Glucagon-like Peptide-1 Receptor Agonists Associated Gastrointestinal Adverse Events: A Cross-Sectional Analysis of the National Institutes of Health All of Us Cohort.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are commonly used diabetes and obesity medications but have been associated with gastrointestinal (GI) adverse events. However, real-world evidence on comparative GI adverse reaction profiles is limited. OBJECTIVES: This study aimed to evaluate GI adverse events among GLP-1 RA users and compare semaglutide, dulaglutide, liraglutide, and exenatide safety regarding the GI adverse reaction profile. METHODS: This retrospective cross-sectional analysis utilized real-world data on 10,328 adults with diabetes/obesity in the National Institutes of Health All of Us cohort. New GLP-1 RA users were identified, and GI adverse events were examined. Logistic regression determined factors associated with GI adverse events. RESULTS: The mean age of the study population was 61.4 ± 12.6 years, 65.7% were female, 51.3% were White, and they had a high comorbidity burden. Abdominal pain (57.6%) was the most common GI adverse event, followed by constipation (30.4%), diarrhea (32.7%), nausea and vomiting (23.4%), GI bleeding (15.9%), gastroparesis (5.1%), and pancreatitis (3.4%). Dulaglutide and liraglutide had higher rates of abdominal pain, constipation, diarrhea, and nausea and vomiting than semaglutide and exenatide. Liraglutide and exenatide had the highest pancreatitis (4.0% and 3.8%, respectively). Compared to semaglutide, dulaglutide and liraglutide had higher odds of abdominal pain, and nausea and vomiting. They also had higher odds of gastroparesis than semaglutide. No significant differences existed in GI bleeding or pancreatitis risks between the GLP-1 RAs. CONCLUSIONS: In this real-world cohort, GI adverse events were common with GLP-1 RAs. Differences in GI safety profiles existed between agents, with exenatide appearing safer than other GLP-1 RAs, except for gastroparesis. These findings can inform GLP-1 RA selection considering GI risk factors. Further studies are needed to evaluate the causal relationship and GLP-1 RA safety with concomitant medication use.

Machine learning algorithms to predict major adverse cardiovascular events in patients with diabetes.

BACKGROUND: Major Adverse Cardiovascular Events (MACE) are common complications of type 2 diabetes mellitus (T2DM) that include myocardial infarction (MI), stroke, and heart failure (HF). The objective of the current study was to predict MACE among T2DM patients. METHODS: Type 2 diabetes mellitus patients above 18 years old were recruited for the study from the All of Us Research Program. Eligible participants were those who took sodium-glucose cotransporter 2 inhibitors. Different Machine learning algorithms: including RandomForest (RF), XGBoost, logistic regression (LR), and weighted ensemble model (WEM) were employed. Clinical attributes, electrolytes and biomarkers were explored in predicting MACE. The feature importance was determined using mean decrease accuracy. RESULTS: Overall, 9, 059 subjects were included in the analyses, of which 5197 (57.4%) were females. The XGBoost Model demonstrated a prediction accuracy of 0.80 [0.78-0.82], which is higher as compared to the RF 0.78[0.76-0.80], the LR model 0.65 [0.62-0.67], and the WEM 0.75 [0.73-0.76], respectively. The classification accuracy of the models for stroke was more than 95%, which was higher than prediction accuracy for MI (∼85%), and HF (∼80%). Phosphate, blood urea nitrogen and troponin levels were the major predictors of MACE. CONCLUSION: The ML models had shown acceptable performance in predicting MACE in T2DM patients, except the LR model. Phosphate, blood urea nitrogen, and other electrolytes were important predictors of MACE, which is consistent between the individual components of MACE, such as stroke, MI, and HF. These parameters can be calibrated as prognostic parameters of MACE events in T2DM patients.

Application of Machine Learning Algorithms to Predict Uncontrolled Diabetes Using the All of Us Research Program Data.

