Has the relationship between wealth and HIV risk in Sub-Saharan Africa changed over time? A temporal, gendered and hierarchical analysis.

This study examines the relationship between wealth and HIV infection in Sub-Saharan Africa to determine whether and how this relationship has varied over time, within and across countries, by gender, and urban environment. The analysis draws on DHS and AIS data from 27 Sub-Saharan African countries, which spanned the 14 years between 2003 and 2016. We first use logistic regression analyses to assess the relationship between individual wealth, HIV infection and gender by country and year stratified on urban environment. We then use meta-regression analyses to assess the relationship between country level measures of wealth and the odds of HIV infection by gender and individual level wealth, stratified on urban environment. We find that there is a persistent and positive relationship between wealth and the odds of HIV infection across countries, but that the strength of this association has weakened over time. The rate of attenuation does not appear to differ between urban/rural strata. Likewise, we also find that these associations were most pronounced for women and that this relationship was persistent over the study period and across urban and rural strata. Overall, our findings suggest that the relationship between wealth and HIV infection is beginning to reverse and that in the coming years, the relationship between wealth and HIV infection in Sub-Saharan Africa may more clearly mirror the predominant global picture.

Primary care provider preferences for glucocorticoid management of acute asthma exacerbations in children.

OBJECTIVE: Primary care providers (PCP) frequently care for children with acute asthma exacerbations in the outpatient setting. The objective of this study is to evaluate PCP preferences and perceptions regarding oral glucocorticoids prescribed from both outpatient primary care and ED settings for the treatment of children with acute asthma exacerbations. METHODS: PCPs belonging to the Colorado Chapter of the American Academy of Pediatrics were surveyed between February and May 2019. Survey items were generated by a multidisciplinary team and underwent content and criteria validation and pilot testing. Survey items evaluated PCP preferred oral glucocorticoid and dosing regimen for children with acute asthma exacerbations, provider- and patient-level factors contributing to glucocorticoid preferences, and perception of glucocorticoid regimens in terms of treatment failure, resolution of symptoms and adherence. RESULTS: A total of 109 of 600 (18.2%) PCPs responded. Equal proportions of PCPs reported preferring oral prednisone/prednisolone (50.5%) and oral dexamethasone (49.5%) for children with acute asthma exacerbations. Forty-four percent of PCPs reported no preference in type of glucocorticoid utilized by surrounding emergency departments (EDs). However, for children receiving dexamethasone in the ED but with persistent symptoms on PCP follow-up, 50.5% of PCPs would switch patients to prednisone/prednisolone. PCPs did not perceive more treatment failure or rapid resolution of symptoms with dexamethasone but reported better adherence with dexamethasone. CONCLUSION: There is variability in PCP glucocorticoid management of pediatric acute asthma exacerbations. There is a need for further investigations to evaluate for differences in clinical outcomes based on PCP glucocorticoid treatment choices.

Socioeconomic characteristics associated with the introduction of new vaccines and full childhood vaccination in Ghana, 2014.

BACKGROUND: Childhood vaccination in Ghana has historically been high, but the impact of recently introduced vaccines on coverage is unknown. We calculate vaccine coverage of Ghanaian children- contrasting newly introduced vaccines and those long available - and describe associations between sociodemographic indicators and full vaccination. METHODS: Data from the 2014 Ghana Demographic and Health Survey was used to calculate full vaccination, defined as receipt of one dose bacillus Calmette-Guérin (BCG); two doses of rotavirus vaccine; 3 doses of pentavalent vaccine, oral polio vaccine (OPV), and pneumococcal conjugate vaccine (PCV); and one dose of measles-rubella vaccine and yellow fever vaccine, among children age 12-24 months. Logistic regression with survey procedures was used to estimate odds ratios for socioeconomic factors' association with full vaccination. RESULTS: The sample comprised a total of 1107 children 12-24 months. Full vaccination coverage was 70.8%. Vaccination coverage was higher for vaccines administered at younger ages (e.g., birth dose of BCG was 97.0%) than at older ages (e.g., yellow fever at 9 months was 88.2%). Newly introduced vaccines had lower coverage: at 10 weeks, pentavalent 2 was 95.4%, versus 91.2% for PCV 2 and 88.8% for rotavirus 2. Living outside of Greater Accra, home delivery, younger maternal age, urban residence, and more than one child under five in the home were all associated with decreased odds of full vaccination in the adjusted analysis whereas sex of the child, wealth, religion, and maternal education were not associated with full vaccination status. CONCLUSION: Ghana has high overall vaccination rates although disparities in full vaccination by sociodemographic status exist. As vaccine recommendations are revised, it will be important to insure equitable access to vaccination for all children regardless of demographic and socioeconomic background.

