motor control pathways from brain to immune targets, these findings indicate a central neuroimmune system to monitor host status and coordinate appropriate host responses.Item Chorioretinal Coloboma Complications: Retinal Detachment and Choroidal Neovascular Membrane(Wolters Kluwer, 2017-01) Hussain, Rehan M.; Abbey, Ashkan M.; Shah, Ankoor R.; Drenser, Kimberly A.; Trese, Michael T.; Capone Jr., Antonio; Department of Ophthalmology, IU School of MedicinePURPOSE: To report the chorioretinal coloboma, and its association with increased risk of retinal detachment (RD) and choroidal neovascularization (CNV). METHODS: This retrospective case series included eyes with chorioretinal coloboma diagnosed between 1995 and 2014 with a focus on RD and CNV as related complications. Cases of CNV were managed with laser photocoagulation or intravitreal injection of bevacizumab. For eyes with CNV, therapeutic success was defined as resolution of the subretinal hemorrhage on fundus examination and resolution of the subretinal and intraretinal fluid on optical coherence tomography (OCT). For eyes with RD, anatomic success following surgical intervention was defined as attachment of the retina at the last follow-up visit. RESULTS: Fifty-one eyes of 31 patients with chorioretinal coloboma were identified for review. Bilateral chorioretinal coloboma was present in 64.5% of subjects. RD developed in 15 eyes (29.4%). Among 15 eyes with RD, 4 eyes (27%) had retinal breaks identified within the coloboma, 5 eyes (33%) had retinal breaks outside the coloboma, 2 eyes (13%) showed retinal breaks both inside and outside the coloboma, and in 4 eyes (27%) the causative retinal break was not localized. The overall rate of anatomic success after RD repair was 85.7%. CNV developed in 7 eyes (13.7%) and was located along the margin of the coloboma in all cases. CNV was bilateral in 2 of the 5 affected individuals (40%). CONCLUSION: RD and CNV were present in a high percentage of eyes with chorioretinal coloboma in these series. The frequent finding of retinal breaks outside the coloboma bed suggests that vitreoretinal interface abnormalities may play a role in development of RD in these eyes.Item Combination therapies prevent the neuropathic, proinflammatory characteristics of bone marrow in streptozotocin-induced diabetic rats(American Diabetes Association, 2015-02) Dominguez, James M.; Yorek, Mark A.; Grant, Maria B.; Department of Ophthalmology, IU School of MedicineWe previously showed that peripheral neuropathy of the bone marrow was associated with loss of circadian rhythmicity of stem/progenitor cell release into the circulation. Bone marrow neuropathy results in dramatic changes in hematopoiesis that lead to microvascular complications, inflammation, and reduced endothelial repair. This series of events represents early pathogenesis before development of diabetic retinopathy. In this study we characterized early alterations within the bone marrow of streptozotocin (STZ)-induced diabetic rats following treatments that prevent experimental peripheral neuropathy. We asked whether bone marrow neuropathy and the associated bone marrow pathology were reversed with treatments that prevent peripheral neuropathy. Three strategies were tested: inhibition of neutral endopeptidase, inhibition of aldose reductase plus lipoic acid supplementation, and insulin therapy with antioxidants. All strategies prevented loss of nerve conduction velocity resulting from STZ-induced diabetes and corrected the STZ-induced diabetes-associated increase of immunoreactivity of neuropeptide Y, tyrosine hydroxylase, and somatostatin. The treatments also reduced concentrations of interleukin-1β, granulocyte colony-stimulating factor, and matrix metalloproteinase 2 in STZ-induced diabetic bone marrow supernatant and decreased the expression of NADPH oxidase 2, nitric oxide synthase 2, and nuclear factor-κB1 mRNA in bone marrow progenitor cells. These therapies represent novel approaches to attenuate the diabetic phenotype within the bone marrow and may constitute an important therapeutic strategy for diabetic microvascular complications.Item Commentary(Medknow Publications and Media Pvt. Ltd., 2015-07) Purvin, Valerie; Department of Ophthalmology, IU School of MedicineItem Comparison of Circumferential and Traditional Trabeculotomy in Pediatric Glaucoma(Elsevier, 2015-04) Lim, Maria E.; Neely, Daniel E.; Wang, Jingyun; Haider, Kathryn M.; Smith, Heather A.; Plager, David A.; Department of Ophthalmology, IU School of MedicinePurpose To compare intraocular pressure (IOP) control of pediatric glaucoma patients undergoing traditional trabeculotomy (<360 degrees or partial) with those receiving 360-degree circumferential