There is a paucity of predictive models for uncontrolled diabetes mellitus. The present study applied different machine learning algorithms on multiple patient characteristics to predict uncontrolled diabetes. Patients with diabetes above the age of 18 from the All of Us Research Program were included. Random forest, extreme gradient boost, logistic regression, and weighted ensemble model algorithms were employed. Patients who had a record of uncontrolled diabetes based on the international classification of diseases code were identified as cases. A set of features including basic demographic, biomarkers and hematological indices were included in the model. The random forest model demonstrated high performance in predicting uncontrolled diabetes, yielding an accuracy of 0.80 (95% CI: 0.79-0.81) as compared to the extreme gradient boost 0.74 (95% CI: 0.73-0.75), the logistic regression 0.64 (95% CI: 0.63-0.65) and the weighted ensemble model 0.77 (95% CI: 0.76-0.79). The maximum area under the receiver characteristics curve value was 0.77 (random forest model), while the minimum value was 0.7 (logistic regression model). Potassium levels, body weight, aspartate aminotransferase, height, and heart rate were important predictors of uncontrolled diabetes. The random forest model demonstrated a high performance in predicting uncontrolled diabetes. Serum electrolytes and physical measurements were important features in predicting uncontrolled diabetes. Machine learning techniques may be used to predict uncontrolled diabetes by incorporating these clinical characteristics.

Strategic response to COVID-19 in Ethiopia.

COVID-19, the novel coronavirus, has posed a major threat to low- and middle-income countries (LMICs) due to inadequate health infrastructure and human resources. Ethiopia, a low-income country with the second largest population in Africa, has coordinated a strategic response, leveraging existing infrastructure and health systems and mobilizing public health professionals and specialist expert physicians for a multifaceted, unified government approach and adaptive response. Resource limitations, particularly in critical care, have still posed challenges, but the public health and clinical interventions thus far have prevented the catastrophic toll that many predicted. As the pandemic continues, Ethiopia expects to use a triple care model integrated at all levels, consisting of COVID-19 care, isolation care for suspected cases, and essential health services, and urges intensified non-pharmaceutical interventions alongside equitable global vaccine distribution as the ultimate answers to pandemic control. This paper draws on existing data, national planning and guidelines, and expertise from health leadership to describe this response in hopes of providing an example of how future large-scale health challenges might be faced in LMICs, using Ethiopia's successes and challenges in facing the pandemic.

COVID-19, le nouveau coronavirus, a représenté une menace majeure pour les pays à revenu faible et intermédiaire (LMIC) en raison de l'insuffisance des infrastructures de santé et des ressources humaines. L'Éthiopie, un pays à faible revenu dont la population est la deuxième plus importante d'Afrique, a coordonné une réponse stratégique, en tirant parti des infrastructures et des systèmes de santé existants et en mobilisant des professionnels de la santé publique et des médecins experts spécialisés pour une approche gouvernementale unifiée à multiples facettes et une réponse adaptative. Les ressources limitées, notamment en matière de soins intensifs, ont encore posé des problèmes, mais les interventions cliniques et de santé publique menées jusqu'à présent ont permis d'éviter le bilan catastrophique que beaucoup prédisaient. Alors que la pandémie se poursuit, l'Éthiopie prévoit d'utiliser un modèle de soins triple intégré à tous les niveaux, composé de soins COVID-19, de soins d'isolement pour les cas suspects et de services de santé essentiels, et préconise l'intensification des interventions non pharmaceutiques parallèlement à une distribution équitable des vaccins à l'échelle mondiale comme réponses ultimes au contrôle de la pandémie. Cet article s'appuie sur les données existantes, la planification et les directives nationales, et l'expertise des responsables de la santé pour décrire cette réponse dans l'espoir de fournir un exemple de la manière dont les futurs défis sanitaires à grande échelle pourraient être relevés dans les LMIC, en utilisant les succès et les défis de l'Éthiopie face à la pandémie.

