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    A biomimetic scaffold for culturing limbal stem cells: A promising alternative for clinical transplantation
    ( 2008-01-01) Dravida, Subhadra ; Gaddipati, Subhash ; Griffith, May ; Merrett, Kim ; Madhira, Soundarya Lakshmi ; Sangwan, Virender S. ; Vemuganti, Geeta K.
    Limbal tissues can be cultured on various types of scaffolds to create a sheet of limbal-corneal epithelium for research as well as clinical transplantation. An optically clear, biocompatible, biomimetic scaffold would be an ideal replacement graft for transplanting limbal stem cells. In this study, we evaluated the physical and culture characteristics of the recombinant human cross-linked collagen scaffold (RHC-III scaffold) and compared it with denuded human amniotic membrane (HAM). Optical/mechanical properties and microbial susceptibility were measured for the scaffolds. With the approval of the institutional review board, 2 mm fresh human limbal tissues were cultured on 2.5 x 2.5 cm2 scaffolds in a medium containing autologous serum in a feeder cell-free submerged system. The cultured cell systems were characterized by morphology and immunohistochemistry for putative stem cells and differentiated cell markers. The refractive index (RI) and tensile strength of the RHC-III scaffold were comparable to human cornea, with delayed in vitro degradation compared to HAM. RHC-III scaffolds were 10-fold less susceptible to microbial growth. Cultures were initiated on day 1, expanded to form a monolayer by day 3 and covered the entire growth surface in 10 days. Stratified epithelium on the scaffolds was visualized by transmission electron microscopy. The cultured cells showed p63 and ABCG2 positivity in the basal layer and were immunoreactive for cytokeratin K3 and K12 in the suprabasal layers. RHC-III scaffold supports and retains the growth and stemness of limbal stem cells, in addition to resembling human cornea; thus, it could be a good replacement scaffold for growing cells for clinical transplantation. Copyright © 2008 John Wiley & Sons, Ltd.
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    A cluster of nocardia keratitis after LASIK
    ( 2007-01-01) Garg, Prashant ; Sharma, Savitri ; Vemuganti, Geeta K. ; Ramamurthy, Balasubramanya
    PURPOSE: To report a cluster of Nocardia asteroides keratitis cases after LASIK. METHODS: Retrospective review of the history and examination of three patients (four eyes) operated on the same day at a single center who developed postoperative keratitis. All patients underwent lifting of the superficial flap for microbiologic evaluation of the corneal scrapings. The operating surgeon was contacted to identify the possible source of contamination. RESULTS: Two patients underwent simultaneous bilateral LASIK; however, only one developed postoperative keratitis in both eyes. One patient had unilateral surgery and developed keratitis in the operated eye. Microscopic examination of smears from all eyes revealed thin, branching, acid-fast, filamentous bacteria that were identified as Nocardia asteroides after culture. The infiltrates resolved with topical administration of amikacin sulphate (2.5%) and topical and oral trimethoprim-sulfamethoxazole. Final visual acuity ranged between 20/25 and 20/80. The operating surgeon had used the same blade and microkeratome in all patients. CONCLUSIONS: Nocardia, a relatively unusual organism, can cause an epidemic of infection after LASIK.
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    A comparative study of epiretinal membranes associated with Eales' disease: A clinicopathologic evaluation
    ( 2006-01-01) Majji, Ajit B. ; Vemuganti, G. K. ; Shah, V. A. ; Singh, S. ; Das, T. ; Jalali, S.
    Aim: To study the histopathologic features and clinical correlation of epiretinal membranes (ERM) obtained from patients of Eales' disease and compare with other vasoproliferative disorders. Methods: Retrospective analysis of epiretinal membranes submitted for histological evaluation between January 1995 and June 2001, from the patients of diabetic retinopathy and vascular occlusions (Group 1; vaso-occlusive disorders) and of Eales' disease (Group 2; vasoinflammatory disorders). Demographics, pre and postoperative visual acuity, and anatomic and histologic characteristics of membranes were studied. Histopathologic features and clinical outcomes were correlated between the groups. The results were analysed statistically by Student's t-test, Fisher's exact test and Kruskal -Wallis test. Results: This study consisted of 42 patients, 24 in Group 1 and 18 in Group 2. Patients in Group 2 (33.0±9.2 years) were significantly younger than the patients in Group 1 (49.9±7.6 years) (P≤0.0001). Final visual acuity of > 20/400 was attained in 79.2% (19/24) patients in Group 1 and 83.3% (15/18) in Group 2 (P =1.0). Inflammatory membranes were significantly associated with presumed Eales' disease (94.4 vs 0%) (P ≤ 0.0001) and fibrovascular membranes with Group 1 (70.8% vs 33.3%) (P = 0.028). Mast cells and eosinophils were observed as special features in epiretinal membranes of patients with Eales' disease. Conclusions: Histological features of ERM in Eales' disease are comparable to other vasoproliferative disorders except for features of inflammation. Presence of mast cells and eosinophils in epiretinal membranes of Eales' disease needs further investigation. © 2006 Nature Publishing Group All rights reserved.