trabeculotomy. Methods The medical records of pediatric glaucoma patients receiving trabeculotomy at a single institution from 2000 to 2012were retrospectively reviewed. Patients were divided into two groups: a traditional trabeculotomy group and 360-degree trabeculotomy group. IOP at baseline and at 1, 3, 6, and 12 months’ follow-up were compared within and each groups. Results A total of 77 eyes of 56 patients (age at surgery, 1.52 ± 2.68 years) in the traditional group and 14 eyes of 10 patients in the 360-degree group (age at surgery, 0.61 ± 0.42 years) were included. Mean baseline IOP was similar in both groups (traditional, 28.75 ± 8.80 mm Hg; 360-degree, 30.35 ± 6.04 mm Hg; t test; P = 0.43). Mean 1-year IOP was 17.05 ± 5.92 mm Hg in the traditional group and 11.0 ± 2.31 mm Hg in the 360-degree group. At 1-year, the surgical success rate was 58.44% in the traditional group and 85.71% in the 360-degree group; 32 eyes in the former and 2 eyes in the latter required another glaucoma procedure within 1 year for IOP control. For both groups, compared to baseline values, IOP decreased significantly with all postoperative measurements (paired t test, all P < 0.01). The 360-degree group had significantly lower IOP compared to the traditional group at 1-year (t test, P < 0.01). Conclusions Both 360-degree and traditional trabeculotomy significantly reduced IOP in children through 1 year’s follow-up, although the former procedure shows better 1-year postoperative IOP control, with higher rate of surgical success.Item Comparison of retinal nerve fiber layer and macular thickness for discriminating primary open-angle glaucoma and normal-tension glaucoma using optical coherence tomography(Wiley, 2016-07) Khanal, Safal; Davey, Pinakin Gunvant; Racette, Lyne; Thapa, Madhu; Department of Ophthalmology, IU School of MedicinePurpose The aim of this study was to evaluate the discrimination capabilities of macular and peripapillary retinal nerve fiber layer (pRNFL) thickness parameters as measured using spectral domain optical coherence tomography (SD-OCT) between primary open-angle glaucoma (POAG) and normal-tension glaucoma (NTG). Methods A total of 90 subjects were enrolled: 30 healthy subjects, 30 subjects with POAG and 30 subjects with NTG, consecutively. Retinal nerve fiber layer thickness, macular thickness and volume measurements were obtained with circular and radial SD-OCT scans. All parameters were compared between groups using an analysis of variance test. Areas under receiver-operating characteristic (AROC) curves with sensitivities at specificities greater than or equal to 90 per cent were generated to compare discrimination capabilities of various parameters between POAG and NTG. Results Macular thickness and volume measurements were the highest in normal subjects, followed by NTG and POAG (p < 0.05). Average retinal nerve fiber layer thickness had perfect discrimination for normal-POAG (AROC: 1.000; sensitivity: 100 per cent) and near perfect discrimination for normal-NTG (AROC: 0.979; sensitivity: 93 per cent) as well as NTG-POAG pairs (AROC: 0.900; sensitivity: 60 per cent). Inferior outer macular thickness (IOMT) and total volume were the best macular thickness and volume parameters having similar AROCs and sensitivities between normal and POAG (IOMT, AROC: 0.987; sensitivity: 92 per cent and total volume, AROC: 0.997; sensitivity: 97 per cent), normal and NTG (IOMT, AROC: 0.862, sensitivity: 47 per cent and total volume, AROC: 0.898, sensitivity: 67 per cent) and also between NTG and POAG (IOMT, AROC: 0.910, sensitivity: 53 per cent and total volume, AROC: 0.922, sensitivity: 77 per cent). In each comparison group, there was no statistically significant difference in AROCs between average retinal nerve fiber layer and inferior outer macular thickness, as well as total volume. Conclusions The macular parameters offer comparable performance to pRNFL parameters for the discrimination of NTG and POAG. Average retinal nerve fiber layer thickness, total macular volume and inferior outer macular thickness were the best SD-OCT parameters with superior discriminating capabilities.Item Compliance and patching and atropine amblyopia treatments(Elsevier, 2015-09) Wang, Jingyun; Department of Ophthalmology, IU School of MedicineIn the past 20 years, there has been a great advancement in knowledge pertaining to compliance with amblyopia treatments. The occlusion dose monitor introduced quantitative monitoring methods in patching, which sparked our initial understanding of the dose–response relationship for patching amblyopia treatment. This review focuses on current compliance knowledge and the impact it has on patching and atropine amblyopia treatment.