Cost Effectiveness of Dapagliflozin Added to Standard of Care for the Management of Diabetic Nephropathy in the USA.

BACKGROUND: Angiotensin-converting enzyme inhibitors have been used as the standard of care for the treatment of diabetic nephropathy. Recently, dapagliflozin has been shown to reduce diabetic nephropathy when added to the standard of care. OBJECTIVE: The objective of this study was to determine the cost effectiveness of dapagliflozin added to the standard of care in diabetic nephropathy in the United States of America (USA). METHODS: A Markov model was developed to determine the cost-effectiveness outcomes from the Medicare/Medicaid health coverage perspective. Model inputs were derived from the literature. The primary outcomes were total costs, quality-adjusted life-years (QALYs), and the incremental cost-effectiveness ratio. Deterministic and probabilistic sensitivity analyses were performed to determine the robustness of our results. A willingness-to-pay threshold of $100,000 per QALY was applied, which is based on previous studies. RESULTS: Dapagliflozin yielded a lifetime QALY of 2.8. The discounted QALY associated with the standard of care was 2.6. The standard of care was the less costly treatment with a lifetime cost of $106,150.25 as compared with dapagliflozin, which costs $110,689.25. Dapagliflozin demonstrated an incremental cost-effectiveness ratio of $21,141.51 per additional QALY. The most influential parameters of the incremental cost-effectiveness ratio were the adverse drug reaction-related cost of the standard of care and dapagliflozin, the acquisition cost, and the adverse drug reaction-related cost of dapagliflozin. The effects and costs of the interventions were consistent between base-case analyses and the probabilistic model (incremental cost-effectiveness ratio: $19,023.35 [$13,637.8-$27,483.1]). CONCLUSIONS: Dapagliflozin added to the standard of care was cost effective relative to the standard of care alone in the USA for patients with diabetic nephropathy.

Degradable porous drug-loaded polymer scaffolds for localized cancer drug delivery and breast cell/tissue growth.

This paper presents the results of a combined experimental and analytical study of blended FDA-approved polymers [polylactic-co-glycolic acid (PLGA), polyethylene glycol (PEG) and polycaprolactone (PCL)] with the potential for sustained localized cancer drug release. Porous drug-loaded 3D degradable PLGA-PEG and PLGA-PCL scaffolds were fabricated using a multistage process that involved solvent casting and particulate leaching with lyophilization. The physicochemical properties including the mechanical, thermal and biostructural properties of the drug-loaded microporous scaffolds were characterized. The release of the encapsulated prodigiosin (PG) or paclitaxel (PTX) drug (from the drug-loaded polymer scaffolds) was also studied experimentally at human body temperature (37 °C) and hyperthermic temperatures (41 and 44 °C). These characteristic controlled and localized in vitro drug release from the properties of the microporous scaffold were analyzed using kinetics and thermodynamic models. Subsequently, normal breast cells (MCF-10A) were cultured for a 28-day period on the resulting 3D porous scaffolds in an effort to study the possible regrowth of normal breast tissue, following drug release. The effects of localized cancer drug release on breast cancer cells and normal breast cell proliferation are demonstrated for scenarios that are relevant to palliative breast tumor surgery for 16 weeks under in vivo conditions. Results from the in vitro drug release show a sustained anomalous (non-Fickian) drug release that best fits the Korsmeyer-Peppas (KP) kinetic model with a non-spontaneous thermodynamic process that leads to a massive decrease in breast cancer cell (MDA-MB-231) viability. Our findings from the animal suggest that localized drug release from drug-based 3D resorbable porous scaffolds can be used to eliminate/treat local recurred triple negative breast tumors and promote normal breast tissue regeneration after surgical resection.

Prescribing trend in cardiovascular patients at Ethiopian university hospital: The number of medications and implication on the clinical improvement.