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    A comprehensive, sensitive and economical approach for the detection of mutations in the RB1 gene in retinoblastoma
    ( 2009-12-01) Parsam, Vidya Latha ; Kannabiran, Chitra ; Honavar, Santosh ; Vemuganti, Geeta K. ; Ali, Mohammad Javed
    Retinoblastoma (Rb) is the most common primary intraocular malignancy in children. It is brought about by the mutational inactivation of both alleles of RB1 gene in the developing retina. To identify the RB1 mutations, we analysed 74 retinoblastoma patients by screening the exons and the promoter region of RB1. The strategy used was to detect large deletions/duplications by fluorescent quantitative multiplex PCR; small deletions/insertions by fluorescent genotyping of RB1 alleles, and point mutations by PCR-RFLP and sequencing. Genomic DNA from the peripheral blood leucocytes of 74 Rb patients (53 with bilateral Rb, 21 with unilateral Rb; 4 familial cases) was screened for mutations. Recurrent mutations were identified in five patients with bilateral Rb, large deletions in 11 patients (nine with bilateral Rb and two with unilateral Rb), small deletions/insertions were found in 12 patients all with bilateral Rb, and point mutations in 26 patients (14 nonsense, six splice site, five substitution and one silent change). Three mutations were associated with variable expressivity of the disease in different family members. Using this method, the detection rates achieved in patients with bilateral Rb were 44/53 (83%) and with unilateral Rb, 5/21 (23.8%). This approach may be feasible for clinical genetic testing and counselling of patients. © 2009 Indian Academy of Sciences.
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    A cross-sectional study on occupational health and safety of municipal solid waste workers in Telangana, India
    ( 2021-07-01) Ramitha, K. ; Ankitha, Thatipally ; Alankrutha, Rayapati ; Anitha, C.
    Background: The occurrence of workplace hazards, occupational diseases, and deaths contribute significantly to the increase in the global burden of diseases. The Municipal Solid Waste (MSW) workers experience occupational stressors throughout the process of waste management that affects their well-being and results in high rates of occupational health problems. It is vital to understand the workplace practices and occupational morbidities of the MSW workers to ensure their safety and well-being. In this context, the study aimed to explore the occupational health and safety practices at the place of work among the MSW workers in Karimnagar and Hyderabad in Telangana, India. Methodology: A cross-sectional study was conducted in two cities of Telangana. A total of 394 MSW workers were surveyed. The number of MSW workers in Karimnagar and Hyderabad were 152 and 194, respectively. A pre-tested questionnaire was administered to the MSW workers to study the occupational morbidities and workplace safety practices. Focused group discussions were conducted among the MSW workers in both cities. In-depth interviews of sanitary supervisors in Karimnagar were conducted. Semi-structured questionnaires and interview guides were used with questions on sociodemographic characteristics, health status, work environment, protection strategy, and healthcare utilization. MS Excel and NVivo-12 were used for data analysis. Results: Musculoskeletal problem was the major reported morbidity among the MSW workers (76.6%). Injuries were reported more among the MSW workers in Hyderabad (39.7%) along with a fear of being hit by vehicles while working on the main roads. About 88.7% of the MSW workers had less than secondary education. There was a wage difference between the contract and permanent MSW workers. There was a lack of provision of personal protective equipment and poor working conditions, overall. Lack of basic amenities such as the provision of drinking water and toilets apart from inadequate social security and healthcare facilities was reported. Conclusion: This paper highlights the unsatisfactory working environment and high-occupational morbidities among the MSW workers in Telangana. There was a lack of basic amenities at the workplace making it difficult for the MSW workers. A comprehensive approach which focuses on the health and safety with social security for the MSW workers is required.
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    A novel strategy for management of uncorrected refractive errors in urban slums
    ( 2015-06-01) Chande, Prema K. ; Korani, Hiral ; Shamanna, B. R.