For What Illnesses Do Asylum Seekers and Undocumented Migrant Workers in Israel Seek Healthcare? An Analysis of Medical Visits at a Large Urgent Care Clinic for the Uninsured in Tel Aviv.

In 2017, there were nearly 80,000 asylum seekers and undocumented migrant workers in Israel, most of whom did not have health insurance. We evaluated trends in medical visits of asylum seekers and undocumented migrant workers who presented to Terem Refugee Clinic (TRC), a large clinic in Tel Aviv available only to uninsured residents of Israel. Data were collected from electronic medical records at TRC from 2013⁻2017. Diagnoses were grouped into categories using ICD-10-equivalent diagnosis codes. We used a chi-squared test for trends to test the significance of trends 2013 to 2017. There were 99,569 medical visits from 2013 to 2017 at TRC. Visits were lowest in 2013 (11,112), and relatively stable from 2014⁻2017 (range: 19,712⁻23,172). Most visits were among adults aged 18⁻35 (41.2%) and children <2 years old (23.7%). Only 3% of visits were from patients aged >50. The percentage of infectious disease diagnoses decreased over the study period, from 9.4% of all diagnoses in adults in 2014 to 5.2% in 2017, and from 32.0% of all diagnoses in children in 2013 to 19.4% in 2017. The annual percentage of respiratory diagnoses in children and adults 18⁻35 years of age, musculoskeletal in all adults, and digestive in adults except women ≥35 years old increased. Over time, asylum seekers and undocumented migrant workers visited TRC with fewer infectious diseases diagnoses overall but more respiratory diseases, including acute respiratory infections and more musculoskeletal diseases.

From Dehydration to Fractures: Medical Issues Faced by People Crossing the United States: Mexico Border.

To quantify the number of Border Crossers seen at our hospitals, broken down by diagnoses and age. We used our electronic medical record to identify the number of patients in custody of the United States Border Patrol who were seen at Banner-University: South and University Campuses during the calendar year 2016. 734 patients were identified, and the electronic medical record was used to identify the primary diagnosis and age for each one. We then manually categorized them into groups of common diagnoses. We also compared the number of border crosser emergency department (ED) visits to overall ED visits. Of 734 patients, 77% were male, 60% were between 16 and 40 years of age, and 18% were under age 18 years. They made up 1.3% of ED visits to South Campus, but less than 0.1% to University Campus. The top categories were musculoskeletal trauma (n = 235, 32%), and dehydration and rhabdomyolysis (n = 95, 13%). The age range of border crossers brought to our EDs varies widely, as do their primary diagnoses, although trends can be seen. They make up a 1.3% of overall emergency department visits at South Campus hospital.

Fibroblast Growth Factor 21 Protects Photoreceptor Function in Type 1 Diabetic Mice.

Retinal neuronal abnormalities occur before vascular changes in diabetic retinopathy. Accumulating experimental evidence suggests that neurons control vascular pathology in diabetic and other neovascular retinal diseases. Therefore, normalizing neuronal activity in diabetes may prevent vascular pathology. We investigated whether fibroblast growth factor 21 (FGF21) prevented retinal neuronal dysfunction in insulin-deficient diabetic mice. We found that in diabetic neural retina, photoreceptor rather than inner retinal function was most affected and administration of the long-acting FGF21 analog PF-05231023 restored the retinal neuronal functional deficits detected by electroretinography. PF-05231023 administration protected against diabetes-induced disorganization of photoreceptor segments seen in retinal cross section with immunohistochemistry and attenuated the reduction in the thickness of photoreceptor segments measured by optical coherence tomography. PF-05231023, independent of its downstream metabolic modulator adiponectin, reduced inflammatory marker interleukin-1ß (IL-1ß) mRNA levels. PF-05231023 activated the AKT-nuclear factor erythroid 2-related factor 2 pathway and reduced IL-1ß expression in stressed photoreceptors. PF-05231023 administration did not change retinal expression of vascular endothelial growth factor A, suggesting a novel therapeutic approach for the prevention of early diabetic retinopathy by protecting photoreceptor function in diabetes.