Investigating the prescribing trend is important to improve rational prescribing. This study aimed at assessing the cardiovascular drug use, pattern, and its impact on clinical outcome. A cross-sectional study was employed in the outpatient department of chronic illness clinic of Gondar University specialized hospital, Ethiopia from 15 January 2017 to 15 March 2017. The independent variables were sociodemographic, medication, and other clinical information while cardiovascular disease improvement is the outcome variable. Binary logistic regression was used to test the association between the independent variables and the outcome variable. Kaplan Meier curve was used to analyze the clinical improvement while the Log-rank test was employed to compare the clinical outcome with the number of medications. Eight hundred thirty-three cardiovascular patient medical records were included in the final analysis. The majority (62.5%) of patients were females and more than 61% were above 50 years of age. Diuretics monotherapy accounted for a third (33.6%) of cardiovascular drug use, followed by combination therapy of angiotensin convertase enzyme inhibitors with Diuretics (21.8%) and calcium channel blockers with diuretics (8.3%). Cardiovascular patients followed for 72 months found to have a good level of clinical improvement on combination medication (Log Rank of 28.9, P = 0.000). In this study, diuretics monotherapy or in combination with angiotensin convertase enzyme inhibitors were found to be the frequently prescribed drugs in cardiovascular patients. Combination therapy has an implication for good cardiovascular improvement on long term follow-up. It seems clinicians were restricted to certain cardiovascular medications while plenty of choices are available from the diverse classes of cardiovascular drugs.

Patient Adherence to Novel Oral Anticoagulants (NOACs) for the Treatment of Atrial Fibrillation and Occurrence of Associated Bleeding Events: A Systematic Review and Meta-analysis.

BACKGROUND: Real-world evidence from published observational studies of adherence to Novel Oral Anticoagulants (NOACs) medications and associated clinical outcome events in Atrial Fibrillation (AF) patients, was reviewed systematically. METHODS: Observational studies assessing patient adherence to NOACs conducted on AF patients between September 2010 and June 2016 were identified by systematic searching keywords to locate eligible studies, in accordance with Cochrane guidelines. PubMed, Scopus and Google Scholar databases were searched to identify the studies. Meta-analysis was performed using a random effects model with DerSimonian-Laird weighting to obtain pooled effect sizes. RESULTS: From 185 potentially relevant citations, 6 studies, comprising 1.6 million AF patients, were included. Among these, successful adherence to NOACs occurred in 75.6%. Adherence levels were higher in patients treated with dabigatran (72.7%) compared with those treated with apixaban (59.9%) or rivaroxaban (59.3%). However, adherence was still suboptimal (relative to an expected 80% adherence rate). Bleeding events in non-adherent patients were found to be 7.5%. CONCLUSION: Suboptimal adherence to NOACs among AF patients was highlighted as a significant risk factor that may affect clinical outcomes, with a higher percentage of non-adherent patients having bleeding events. There is an urgent need for research on the effects of specific interventions to improve patient adherence to NOACs and to assess the related outcome factors that may be associated with adherence.

Metabolomics signatures associated with an oral glucose challenge in pregnant women.