    Background: Blindness and Vision impairment remains a major public health issue not only in rural but also in urban areas. Concept of using peripheral health centers to render primary health care services to the community was a WHO proposed model. However, establishing them in urban slums is a challenge as most of the slums are illegal establishments. So, aim was to establish vision centers for providing primary eye care services in the urban slums of Mumbai, West India. Methods: Vision centers were established in various slum pockets of Mumbai from the year 2008 till 2009. Refraction and screening for ocular morbidity were carried out for those who attended this center and management for uncorrected refractive errors was done. Results: Data from 6 such vision centers located in various slum pockets of Mumbai city from April 9 to March 2011 were collected and analyzed. Of the 19,550 adults, 2270 (11.61%) had moderate vision impairment with presenting visual acuity of < 0.5 LogMAR in both eyes. Severe Visual impairment was seen in (723) 3.70%. Blindness was seen in (357) 1.82%. Of the 2993, which were moderately and severely visually impaired, 1893 subjects that is, 63.24% of them improved to 0.2 LogMAR or better with spectacle correction Conclusions: About 63.24% of visual impairment was due to uncorrected refractive errors, these included both moderately and severely vision impaired. Totally, 357 (1.82%) were also identified as blind. This model of vision centers has a role in the identification and management of sight-threatening problems.
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    A population-based assessment of presbyopia in the state of Andhra Pradesh, south India: The Andhra Pradesh eye disease study
    ( 2006-06-01) Nirmalan, Praveen K. ; Krishnaiah, Sannapaneni ; Shamanna, Bindiganavale R. ; Rao, Gullapalli N. ; Thomas, Ravi
    PURPOSE. To determine the prevalence of presbyopia in the state of Andhra Pradesh in south India. METHODS. Comprehensive ocular examinations including log-MAR (logarithm of the minimum angle of resolution) distance and near (presenting and best corrected) visual acuity, slit lamp biomicroscopy of the anterior segment, and dilated posterior segment examinations were performed using a standardized protocol for subjects identified through a random cluster-sampling strategy in Andhra Pradesh. Information of difficulty in performing near tasks was collected as part of a visual function questionnaire administered to all subjects. A person was defined as having presbyopia if the person required an addition of at least 1.0 D in either eye for near vision in addition to their best corrected distance correction to improve near vision to at least N8 and if they had graded lens opacities (Lens Opacities Classification System [LOCS III] system). RESULTS. Examined in the study were 5587 subjects 30 years of age or older (mean age 47.5 ± 13.0 years). The age-, gender-, and area-adjusted prevalence of presbyopia was 55.3% (95% confidence interval [CI]: 54.0 -56.6). One third (n = 1173; 30.0%) of the 3907 subjects with presbyopia were currently using spectacles. Of the 2734 subjects with presbyopia and not using spectacles, 528 (19.3%) had moderate to severe difficulty in reading small print, and 2085 (76.3%) had moderate to severe difficulty in recognizing small objects and performing near work, including 1057 (38.6%) subjects who were unable to manage any near work. On multivariate analysis, female sex (OR: 1.4, 95% CI: 1.1-1.8), rural residence (OR: 1.5, 95% CI: 1.2-1.8), alcohol consumption (OR: 0.8, 95% CI: 0.6-0.9), nuclear opacity of the lens greater than grade 2 LOCS III (OR: 4.8, 95% CI: 1.4 -16.8), myopia (OR: 1.6, 95% CI: 1.3-2.1), and hyperopia (OR: 3.6, 95% CI: 2.7-5.2) were associated with presbyopia. CONCLUSIONS. The high prevalence of presbyopia and the stated effect on performing activities related to near vision needs to be translated into programs and strategies that specifically target presbyopia. Copyright © Association for Research in Vision and Ophthalmology.
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    Acanthamoeba keratitis after LASIK
    ( 2006-01-01) Balasubramanya, Ramamurthy ; Garg, Prashant ; Sharma, Savitri ; Vemuganti, Geeta K.