Contemporary Social Disparities in TB Infection and Disease in the USA: a Review.

PURPOSE OF REVIEW: Socioeconomic status (SES) has long been understood to be a key determinant of the distribution of tuberculosis (TB), and the role of social factors has long been a truism of TB epidemiology. We review studies that have examined the social determinants of TB in the USA in the past 20 years. We pay particular attention to how the findings of these studies fit within the framework of fundamental cause theory and argue that a more explicit linkage with fundamental cause theory is critical for understanding the current state of TB health disparities in the USA and for charting a way towards TB elimination in the USA. RECENT FINDINGS AND SUMMARY: Our review finds that while in the past 20 years there have been studies that have documented the ongoing association between social factors and TB disease in the USA, few studies explore the precise mechanisms through which social factors continue to influence TB patterns. We advocate for a move towards a system-based approach both in theory development and analyses, allowing for the incorporation of more complex social dynamics to address long-standing disparities in TB disease.

Therapeutic Effects of a Novel Agonist of Peroxisome Proliferator-Activated Receptor Alpha for the Treatment of Diabetic Retinopathy.

Purpose: Clinical studies have shown that peroxisome proliferator-activated receptor alpha (PPARα) agonist fenofibrate has therapeutic effects on diabetic retinopathy (DR). The purpose of this study was to identify a novel PPARα agonist and to evaluate its beneficial effects on DR. Methods: The transcriptional activity of PPARα was measured by a luciferase-based promoter assay. TUNEL was used to evaluate apoptosis in retinal precursor cells (R28). Diabetes was induced in rats by injection of streptozotocin. Retinal inflammation was examined using leukostasis assay, and retinal vascular leakage was measured using permeability assay. Retinal function was measured using electroretinogram (ERG) recording, and retinal apoptosis was quantified using the cell death ELISA. The anti-angiogenic effect was evaluated in the oxygen-induced retinopathy (OIR) model. Results: A compound, 7-chloro-8-methyl-2-phenylquinoline-4-carboxylic acid (Y-0452), with a chemical structure distinct from existing PPARα agonists, activated PPARα transcriptional activity and upregulated PPARα expression. Y-0452 significantly inhibited human retinal capillary endothelial cell migration and tube formation. The compound also protected R28 cells against apoptosis and inhibited NF-κB signaling in R28 cells exposed to palmitate. In diabetic rats, Y-0452 ameliorated leukostasis and vascular leakage in the retina. In addition, Y-0452 preserved the retinal function and reduced retinal cell death in diabetic rats. Y-0452 also alleviated retinal neovascularization in the OIR model. Conclusions: Y-0452 is a novel PPARα agonist and has therapeutic potential for DR.

Valgus slipped capital femoral epiphysis with contralateral pre-slip.

Slipped capital femoral epiphysis (SCFE) is a common hip disorder in older children and adolescents, classically with medial and posterior slippage of the proximal femoral epiphysis. However, valgus SCFE is a very rare entity, where the proximal femoral epiphysis slips laterally and posteriorly. To our knowledge, valgus SCFE with magnetic resonance imaging (MRI) features of contralateral pre-slip has not yet been reported. We present a case of a 9 year old girl with symptomatic valgus SCFE on the left and asymptomatic contralateral pre-slip on the right with concurrent radiographic, sonographic, and MRI findings. Such findings include bilateral coxa valga, radiographic irregularity of the left proximal femoral physis, bilateral hip effusions, abnormal MRI signal and enhancement about both proximal femoral physes, and minimal posterolateral slippage of the left proximal femoral epiphysis. We highlight these pertinent imaging findings and review the importance of accurately diagnosing this rare entity for appropriate surgical management.