AIM: The oral glucose tolerance test (OGTT), widely used as a gold standard for gestational diabetes mellitus (GDM) diagnosis, provides a broad view of glucose pathophysiology in response to a glucose challenge. We conducted the present study to evaluate metabolite changes before and after an oral glucose challenge in pregnancy; and to examine the extent to which metabolites may serve to predict GDM diagnosis in pregnant women. METHODS: Peruvian pregnant women (n=100) attending prenatal clinics (mean gestation 25 weeks) participated in the study with 23% of them having GDM diagnosis. Serum samples were collected immediately prior to and 2-hours after administration of a 75-g OGTT. Targeted metabolic profiling was performed using a LC-MS based metabolomics platform. Changes in metabolite levels were evaluated using paired Student's t-tests and the change patterns were examined at the level of pathways. Multivariate regression procedures were used to examine metabolite pairwise differences associated with subsequent GDM diagnosis. RESULTS: Of the 306 metabolites detected, the relative concentration of 127 metabolites were statistically significantly increased or decreased 2-hours after the oral glucose load (false discovery rate [FDR] corrected P-value<0.001). We identified relative decreases in metabolites in acylcarnitines, fatty acids, and diacylglycerols while relative increases were noted among bile acids. In addition, we found that C58:10 triacylglycerol (ß=-0.08, SE=0.04), C58:9 triacylglycerol (ß=-0.07, SE=0.03), adenosine (ß=0.70, SE=0.32), methionine sulfoxide (ß=0.36, SE=0.13) were significantly associated with GDM diagnosis even after adjusting for age and body mass index. CONCLUSIONS: We identified alterations in maternal serum metabolites, representing distinct cellular and metabolic pathways including fatty acid metabolism, in response to an oral glucose challenge. These findings offer novel perspectives on the pathophysiological mechanisms underlying GDM.

Xpert MTB/RIF assay for the diagnosis of extrapulmonary tuberculosis: a diagnostic evaluation study.

OBJECTIVES: The diagnosis of extrapulmonary tuberculosis (EPTB) is often made on clinical suspicion alone, resulting in both under- and overdiagnosis and relatively poor outcomes. In this study, we evaluated the clinical utility of the Xpert MTB/RIF on routinely collected extrapulmonary specimens in Ethiopia. METHODS: This study was carried out at Jimma University Specialized Hospital, Southwest Ethiopia. Extrapulmonary specimens were collected from 572 patients clinically suspected of suffering from EPTB. All specimens were tested for TB by smear microscopy, culture, and Xpert MTB/RIF. The diagnostic accuracy of Xpert MTB/RIF was calculated and compared to a composite reference standard (CRS), comprising clinical and laboratory results. RESULTS: In total, 572 extrapulmonary specimens (279 lymph node, 159 pleural, 80 peritoneal, 45 cerebrospinal, and nine pericardial fluids) were tested. The pooled sensitivity and specificity of Xpert MTB/RIF were calculated to be 75% (95% CI 70-80) and 98% (95% CI 97-100) respectively when compared to the CRS. The highest sensitivity was documented for lymph node specimens (90%; 95% CI 86-94), moderate sensitivity for cerebrospinal fluid (53%; 95% CI 28-79), while the sensitivity was lowest for pleural (30%; 95% CI 17-44) and peritoneal (32%; 95% CI 12-51) fluids. Xpert MTB/RIF in addition detected rifampicin resistance in 13 patients, in perfect agreement with results from the line probe assay. CONCLUSIONS: Xpert MTB/RIF may be used as initial diagnostic tool for testing of lymph node specimens from patients suspected of having TB lymphadenitis. The added value of Xpert MTB/RIF to diagnose pleural or peritoneal TB is limited by its poor sensitivity.

Magnitude and determinants of uncontrolled blood pressure among hypertensive patients in Ethiopia: hospital-based observational study.

BACKGROUND: Hypertension is an important public health problem worldwide. There is lack of data on uncontrolled blood pressure in developing countries. OBJECTIVES: To determine the magnitude and predicting factors of uncontrolled blood pressure in hypertensive patients attending Gondar university hospital, Ethiopia. METHODS: A hospital-based cross-sectional survey was conducted from July 2015 to March 2016. All hypertensive patients were followed and the blood pressure levels were measured. Binary logistic regression analysis was done to determine the predictors of uncontrolled blood pressure. A p-value of <0.05 was set at priori with 95% confidence interval to test the level of significance. RESULTS: Of the total 578 hypertension patients, 543 (93.9%) fulfilled the study criteria and were included in the final analysis. The mean age of the participants was 55.96±14.6 years. Nearly two-third (58.2%) of the participants were females. More than one-tenth (11.4%) of the respondents had uncontrolled blood pressure. High salt intake carried six times more risk of uncontrolled blood pressure. Elderly individuals had lower risk as compared to young age group. However, comorbidities were not related with uncontrolled blood pressure. CONCLUSIONS: Blood pressure control was relatively high in the hospital studied. High salt intake was strongly linked with uncontrolled blood pressure. Individuals with high salt intake should be followed for their medication experience and disease knowledge.