    PURPOSE: To report a case of Acanthamoeba infection following LASIK. METHODS: A 20-year-old woman developed pain, redness, decreased vision, and corneal infiltrate in the right eye 15 days after bilateral LASIK. She did not use contact lenses postoperatively. Patient examination 3 months after surgery revealed a large, central, full-thickness corneal infiltrate with multiple satellite lesions in the right eye. Corneal scrapings were taken and the flap excised, and submitted for histopathologic examination. RESULTS: Microscopic examination of smears revealed Acanthamoeba cysts and non-nutrient agar showed a significant growth of Acanthamoeba. Histopathology examination of the excised flap demonstrated numerous Acanthamoeba cysts in tissue sections. The infiltrate was treated with a combination of topical polyhexamethylene biguanide, chlorhexidine, atropine sulfate, and oral itraconazole and resolved within 2 months. CONCLUSIONS: Laser in situ keratomileusis can be complicated by Acanthamoeba infection. Microbiologic evaluation is essential for accurate early diagnosis and treatment.
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    Acanthamoeba keratitis presenting as a plaque
    ( 2008-10-01) Sahu, Srikant K. ; Das, Sujata ; Sharma, Savitri ; Vemuganti, Geeta K.
    Purpose: To report a case of Acanthamoeba keratitis clinically presenting with a plaque-like lesion typical of fungal keratitis. Methods: A 55-year-old woman presented with a yellow plaque-like lesion on the cornea surrounded by an infiltrate. Smears and culture were taken. The plaque was removed and subjected to histopathological investigation. Results: Smear, culture, and histopathology results confirmed Acanthamoeba (cysts). The patient was treated with intensive topical medication. The infection resolved after 8 weeks of treatment. Conclusions: Acanthamoeba infection of cornea may present as a plaque-like lesion. In addition to topical medication, plaque removal helps in early resolution of the infection. © 2008 by Lippincott Williams & Wilkins.
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    Access to health care and employment status of people with disabilities in South India, the SIDE (South India Disability Evidence) study
    ( 2014-11-01) Gudlavalleti, Murthy Venkata S. ; John, Neena ; Allagh, Komal ; Sagar, Jayanthi ; Kamalakannan, Sureshkumar ; Ramachandra, Srikrishna S. ; Shamanna, B. R. ; Noe, Christiane ; Pant, Hira Ballabh ; Soji, Fairlene ; Mani, Srinivasan
    Background: Data shows that people with disability are more disadvantaged in accessing health, education and employment opportunities compared to people without a disability. There is a lack of credible documented evidence on health care access and barriers to access from India. The South India Disability Evidence (SIDE) Study was undertaken to understand the health needs of people with disabilities, and barriers to accessing health services. Methods: The study was conducted in one district each in two States (Andhra Pradesh and Karnataka) in 2012. Appropriate age and sex-matched people without a disability were recruited to compare with people with disability who were identified through a population-based survey and available government disability records by trained key informants. These people were then examined by a medical team to confirm the diagnosis. Investigators administered questionnaire schedules to people with and without a disability to harness information on employment and health service access, utilization and barriers. Results: A total of 839 people with disabilities and 1153 age and sex matched people without a disability, aged 18 years or more were included. People with disability had significantly lower employment rates. On univariate analysis, people with disability (18.4%) needed to visit a hospital significantly more often in the preceding year compared to people without a disability (8.8%) (χ2- 40.0562; P < =0.001). However adjusted odds ratios did not show a statistically significant difference. Significant differences were also observed with respect to past hospitalization. People with disabilities had 4.6 times higher risk of suffering from diabetes and 5.8 times higher risk of suffering from depression compared to people without a disability and the risk was significantly higher in males compared to females with disability. People with disability faced significantly more barriers to accessing health services compared to people without a disability. Barriers included ignorance regarding availability of services, costs of services and transportation. Conclusions: This study highlights the challenges that people with disability face in accessing health-care and employment opportunities. The study findings have public health implications and should be used for planning need-based appropriate strategies to improve health care access for people with disabilities.
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    Acute scleritis as a manifestation of congenital erythropoietic porphyria
    ( 2002-07-02) Veenashree, M. P. ; Sangwan, Virender S. ; Vemuganti, Geeta K. ; Parthasaradhi, Anchala
    Purpose. To report a case of congenital erythropoietic porphyria that presented as acute scleritis over a bilateral scleromalacia perforans in the interpalpebral fissure. Methods. An 18-year-old man presented with painful red eye, a history of photophobia, and passing highly colored urine since childhood. Dermatological and biochemical evaluations were done. Results. The patient had normal vision in both eyes with bilateral scleromalacia perforans. The right eye showed painful, nodular scleritis. Dermatological examination revealed multiple, vesciculobullous cutaneous lesions with atrophy and pseudoscleroderma changes, hypertrichosis, and bluish discoloration of teeth. Immunofluorescent microscopy of fresh peripheral smear showed brilliant red fluorescence of erythrocytes. Spectroscopic analysis of urine revealed excretion of porphyrin, thus confirming a diagnosis of congenital erythropoietic porphyria. The patient's condition improved with local and systemic steroid therapy along with general photoprotective measures for the exposed parts of the body. Conclusion. Acute scleritis could be the presenting feature in a rare case of congenital erythropoietic porphyria, warranting systemic evaluation.