Pathogenic Role of microRNA-21 in Diabetic Retinopathy Through Downregulation of PPARα.

Fenofibrate, a specific agonist of peroxisome proliferator-activated receptor-α (PPARα), displays robust therapeutic effects on diabetic retinopathy (DR) in patients with type 2 diabetes. Our recent studies have shown that PPARα is downregulated in the diabetic retina, which contributes to the pathogenesis of DR. However, the mechanism for diabetes-induced downregulation of PPARα remains unknown. We investigated the role of microRNA-21 (miR-21) in regulating PPARα in DR. miR-21 was overexpressed, while PPARα levels were decreased in the retina of db/db mice, a model of type 2 diabetes. Such alterations were also observed in palmitate-treated retinal endothelial cells. miR-21 targeted PPARα by inhibiting its mRNA translation. Knockout of miR-21 prevented the decrease of PPARα, alleviated microvascular damage, ameliorated inflammation, and reduced cell apoptosis in the retina of db/db mice. Intravitreal injection of miR-21 inhibitor attenuated PPARα downregulation and ameliorated retinal inflammation in db/db mice. Further, retinal miR-21 levels were increased, while PPARα levels were decreased in oxygen-induced retinopathy (OIR). Knockout of miR-21 prevented PPARα downregulation and ameliorated retinal neovascularization and inflammation in OIR retinas. In conclusion, diabetes-induced overexpression of miR-21 in the retina is at least partly responsible for PPARα downregulation in DR. Targeting miR-21 may represent a novel therapeutic strategy for DR.

Neurovascular cross talk in diabetic retinopathy: Pathophysiological roles and therapeutic implications.

Diabetic retinopathy (DR) is the leading cause of blindness in the working-age population in developed countries, and its prevalence will increase as the global incidence of diabetes grows exponentially. DR begins with an early nonproliferative stage in which retinal blood vessels and neurons degenerate as a consequence of chronic hyperglycemia, resulting in vasoregression and persistent retinal ischemia, metabolic disequilibrium, and inflammation. This is conducive to overcompensatory pathological neovascularization associated with advanced proliferative DR. Although DR is considered a microvascular complication, the retinal microvasculature is intimately associated with and governed by neurons and glia; neurodegeneration, neuroinflammation, and dysregulation of neurovascular cross talk are responsible in part for vascular abnormalities in both early nonproliferative DR and advanced proliferative DR. Neuronal activity directly regulates microvascular dilation and blood flow in the process of neurovascular coupling. Retinal neurons also secrete guidance cues in response to injury, ischemia, or metabolic stress that may either promote or suppress vascular outgrowth, either alleviating or exacerbating DR, contingent on the stage of disease and retinal microenvironment. Neurodegeneration, impaired neurovascular coupling, and dysregulation of neuronal guidance cues are key events in the pathogenesis of DR, and correcting these events may prevent or delay development of advanced DR. The review discusses the mechanisms of neurovascular cross talk and its dysregulation in DR, and their potential therapeutic implications.

Cytochrome P450 Oxidase 2C Inhibition Adds to ω-3 Long-Chain Polyunsaturated Fatty Acids Protection Against Retinal and Choroidal Neovascularization.