Magnitude and determinants of uncontrolled blood pressure among hypertensive patients in Ethiopia: hospital-based observational study

Background: Hypertension is an important public health problem worldwide. There is lack of data on uncontrolled blood pressure in developing countries. Objectives: To determine the magnitude and predicting factors of uncontrolled blood pressure in hypertensive patients attending Gondar university hospital, Ethiopia. Methods: A hospital-based cross-sectional survey was conducted from July 2015 to March 2016. All hypertensive patients were followed and the blood pressure levels were measured. Binary logistic regression analysis was done to determine the predictors of uncontrolled blood pressure. A p-value of <0.05 was set at priori with 95% confidence interval to test the level of significance. Results: Of the total 578 hypertension patients, 543 (93.9%) fulfilled the study criteria and were included in the final analysis. The mean age of the participants was 55.96±14.6 years. Nearly two-third (58.2%) of the participants were females. More than one-tenth (11.4%) of the respondents had uncontrolled blood pressure. High salt intake carried six times more risk of uncontrolled blood pressure. Elderly individuals had lower risk as compared to young age group. However, comorbidities were not related with uncontrolled blood pressure. Conclusions: Blood pressure control was relatively high in the hospital studied. High salt intake was strongly linked with uncontrolled blood pressure. Individuals with high salt intake should be followed for their medication experience and disease knowledge

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Novel genomic targets in oxidant-induced vascular injury.

To study the complex interaction between oxidative injury and the pathogenesis of vascular disease, vascular gene expression was examined in male Sprague-Dawley rats given 35 or 70 mg/kg allylamine, a synthetic amine converted to acrolein and hydrogen peroxide within the vascular wall. Vascular lesions and extensive vascular remodeling, coupled to increased production of 8-epi-PGF2alpha, nuclear localization of NFkappaB, and alterations in glutathione homeostasis, were observed in animals treated with allylamine for up to 20 days. Transcriptional profiling, immunohistochemistry, and in situ hybridization showed that genes involved in adhesion and extracellular matrix (ECM) (alpha(1) integrin, collagen), cytoskeletal rearrangements (alpha-smooth muscle actin, alpha-tropomyosin), and signal transduction (NFkappaB, osteopontin, and LINE) were altered by oxidant treatment. To evaluate mechanisms of gene dysregulation, cultured aortic smooth muscle cells were challenged with allylamine or its metabolites and processed for molecular analysis. These agents increased formation of reactive oxygen species and elicited changes in gene expression similar to those observed in vivo. Oxidative stress and changes in gene expression were inhibited by N-acetyl cysteine, a precursor of glutathione. These results indicate that genes along the ECM-integrin-cytoskeletal axis, in addition to LINE, are molecular targets in oxidant-induced vascular injury.

Genomic profiles and predictive biological networks in oxidant-induced atherogenesis.