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    Adiponectin deficiency increases leukocyte-endothelium interactions via upregulation of endothelial cell adhesion molecules in vivo
    ( 2007-06-01) Ouedraogo, Raogo ; Gong, Yulan ; Berzins, Brett ; Wu, Xiandong ; Mahadev, Kalyankar ; Hough, Kelly ; Chan, Lawrence ; Goldstein, Barry J. ; Scalia, Rosario
    This study reports on what we believe are novel mechanism(s) of the vascular protective action of adiponectin. We used intravital microscopy to measure leukocyte-endothelium interactions in adiponectin-deficient (Ad -/-) mice and found that adiponectin deficiency was associated with a 2-fold increase in leukocyte rolling and a 5-fold increase in leukocyte adhesion in the microcirculation. Measurement of endothelial NO (eNO) revealed that adiponectin deficiency drastically reduced levels of eNO in the vascular wall. Immunohistochemistry demonstrated increased expression of E-selectin and VCAM-1 in the vascular endothelium of Ad-/- mice. Systemic administration of the recombinant globular adiponectin domain (gAd) to Ad -/- mice significantly attenuated leukocyte-endothelium interactions and adhesion molecule expression in addition to restoring physiologic levels of eNO. Importantly, prior administration of gAd also protected WT mice against TNF-α-induced leukocyte-endothelium interactions, indicating a pharmacologic action of gAd. Mechanistically, blockade of eNOS with N ω-nitro-L-arginine methyl ester (L-NAME) abolished the inhibitory effect of gAd on leukocyte adhesion, demonstrating the obligatory role of eNOS signaling in the antiinflammatory action of gAd. We believe this is the first demonstration that gAd protects the vasculature in vivo via increased NO bioavailability with suppression of leukocyte-endothelium interactions. Overall, we provide evidence that loss of adiponectin induces a primary state of endothelial dysfunction with increased leukocyte-endothelium adhesiveness.
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    Adiponectin inhibits vascular endothelial growth factor-induced migration of human coronary artery endothelial cells
    ( 2008-05-01) Mahadev, Kalyankar ; Wu, Xiangdong ; Donnelly, Sylvia ; Ouedraogo, Raogo ; Eckhart, Andrea D. ; Goldstein, Barry J.
    Aims: Vascular endothelial growth factor (VEGF)-induced endothelial cell migration and angiogenesis are associated with the vascular complications of diabetes mellitus, and adiponectin is an abundant plasma adipokine that exhibits salutary effects on endothelial function. We investigated whether adiponectin suppresses VEGF-induced migration and related signal transduction responses in human coronary artery endothelial cells (HCAECs). Methods and results: Using a modified Boyden chamber technique and a monolayer 'wound-healing' assay, both the recombinant adiponectin globular domain and full-length adiponectin protein potently suppressed the migration of HCAEC induced by VEGF. Adiponectin did not increase endothelial cell apoptosis, as measured by Terminal deoxynucleotidyl Transferase Biotin-dUTP Nick End Labelling assay. Adiponectin also suppressed VEGF-induced reactive oxygen species generation, activation of Akt, the mitogen-activated protein kinase ERK and the RhoGTPase RhoA, and induction of the formation of actin stress fibres and focal cellular adhesions. VEGF-stimulated cell migration was inhibited by activation of adenylyl cyclase with forskolin, and adiponectin treatment increased cellular cyclic adenosine monophosphate (cAMP) levels and protein kinase A (PKA) enzymatic activity. Pharmacological inhibition of either adenylyl cyclase or PKA significantly abrogated the effect of adiponectin globular domain to suppress VEGF-induced cell migration. Conclusion: Adiponectin suppresses VEGF-stimulated HCAEC migration via cAMP/PKA-dependent signalling, an important effect with implications for a regulatory role of adiponectin in vascular processes associated with diabetes and atherosclerosis. © The Author 2008.
