153 research outputs found

    Dual A 1 /A 2B Receptor Blockade Improves Cardiac and Renal Outcomes in a Rat Model of Heart Failure with Preserved Ejection Fraction

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    ABSTRACT Heart failure with preserved ejection fraction (HFpEF) is prevalent and often accompanied by metabolic syndrome. Current treatment options are limited. Here, we test the hypothesis that combined A 1 /A 2B adenosine receptor blockade is beneficial in obese ZSF 1 rats, an animal model of HFpEF with metabolic syndrome. The combined A 1 /A 2B receptor antagonist 3-[4-(2,6-dioxo-1,3-dipropyl-7H-purin-8-yl)-1-bicyclo[2.2.2]octanyl]propanoic acid (BG9928) was administered orally (10 mg/kg/day) to obese ZSF 1 rats (n 5 10) for 24 weeks (from 20 to 44 weeks of age). Untreated ZSF 1 rats (n 5 9) served as controls. After 24 weeks of administration, BG9928 significantly lowered plasma triglycerides (in mg/dl: control group, 4351 6 550; BG9928 group, 2900 6 551) without adversely affecting plasma cholesterol or activating renin release. BG9928 significantly decreased 24-hour urinary glucose excretion (in mg/kg/day: control group, 823 6 179; BG9928 group, 196 6 80) and improved oral glucose tolerance, polydipsia, and polyuria. BG9928 significantly augmented left ventricular diastolic function in association with a reduction in cardiac vasculitis and cardiac necrosis. BG9928 significantly reduced 24-hour urinary protein excretion (in mg/kg/ day: control group, 1702 6 263; BG9928 group, 1076 6 238), and this was associated with a reduction in focal segmental glomerulosclerosis, tubular atrophy, tubular dilation, and deposition of proteinaceous material in the tubules. These findings show that, in a model of HFpEF with metabolic syndrome, A 1/ A 2B receptor inhibition improves hyperlipidemia, exerts antidiabetic actions, reduces HFpEF, improves cardiac histopathology, and affords renal protection. We conclude that chronic administration of combined A 1/ A 2B receptor antagonists could be beneficial in patients with HFpEF, in particular those with comorbidities such as obesity, diabetes, and dyslipidemias

    The Relationship of Age and Other Baseline Factors to Outcome of Initial Surgery for Intermittent Exotropia

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    Purpose: To determine whether age at surgery is associated with surgical outcome of intermittent exotropia (IXT) at 3 years. Design: Secondary analysis of pooled data from a randomized trial. Methods: A total of 197 children 3 to <11 years of age with basic-type IXT of 15-40 prism diopters (Δ) were randomly assigned to 1 of 2 surgical procedures for treatment of intermittent exotropia. Masked examinations were conducted every 6 months for 3 years. The primary outcome was suboptimal surgical outcome by 3 years, defined as constant or intermittent exotropia of ≥10 Δ at distance or near by simultaneous prism and cover test (SPCT); constant esotropia of ≥6 Δ at distance or near by SPCT; or decrease in near stereoacuity of ≥2 octaves, at any masked examination; or reoperation without meeting any of these criteria. Results: The cumulative probability of a suboptimal surgical outcome by 3 years was 28% (19 of 72) for children 3 to <5 years of age, compared with 50% (57 of 125) for children 5 to <11 years of age (adjusted hazard ratio = 2.05; 95% confidence interval = 1.16 to 3.60). No statistically significant associations were found between suboptimal outcome and other baseline factors (magnitude of deviation, control score, fixation preference, or near stereoacuity) (P values ≥ .20). Conclusions: This analysis suggests that in children with IXT, younger age at surgery (3 to <5 years) is associated with better surgical outcomes; however, further evidence from a randomized trial comparing immediate with delayed surgery is needed for confirmation

    Prdm5 Regulates Collagen Gene Transcription by Association with RNA Polymerase II in Developing Bone

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    PRDM family members are transcriptional regulators involved in tissue specific differentiation. PRDM5 has been reported to predominantly repress transcription, but a characterization of its molecular functions in a relevant biological context is lacking. We demonstrate here that Prdm5 is highly expressed in developing bones; and, by genome-wide mapping of Prdm5 occupancy in pre-osteoblastic cells, we uncover a novel and unique role for Prdm5 in targeting all mouse collagen genes as well as several SLRP proteoglycan genes. In particular, we show that Prdm5 controls both Collagen I transcription and fibrillogenesis by binding inside the Col1a1 gene body and maintaining RNA polymerase II occupancy. In vivo, Prdm5 loss results in delayed ossification involving a pronounced impairment in the assembly of fibrillar collagens. Collectively, our results define a novel role for Prdm5 in sustaining the transcriptional program necessary to the proper assembly of osteoblastic extracellular matrix

    The genetic architecture of aniridia and Gillespie syndrome

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