Atherogenic stimuli trigger complex responses in vascular smooth muscle cells (VSMCs) that culminate in activation/repression of overlapping signal transduction cascades involving oxidative stress. In the case of benzo[a]pyrene (BaP), a polycyclic aromatic hydrocarbon present in tobacco smoke, the atherogenic response involves interference with redox homeostasis by oxidative intermediates of BaP metabolism. The present studies were conducted to define genomic profiles and predictive gene biological networks associated with the atherogenic response of murine (aortic) VSMCs to BaP. A combined oxidant-antioxidant treatment regimen was used to identify redox-sensitive targets during the early course of the atherogenic response. Gene expression profiles were defined using cDNA microarrays coupled to analysis of variance and several clustering methodologies. A predictor algorithm was then applied to gain insight into critical gene-gene interactions during atherogenesis. Supervised and nonsupervised analyses identified clones highly regulated by BaP, unaffected by antioxidant, and neutralized by combined chemical treatments. Lymphocyte antigen-6 complex, histocompatibility class I component factors, secreted phosphoprotein, and several interferon-inducible proteins were identified as novel redox-regulated targets of BaP. Predictor analysis confirmed these relationships and identified immune-related genes as critical molecular targets of BaP. Redox-dependent patterns of gene deregulation indicate that oxidative stress plays a prominent role during the early stages of BaP-induced atherogenesis.

Lack of effect of gender on retinopathy in the mouse.

BACKGROUND: The reported effect of gender on retinopathy of prematurity has been controversial. The goal of this study was to determine the effect of gender on oxygen-induced retinopathy in a mouse model. METHODS: Oxygen-induced retinopathy was produced in C57BL6 mice by exposure to 75% oxygen from postnatal day (P) 7 for 5 days. Animals were returned to room air on P12 and killed on P17-21. Gender was determined by inspection. Retinopathy was evaluated by a retinopathy scoring system and by quantifcation of extraretinal neovascular nuclei on retinal sections. RESULTS: Both males and females developed similar degrees of retinopathy. Males had a median total retinopathy score of 9 (25th, 75th quartile: 8, 11) and females had score of 9 (25th, 75th quartile: 7, 10). Retinal subscores of blood vessel growth, blood vessel tufts, extraretinal neovascularzation, haemorrhage and blood vessel tortuosity were similar in both groups. Males and females had a similar number of neovascular nuclei on retinal sections. CONCLUSIONS: Gender does not alter the development of oxygen-induced retinopathy in the C57BL6 mouse.

Captopril improves retinal neovascularization via endothelin-1.

PURPOSE: The purpose of this study was to determine the effect of an angiotensin converting enzyme inhibitor, captopril, on oxygen-induced retinopathy (OIR) in the mouse. Endothelin-1 (ET-1) expression is assessed in a mouse model of OIR. METHODS: OIR was produced in C57BL6 mice. Captopril (0.5mg/kg/d SC) was given from P7 (post natal day 7) for 5 days. Retinopathy was assessed by a retinal scoring system and by quantification of extra retinal neovascular nuclei on retinal sections at P17 to P20. The expression of ET-1 was determined using a reverse transcriptase polymerase chain reaction. RESULTS: Pups treated with captopril during hyperoxia had a lower median retinopathy score of 4.5 (25th, 75th quartile: 3, 6.4) compared with animals exposed to hyperoxia alone with median score 9.5 (25th, 75th quartile: 7.1, 10.4; P < 0.001). The pups treated with captopril during hyperoxia had significant reduction in number of nuclei extending beyond the inner limiting membrane (15.8 +/- 16.7, mean +/- SD) when compared with the animals exposed to hyperoxia only (50.4 +/- 28.0; P < 0.01). ET-1 expression in the retina increased 4.1-fold from P7 to P12 and a 1.9-fold increase from P12 to P17. Overall, there was an 8-fold increase in ET-1 expression from P7 to P17. Hyperoxia increased ET-1 expression by 2.1-fold at P12 over room air-reared animals. At P17, there was a 2.9-fold increase in retinal ET-1 expression when compared with room air. At P17, there was a 6.2-fold suppression in ET-1 expression in captopril-treated animals when compared with the oxygen only-treated animals. CONCLUSIONS: Captopril reduces retinal neovascularization in a mouse model of oxygen-induced retinopathy. ET-1 expression is increased from P7 to P17, altered by hyperoxic exposure and relative hypoxic recovery and modulated by captopril in a mouse model of OIR.