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    Adiponectin protects against angiotensin II or tumor necrosis factor α-induced endothelial cell monolayer hyperpermeability: Role of cAMP/PKA signaling
    ( 2008-05-01) Xu, Shi Qiong ; Mahadev, Kalyankar ; Wu, Xiangdong ; Fuchsel, Lauren ; Donnelly, Sylvia ; Scalia, Rosario G. ; Goldstein, Barry J.
    OBJECTIVE - Angiotensin II (Ang II) and tumor necrosis factor (TNF)-α levels increase endothelial permeability, and we hypothesized that adiponectin suppressed these responses in a cAMP-dependent manner. METHODS AND RESULTS - The effect of adiponectin on transendothelial electric resistance (TEER) and diffusion of albumin through human umbilical vein and bovine aortic endothelial cell monolayers induced by Ang II (100 nmol/L) or TNF-α (5 ng/mL) was measured. Treatment with the globular domain of adiponectin (3 μg/mL) for 16 hours abrogated the adverse TEER effect of TNF-α (-35 versus -12 Ω/cm at 45 minutes, P < 0.05) and Ang II (-25 versus -5 Ω/cm at 45 minutes, P < 0.01) and partially suppressed the increased diffusion of albumin with Ang II (40% versus 10% change, P < 0.05) or TNF-α (40% versus 20% change, P < 0.05). Full-length adiponectin also suppressed Ang II-induced monolayer hyperpermeability. Adiponectin treatment also suppressed Ang II-induced increased actin stress fiber development, intercellular gap formation, and β-tubulin disassembly. Adiponectin increased cAMP levels, and its effects were abrogated by inhibition of adenylyl cyclase or cAMP-dependent protein kinase signaling. CONCLUSIONS - Adiponectin protects the endothelial monolayer from Ang II or TNF-α-induced hyperpermeability by modulating microtubule and cytoskeleton stability via a cAMP/ PKA signaling cascade. © 2008 American Heart Association, Inc.
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    Adiponectin suppresses IκB kinase activation induced by tumor necrosis factor-α or high glucose in endothelial cells: Role of cAMP and AMP kinase signaling
    ( 2007-12-01) Wu, Xiangdong ; Mahadev, Kalyankar ; Fuchsel, Lauren ; Ouedraogo, Raogo ; Xu, Shi Qiong ; Goldstein, Barry J.
    Adiponectin is a protein secreted from adipocytes that exhibits salutary effects in the vascular endothelium by signaling mechanisms that are not well understood. In obesity-related disease states and type 2 diabetes, circulating substances, including tumor necrosis factor-α (TNFα) and high glucose, activate IκB kinase (IKK)β and reduce the abundance of its substrate, inhibitor of κB (IκB)α, leading to nuclear translocation of the transcription factor NF-κB and stimulation of an inflammatory signaling cascade closely associated with endothelial dysfunction. The present study demonstrates that the globular domain of adiponectin (gAd) potently suppresses the activation of IKKβ by either TNFα or high glucose in human umbilical vein endothelial cells and ameliorates the associated loss of IκBα protein. Interestingly, activation of AMP kinase was substantially more effective than cAMP signaling in suppressing high glucose-induced IKKβ activity, whereas both pathways were comparably active in suppressing the TNFα-induced increase in IKKβ. Both cAMP/protein kinase A signaling and activation of the AMP kinase pathway played a role in the suppression by gAd of TNFα- and high glucose-mediated IKKβ activation. These findings support an important role for adiponectin in anti-inflammatory signaling in the endothelium and also imply that multiple pathways are involved in the cellular effects of adiponectin. Copyright © 2007 the American Physiological Society.
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    Adiponectin suppresses proliferation and superoxide generation and enhances eNOS activity in endothelial cells treated with oxidized LDL
    ( 2004-03-05) Motoshima, Hiroyuki ; Wu, Xiangdong ; Mahadev, Kalyankar ; Goldstein, Barry J.