OBJECTIVE: Pathological ocular neovascularization is a major cause of blindness. Increased dietary intake of ω-3 long-chain polyunsaturated fatty acids (LCPUFA) reduces retinal neovascularization and choroidal neovascularization (CNV), but ω-3 LCPUFA metabolites of a major metabolizing pathway, cytochrome P450 oxidase (CYP) 2C, promote ocular pathological angiogenesis. We hypothesized that inhibition of CYP2C activity will add to the protective effects of ω-3 LCPUFA on neovascular eye diseases. APPROACH AND RESULTS: The mouse models of oxygen-induced retinopathy and laser-induced CNV were used to investigate pathological angiogenesis in the retina and choroid, respectively. The plasma levels of ω-3 LCPUFA metabolites of CYP2C were determined by mass spectroscopy. Aortic ring and choroidal explant sprouting assays were used to investigate the effects of CYP2C inhibition and ω-3 LCPUFA-derived CYP2C metabolic products on angiogenesis ex vivo. We found that inhibition of CYP2C activity by montelukast added to the protective effects of ω-3 LCPUFA on retinal neovascularization and CNV by 30% and 20%, respectively. In CYP2C8-overexpressing mice fed a ω-3 LCPUFA diet, montelukast suppressed retinal neovascularization and CNV by 36% and 39% and reduced the plasma levels of CYP2C8 products. Soluble epoxide hydrolase inhibition, which blocks breakdown and inactivation of CYP2C ω-3 LCPUFA-derived active metabolites, increased oxygen-induced retinopathy and CNV in vivo. Exposure to selected ω-3 LCPUFA metabolites of CYP2C significantly reversed the suppression of both angiogenesis ex vivo and endothelial cell functions in vitro by the CYP2C inhibitor montelukast. CONCLUSIONS: Inhibition of CYP2C activity adds to the protective effects of ω-3 LCPUFA on pathological retinal neovascularization and CNV.

sFlt Multivalent Conjugates Inhibit Angiogenesis and Improve Half-Life In Vivo.

Current anti-VEGF drugs for patients with diabetic retinopathy suffer from short residence time in the vitreous of the eye. In order to maintain biologically effective doses of drug for inhibiting retinal neovascularization, patients are required to receive regular monthly injections of drug, which often results in low patient compliance and progression of the disease. To improve the intravitreal residence time of anti-VEGF drugs, we have synthesized multivalent bioconjugates of an anti-VEGF protein, soluble fms-like tyrosine kinase-1 (sFlt) that is covalently grafted to chains of hyaluronic acid (HyA), conjugates that are termed mvsFlt. Using a mouse corneal angiogenesis assay, we demonstrate that covalent conjugation to HyA chains does not decrease the bioactivity of sFlt and that mvsFlt is equivalent to sFlt at inhibiting corneal angiogenesis. In a rat vitreous model, we observed that mvsFlt had significantly increased intravitreal residence time compared to the unconjugated sFlt after 2 days. The calculated intravitreal half-lives for sFlt and mvsFlt were 3.3 and 35 hours, respectively. Furthermore, we show that mvsFlt is more effective than the unconjugated form at inhibiting retinal neovascularization in an oxygen-induced retinopathy model, an effect that is most likely due to the longer half-life of mvsFlt in the vitreous. Taken together, our results indicate that conjugation of sFlt to HyA does not affect its affinity for VEGF and this conjugation significantly improves drug half-life. These in vivo results suggest that our strategy of multivalent conjugation could substantially improve upon drug half-life, and thus the efficacy of currently available drugs that are used in diseases such as diabetic retinopathy, thereby improving patient quality of life.

Glucocorticoid receptor-mediated cis-repression of osteogenic genes requires BRM-SWI/SNF.

Glucocorticoids are an effective therapy for a variety of severe inflammatory and autoimmune disorders; however, the therapeutic use of glucocorticoids is severely limited by their negative side effects, particularly on osteogenesis. Glucocorticoids regulate transcription by binding to the glucocorticoid receptor (GR), which then binds the promoters of target genes to induce either activation or repression. The gene activation effects of nuclear hormone receptors broadly require the cooperation of the chromatin remodeling complex known as SWI/SNF, which is powered by an ATPase core. The well-studied SWI/SNF ATPase, BRG1, is required for gene activation by a spectrum of nuclear hormone receptors including GR. However, glucocorticoid-induced side effects specifically related to impaired osteogenesis are mostly linked with GR-mediated repression. We have considered whether cis-repression of osteogenic genes by GR may be mediated by a distinct subclass of SWI/SNF powered by the alternative ATPase, BRM. BRM does not have an essential role in mammalian development, but plays a repressor role in osteoblast differentiation and favors adipogenic lineage selection over osteoblast commitment, effects that mirror the repressor effects of GR. The studies reported here examine three key GR cis-repression gene targets, and show that GR association with these promoters is sharply reduced in BRM deficient cells. Each of these GR-targeted genes act in a different way. Bglap encodes osteocalcin, which contributes to normal maturation of osteoblasts from committed pre-osteoblasts. The Per3 gene product acts in uncommitted mesenchymal stem cells to influence the osteoblast/adipocyte lineage selection point. Fas ligand, encoded by FasL, is a means by which osteoblasts can modulate bone degradation by osteoclasts. Repression of each of these genes by glucocorticoid favors bone loss. The essential role of BRM in cooperation with GR at each of these control points offers a novel mechanistic understanding of the role of GR in bone loss.

