Abstract: PURPOSE: To test the hypotheses that, in mice, breathing carbogen (95% O(2)-5% CO(2)) oxygenates the retina better than breathing 100% oxygen, the superior hemiretinal oxygenation response to carbogen inhalation is subnormal early in diabetes, and diabetes-induced elevation of retinal protein kinase C (PKC)-beta contributes to this pathophysiology. METHODS: Retinal oxygenation response (DeltaPO(2)) was measured using functional magnetic resonance imaging (MRI) and either carbogen or 100% oxygen inhalation challenge in C57BL/6J control (C) mice. Retinal DeltaPO(2) during carbogen breathing was also measured in PKCbeta knockout (C57BL6-Prkcb1; [KO]), 4 month C57BL/6J diabetic (D), and 4-month diabetic PKCbeta KO (D+KO) mice. Retinal PKCbeta protein expression was assessed by Western analysis. RESULTS: In C mice, retinal DeltaPO(2) during carbogen breathing was significantly greater (P < 0.05) than during oxygen breathing. In D mice, DeltaPO(2) during carbogen breathing was significantly lower than normal in the superior, but not the inferior, hemiretina and was normal (P > 0.0 5) in the KO group. In the D+KO mice DeltaPO(2) was normal (P > 0.05) only at distances less than 1.5 mm from the optic nerve head. PKCbeta expression was elevated in the retina in diabetes (P < 0.05), but was significantly decreased (P < 0.05) in D+KO mice. CONCLUSIONS: The present study confirms that, in the mouse, retinal DeltaPO(2) patterns during different inhalation challenges or in the presence of diabetes are similar to what has been reported in rats. Diabetes-induced elevation of PKC appears to contribute only focally to subnormal retinal DeltaPO(2). This raises the possibility that PKC inhibition therapy may be only regionally effective in treating retinal pathophysiology associated with diabetic retinopathy.
Title: Effect of PKCbeta on retinal oxygenation response in experimental diabetes.
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Answer: 


Experimentally induced diabetes

Abstract: AIMS/HYPOTHESIS: Patients with Type II (non-insulin-dependent) diabetes mellitus are at increased risk of macrovascular and microvascular disease, both of which are reduced by controlling raised blood pressure in hypertensive patients. Intensive glycaemic control has also been shown to reduce microvascular disease but the effects on macrovascular disease remain uncertain. This study will examine the hypotheses that lowering blood pressure with an ACE inhibitor-diuretic combination and intensively controlling gylcaemia with a sulphonylurea-based regimen in high-risk patients with Type II diabetes (both hypertensive and non-hypertensive) reduces the incidence of macrovascular and microvascular disease. METHODS: The study is a 2 x 2 factorial randomised controlled trial that will include 10000 adults with Type II diabetes at high risk of vascular disease. Following 6 weeks on open label perindopril-indapamide combination, eligible patients are randomised to continued perindopril-indapamide or matching placebo, and to an intensive gliclazide MR-based glucose control regimen or usual guidelines-based therapy. Primary outcomes are, first, the composite of nonfatal stroke, non-fatal myocardial infarction or cardiovascular death and, second, the composite of new or worsening nephropathy or diabetic eye disease. The scheduled average duration of treatment and follow-up is 4.5 years. The study will be conducted in approximately 200 centres in Australasia, Asia, Europe and North America. CONCLUSION/INTERPRETATION: ADVANCE is designed to provide reliable evidence on the balance of benefits and risks conferred by blood pressure lowering therapy and intensive glucose control therapy in high-risk diabetic patients, regardless of initial blood pressure or glucose concentrations.
Title: Study rationale and design of ADVANCE: action in diabetes and vascular disease--preterax and diamicron MR controlled evaluation.
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Answer: 


Type 2 diabetes