    Adiponectin (also known as 30-kDa adipocyte complement-related protein or Acrp30) is an abundant adipocyte-derived plasma protein with anti-atherosclerotic and insulin-sensitizing properties. In order to investigate the potential mechanism(s) of the vascular protective effect of adiponectin, we used cultured bovine endothelial cells (BAECs) to study the effect of recombinant globular adiponectin (gAd) on cellular proliferation and the generation of reactive oxygen species (ROS) induced by oxidized LDL (oxLDL). By RT-PCR, we found that BAECs preferentially express AdipoR1, the high-affinity receptor for gAd. Treatment of BAECs with oxLDL (10μg/ml) for 16h stimulated cell proliferation by ∼60%, which was inhibited by co-incubation with gAd. Cell treatment with gAd also inhibited basal and oxLDL-induced superoxide release, and suppressed the activation of p42/p44 MAP kinase by oxLDL. The effects of gAd were blocked by a specific polyclonal anti-adiponectin antibody (TJ414). OxLDL-induced BAEC proliferation and superoxide release were inhibited by the NAD(P)H oxidase inhibitor diphenyleneiodonium (DPI), but not the eNOS inhibitor L-nitroarginine methyl ester (L-NAME). Finally, gAd ameliorated the suppression of eNOS activity by oxLDL. These data indicate that gAd inhibits oxLDL-induced cell proliferation and suppresses cellular superoxide generation, possibly through an NAD(P)H oxidase-linked mechanism. © 2004 Elsevier Inc. All rights reserved.
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    Adiponectin suppression of high-glucose-induced reactive oxygen species in vascular endothelial cells: Evidence for involvement of a cAMP signaling pathway
    ( 2006-09-11) Ouedraogo, Raogo ; Wu, Xiangdong ; Xu, Shi Qiong ; Fuchsel, Lauren ; Motoshima, Hiroyuki ; Mahadev, Kalyankar ; Hough, Kelly ; Scalia, Rosario ; Goldstein, Barry J.
    Adiponectin is an abundant adipocyte-derived plasma protein with antiatherosclerotic effects. Vascular signal transduction by adiponectin is poorly understood and may involve 5′-AMP-activated protein kinase (AMPK), cAMP signaling, and other pathways. Hyperglycemia sharply increases the production of reactive oxygen species (ROS), which play a key role in endothelial dysfunction in diabetes. Because the recombinant globular domain of human adiponectin (gAd) reduces the generation of endothelial ROS induced by oxidized LDL, we sought to determine whether adiponectin could also suppress ROS production induced by high glucose in cultured human umbilical vein endothelial cells. Incubation in 25 mmol/l glucose for 16 h increased ROS production 3.8-fold (P < 0.05), using a luminol assay. Treatment with gAd for 16 h suppressed glucose-induced ROS in a dose-dependent manner up to 81% at 300 nmol/l (P < 0.05). The AMPK activator 5-aminoimidazole-4-carboxamide-1- β-D-ribofuranoside (AICAR; 1 mmol/l, 16 h) only partially decreased glucose-induced ROS by 22% (P < 0.05). Cell pretreatment with AMPK inhibitors, however, failed to block the effect of gAd to suppress glucose-induced ROS, suggesting that the action of gAd was independent of AMPK. Interestingly, activation of cAMP signaling by treatment with forskolin (2 μmol/l) or dibutyryl-cAMP (0.5 mmol/l) reduced glucose-induced ROS generation by 43 and 67%, respectively (both P < 0.05). Incubation with the cAMP-dependent protein kinase (PKA) inhibitor H-89 (1 μmol/l) fully abrogated the effect of gAd, but not that of AICAR, on ROS induced by glucose. gAd also increased cellular cAMP content by 70% in an AMPK-independent manner. Full-length adiponectin purified from a eukaryotic expression system also suppressed ROS induced by high glucose or by treatment of endothelial cells with oxidized LDL. Thus, adiponectin suppresses excess ROS production under high-glucose conditions via a cAMP/PKA-dependent pathway, an effect that has implications for vascular protection in diabetes. © 2006 by the American Diabetes Association.
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    Amniotic membrane transplantation for reconstruction of corneal epithelial surface in cases of partial limbal stem cell deficiency
    ( 2004-12-01) Sangwan, Virender S. ; Matalia, Himanshu P. ; Vemuganti, Geeta K. ; Rao, Gullapalli N.
    Purpose: To assess the efficacy of amniotic membrane for treatment of partial limbal stem cell deficiency (LSCD). Methods: Medical records of four patients with partial LSCD who underwent pannus resection and amniotic membrane transplantation (AMT) were reviewed for ocular surface stability and improvement in visual acuity. Clinico-histopathological correlation was done with the resected pannus tissue. Results: All the eyes exhibited stable corneal epithelial surface by an average of 7 weeks postoperatively with improvement in subjective symptoms. Best corrected visual acuity improved from preoperative (range: 6/9p-6/120) to postoperative (range: 6/6p-6/15) by an average of 4.5 lines on Snellen visual acuity charts. Histopathological examination of excised tissue showed features of conjunctivalisation. Conclusion: Amniotic membrane transplantation appears to be an effective means of reconstructing the corneal epithelial surface and for visual rehabilitation of patients with partial limbal stem cell deficiency. It may be considered as an alternative primary procedure to limbal transplantation in these cases.