SWI/SNF-Mediated Lineage Determination in Mesenchymal Stem Cells Confers Resistance to Osteoporosis.

Redirecting the adipogenic potential of bone marrow-derived mesenchymal stem cells to other lineages, particularly osteoblasts, is a key goal in regenerative medicine. Controlling lineage selection through chromatin remodeling complexes such as SWI/SNF, which act coordinately to establish new patterns of gene expression, would be a desirable intervention point, but the requirement for the complex in essentially every lineage pathway has generally precluded selectivity. However, a novel approach now appears possible by targeting the subset of SWI/SNF powered by the alternative ATPase, mammalian brahma (BRM). BRM is not required for development, which has hindered understanding of its contributions, but knockdown genetics here, designed to explore the hypothesis that BRM-SWI/SNF has different regulatory roles in different mesenchymal stem cell lineages, shows that depleting BRM from mesenchymal stem cells has a dramatic effect on the balance of lineage selection between osteoblasts and adipocytes. BRM depletion enhances the proportion of cells expressing markers of osteoblast precursors at the expense of cells able to differentiate along the adipocyte lineage. This effect is evident in primary bone marrow stromal cells as well as in established cell culture models. The altered precursor balance has major physiological significance, which becomes apparent as protection against age-related osteoporosis and as reduced bone marrow adiposity in adult BRM-null mice.

Therapeutic Effects of PPAR α on Neuronal Death and Microvascular Impairment.

Peroxisome-proliferator activated receptor-alpha (PPARα) is a broadly expressed nuclear hormone receptor and is a transcription factor for diverse target genes possessing a PPAR response element (PPRE) in the promoter region. The PPRE is highly conserved, and PPARs thus regulate transcription of an extensive array of target genes involved in energy metabolism, vascular function, oxidative stress, inflammation, and many other biological processes. PPARα has potent protective effects against neuronal cell death and microvascular impairment, which have been attributed in part to its antioxidant and anti-inflammatory properties. Here we discuss PPARα's effects in neurodegenerative and microvascular diseases and also recent clinical findings that identified therapeutic effects of a PPARα agonist in diabetic microvascular complications.

p107-Dependent recruitment of SWI/SNF to the alkaline phosphatase promoter during osteoblast differentiation.

The retinoblastoma protein family is intimately involved in the regulation of tissue specific gene expression during mesenchymal stem cell differentiation. The role of the following proteins, pRB, p107 and p130, is particularly significant in differentiation to the osteoblast lineage, as human germ-line mutations of RB1 greatly increase susceptibility to osteosarcoma. During differentiation, pRB directly targets certain osteogenic genes for activation, including the alkaline phosphatase-encoding gene Alpl. Chromatin immunoprecipitation (ChIP) assays indicate that Alpl is targeted by p107 in differentiating osteoblasts selectively during activation with the same dynamics as pRB, which suggests that p107 helps promote Alpl activation. Mouse models indicate overlapping roles for pRB and p107 in bone and cartilage formation, but very little is known about direct tissue-specific gene targets of p107, or the consequences of targeting by p107. Here, the roles of p107 and pRB were compared using shRNA-mediated knockdown genetics in an osteoblast progenitor model, MC3T3-E1 cells. The results show that p107 has a distinct role along with pRB in induction of Alpl. Deficiency of p107 does not impede recruitment of transcription factors recognized as pRB co-activation partners at the promoter; however, p107 is required for the efficient recruitment of an activating SWI/SNF chromatin-remodeling complex, an essential event in Alpl induction.

Protective and antioxidant effects of PPARα in the ischemic retina.