Dexamethasone alters TNF-alpha expression in retinopathy.

TNF-alpha has been found in the retina. Hyperoxia and hypoxia regulate TNF-alpha expression. TNF-alpha is an important factor in inflammation and angiogenesis. Dexamethasone inhibits TNF-alpha production. Changes in TNF-alpha expression in the retina may play an important role in the development of oxygen-induced retinopathy. Oxygen-induced retinopathy was produced in C57BL6 mice by exposure to 75% oxygen at Postnatal Day 7 (P7) for 5 days and the mice recovered in room air until Day 17 (P17). Dexamethasone was administered at 0.5 mg/kg/day once daily subcutaneously during the 5 days of oxygen exposure. TNF-alpha expression was evaluated at Day 7 prior to oxygen exposure, at Day 12 (P12) immediately upon removal from oxygen, and at Day 17, the time of maximal vasoproliferation by RT-PCR. TNF-alpha is developmentally regulated in the retinae of C57BL6 mice. From P7 to P12, there is a 3-fold increase in TNF-alpha expression and from P7 to P17 there is a 2.7-fold increase. There was 2.7-fold suppression in expression immediately following oxygen exposure at P12. The expression was dramatically increased at P17, the time of maximal vasoproliferation. Dexamethasone inhibited the expression of TNF-alpha at P17 by 6.4-fold. At this dose, it also suppressed the baseline TNF-alpha expression in the mouse model. In summary, TNF-alpha is altered in the development of oxygen-induced retinopathy in the mouse. It increased markedly during the vasoproliferative phase and was suppressed by dexamethasone. Modulation of TNF-alpha expression may provide a potential site of action for future therapeutic targets.

Dexamethasone and critical effect of timing on retinopathy.

PURPOSE: Administration of corticosteroids soon after birth has been reported to have deleterious, protective, and no effect on retinopathy of prematurity. Conflicting results may be due to timing of corticosteroid administration. The goal of this study was to determine effects of pretreatment and late dexamethasone on retinopathy in a mouse model. METHODS: The C57BL6 mouse model of oxygen-induced retinopathy (by placing animals in 75% oxygen from postnatal days 7 through 12) was used to create retinal neovascularization. Dexamethasone at 0.5 mg/kg per day was administered from day 1 through day 5 in the pretreatment group. The late-treatment group received 5 days of dexamethasone at the same dose beginning on day 12. Mice were killed at days 17 through 20, and retinal vasculature was assessed by a retinal scoring system of wholemount preparation after high-molecular-weight fluorescein-labeled dextran perfusion. In addition, retinal neovascularization was assessed by quantification of extraretinal neovascular nuclei in retinal sections. Statistical significance was defined as P: < 0.05 and was determined by the Kruskal-Wallis test, Mann-Whitney test, and Student's t-test. RESULTS: Oxygen-exposed animals that received treatment with dexamethasone before oxygen exposure had an improvement in retinopathy, with a median score of 6 (5,7; 25th,75th quartiles) compared with 10 (8,11) in the untreated oxygen-exposed (P: < 0.05). The group treated late (after oxygen exposure) with dexamethasone had a median score of 10 (9,11). Pretreatment reduced extraretinal vascularization, when assessed by quantification of neovascular nuclei, to a mean +/- SEM of 19 +/- 9, significantly less than in the untreated oxygen-exposed group (55 +/- 12; P: < 0.05). No difference was observed in the late-treatment group when compared with the untreated oxygen-exposed group. Significant growth retardation, indicated by body weight, was observed in the pretreatment (P: < 0.01) and late-treatment (P: < 0. 05) groups when compared with the control group. CONCLUSIONS: Timing of dexamethasone administration was critical to the inhibition of development of retinopathy in the mouse model. Degree of growth retardation, measured by body weight, also appeared to be time dependent. These data may explain the different results of clinical observations with respect to corticosteroid treatment, timing, and development of retinopathy.