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    Angiotensin receptor agonistic autoantibody is highly prevalent in preeclampsia: Correlation with disease severity
    ( 2010-02-01) Siddiqui, Athar H. ; Irani, Roxanna A. ; Blackwell, Sean C. ; Ramin, Susan M. ; Kellems, Rodney E. ; Xia, Yang
    Preeclampsia (PE), a syndrome affecting 5% of pregnancies, characterized by hypertension and proteinuria, is a leading cause of maternal and fetal morbidity and mortality. The condition is often accompanied by the presence of a circulating maternal autoantibody, the angiotensin II type I receptor agonistic autoantibody (AT1-AA). However, the prevalence of AT1-AA in PE remains unknown, and the correlation of AT1-AA titers with the severity of the disease remains undetermined. We used a sensitive and high-throughput luciferase bioassay to detect AT1-AA levels in the serum of 30 normal, 37 preeclamptic (10 mild and 27 severe), and 23 gestational hypertensive individuals. Here we report that AT1-AA is highly prevalent in PE (95%). Next, by comparing the levels of AT1-AA among women with mild and severe PE, we found that the titer of AT1-AA is proportional to the severity of the disease. Intriguingly, among severe preeclamptic patients, we discovered that the titer of AT1-AA is significantly correlated with the clinical features of PE: systolic blood pressure (r=0.56), proteinuria (r=0.70), and soluble fms-like tyrosine kinase-1 level (r=0.71), respectively. Notably, only AT1-AA, and not soluble fms-like tyrosine kinase-1, levels are elevated in gestational hypertensive patients. These data serve as compelling clinical evidence that AT1-AA is highly prevalent in PE, and its titer is strongly correlated to the severity of the disease. © 2010 American Heart Association. All rights reserved.
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    Angiotensin receptor agonistic autoantibody-mediated soluble fms-like tyrosine kinase-1 induction contributes to impaired adrenal vasculature and decreased aldosterone production in preeclampsia
    ( 2013-02-01) Siddiqui, Athar H. ; Irani, Roxanna A. ; Zhang, Weiru ; Wang, Wei ; Blackwell, Sean C. ; Kellems, Rodney E. ; Xia, Yang
    Preeclampsia (PE) is a life-threatening hypertensive disorder during pregnancy associated with decreased circulating aldosterone levels. However, the molecular mechanisms underlying aldosterone reduction in PE remain unidentified. Here we demonstrate that reduced circulating aldosterone levels in preeclamptic women are associated with the presence of angiotensin II type 1 receptor agonistic autoantibody and elevated soluble Fms-like tyrosine kinase-1, 2 prominent pathogenic factors in PE. Using an adoptive transfer animal model of PE, we provide in vivo evidence that the injection of IgG from women with PE, but not IgG from normotensive individuals, resulted in hypertension, proteinuria, and a reduction in aldosterone production from 1377±272 pg/mL to 544±92 pg/mL (P < 0.05) in pregnant mice. These features were prevented by coinjection with an epitope peptide that blocks antibody-mediated angiotensin type 1 receptor activation. In contrast, injection of IgG from preeclamptic women into nonpregnant mice induced aldosterone levels from 213±24 pg/mL to 615±48 pg/mL (P < 0.05). These results indicate that maternal circulating autoantibody in preeclamptic women is a detrimental factor causing decreased aldosterone production via angiotensin type 1 receptor activation in a pregnancy-dependent manner. Next, we found that circulating soluble Fms-like tyrosine kinase-1 was only induced in autoantibody-injected pregnant mice but not nonpregnant mice. As such, we further observed vascular impairment in adrenal glands of pregnant mice. Finally, we demonstrated that infusion of vascular endothelial growth factor121 attenuated autoantibody-induced adrenal gland vascular impairment resulting in a recovery in circulating aldosterone (from 544±92 to 1110±269 pg/mL; P < 0.05). Overall, we revealed that angiotensin II type 1 receptor agonistic autoantibody-induced soluble Fms-like tyrosine kinase-1 elevation is a novel pathogenic mechanism underlying decreased aldosterone production in PE. © 2012 American Heart Association, Inc.