PURPOSE: Previous studies have demonstrated that peroxisome proliferator-activated receptor-alpha (PPARα) agonists have therapeutic effects in diabetic retinopathy, although the mechanism of action remains incompletely understood. The purpose of this study was to evaluate PPARα's protective effects in the ischemic retina, and to delineate its molecular mechanism of action. METHODS: For the oxygen-induced retinopathy (OIR) model, wild-type (WT), and PPARα knockout (PPARα(-/-)) mice were exposed to 75% O2 from postnatal day 7 (P7) to P12 and treated with the PPARα agonist fenofibric acid (Feno-FA) from P12 to P16. At P17, the effects of Feno-FA on retinal glial fibrillary acidic protein (GFAP) expression, apoptotic DNA cleavage, and TUNEL labeling were analyzed. Cultured retinal cells were exposed to CoCl2 to induce hypoxia, and TUNEL staining and 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein dye were used to measure apoptosis and reactive oxygen species (ROS) generation. Western blotting was used to measure GFAP levels and cell signaling. RESULTS: Feno-FA decreased retinal apoptosis and oxidative stress in WT but not PPARα(-/-) OIR mice. Peroxisome proliferator-activated receptor-alpha knockout OIR mice showed increased retinal cell death and glial activation in comparison to WT OIR mice. Feno-FA treatment and PPARα overexpression protected cultured retinal cells from hypoxic cell death and decreased ROS levels. Nuclear hypoxia-inducible factor-α (HIF-1α) and nicotine adenine dinucleotide phosphate oxidase-4 (Nox 4) were increased in OIR retinas and downregulated by Feno-FA in WT but not in PPARα(-/-) mice. CONCLUSIONS: Peroxisome proliferator-activated receptor-alpha has a potent antiapoptotic effect in the ischemic retina. This protective effect may be mediated in part through downregulation of HIF-1α/Nox 4 and consequently alleviation of oxidative stress.

PPARα regulates mobilization and homing of endothelial progenitor cells through the HIF-1α/SDF-1 pathway.

PURPOSE: The mechanism for the antiangiogenic activity of peroxisome proliferator-activated receptor alpha (PPARα) remains incompletely understood. Endothelial progenitor cells (EPC) are known to participate in neovascularization (NV). The purpose of this study was to investigate whether PPARα regulates EPC during retinal NV. METHODS: Retinal NV was induced by oxygen-induced retinopathy (OIR). Mice with OIR were injected intraperitoneally with the PPARα agonist fenofibric acid (FA) or with adenovirus expressing PPARα (Ad-PPARα). Flow cytometry was used to quantify circulating and retinal EPC. Serum stromal cell-derived factor 1 (SDF-1) levels were measured by ELISA. Hypoxia was induced in primary human retinal capillary endothelial cells (HRCEC) and mouse brain endothelial cells (MBEC) by CoCl2. Levels of SDF-1 and hypoxia-inducible factor 1 alpha (HIF-1α) were measured by Western blotting. RESULTS: Fenofibric acid and overexpression of PPARα attenuated the increase of circulating and retinal EPC, correlating with suppressed retinal NV in OIR mice at P17. The PPARα knockout enhanced the OIR-induced increase of circulating and retinal EPC. Fenofibric acid decreased retinal HIF-1α and SDF-1 levels as well as serum SDF-1 levels in the OIR model. In HRCEC, PPARα inhibited HIF-1α nuclear translocation and SDF-1 overexpression induced by hypoxia. Further, MBEC from PPARα(-/-) mice showed more prominent activation of HIF-1α and overexpression of SDF-1 induced by hypoxia, compared with the wild-type (WT) MBEC. PPARα failed to block SDF-1 overexpression induced by a constitutively active mutant of HIF-1α, suggesting that regulation of SDF-1 by PPARα was through blockade of HIF-1α activation. CONCLUSIONS: Peroxisome proliferator-activated receptor alpha suppresses ischemia-induced EPC mobilization and homing through inhibition of the HIF-1α/SDF-1 pathway. This represents a novel molecular mechanism for PPARα's antiangiogenic effects.