Hypercalcemia stimulates expression of intrarenal phospholipase A2 and prostaglandin H synthase-2 in rats. Role of angiotensin II AT1 receptors.

In chronic hypercalcemia, inhibition of thick ascending limb sodium chloride reabsorption is mediated by elevated intrarenal PGE2. The mechanisms and source of elevated PGE2 in hypercalcemia are not known. We determined the effect of hypercalcemia on intrarenal expression of cytosolic phospholipase A2 (cPLA2), prostaglandin H synthase-1 (PGHS-1), and prostaglandin H synthase-2 (PGHS-2), enzymes important in prostaglandin production. In rats fed dihydrotachysterol to induce hypercalcemia, Western blot analysis revealed significant upregulation of both cPLA2 and PGHS-2 in the kidney cortex and the inner and outer medulla. Immunofluorescence localized intrarenal cPLA2 and PGHS-2 to interstitial cells of the inner and outer medulla, and to macula densa and cortical thick ascending limbs in both control and hypercalcemic rats. Hypercalcemia had no effect on intrarenal expression of PGHS-1. To determine if AT1 angiotensin II receptor activation was involved in the stimulation of cPLA2 and PGHS-2 in hypercalcemia, we treated rats with the AT1 receptor antagonist, losartan. Losartan abolished the polydipsia associated with hypercalcemia, prevented the increase in cPLA2 protein in all regions of the kidney, and diminished PGHS-2 expression in the inner medulla. In addition, losartan completely prevented the increase in urinary PGE2 excretion in hypercalcemic rats. Intrarenal levels of angiotensin II were unchanged in hypercalcemia. These data indicate that hypercalcemia stimulates intrarenal cPLA2 and PGHS-2 protein expression. Our results further support a role for angiotensin II, acting on AT1 receptors, in mediating this stimulation.     

Efficacy of Ozurdex implant in recalcitrant diabetic macular edema—a single-center experience

The purpose of this study is to report the efficacy of intravitreal Ozurdex implant in managing recalcitrant diabetic macular edema. Retrospective interventional non-randomized study of patients with recalcitrant diabetic macular edema who received intravitreal Ozurdex implant. Main outcome measures were change in the central macular thickness, visual acuity, and intraocular pressure. Sixty-seven eyes of 52 patients with recalcitrant diabetic macular edema with a mean duration of 45.4 ± 22.5 months (range 6–96 months) were studied. Mean central macular thickness decreased from 514.2 ± 177.8 µm at baseline to 394.3 ± 152.2 µm (p = 0.007), 301.8 ± 93.0 µm (p < 0.000), 316.4 ± 115.6 µm (p < 0.000), and 419.9 ± 186.3 µ (p = 0.03) at 1, 6, 12, and 24 weeks, respectively. Mean best corrected visual acuity changed from 0.82 ± 0.46 log MAR to 0. 69 ± 0.44 log MAR (p = 0.122), 0.61 ± 0.40 log MAR (p = 0.007), 0.65 ± 0.37 log MAR (p = 0.024), and 0.68 ± 0.49 log MAR (p = 0.091) at 1, 6, 12, and 24 weeks, respectively. Single injection of intravitreal Ozurdex implant led to progressive decrease in central macular thickness with maximum percentage decrease at 6 weeks (41.2 %) from the baseline which was maintained up to 12 weeks. Eight eyes showed transient rise in intraocular pressure at 2 months which was controlled by antiglaucoma medications.     

Evaluation and management of atrial fibrillation

Atrial fibrillation (AF) is the most common clinically encountered arrhythmia affecting 0.4% of the general population. Its prevalence increases with age, affecting more than 6% of people over 80 years of age. The annual risk of ischemic stroke in patients with lone AF is approximately 1.3%. This annual risk increases up to 10% -12% in patients with a prior stroke or transient ischemic attack. Randomized clinical trials (RCT) comparing adjusted-dose oral anticoagulation and placebo showed a risk reduction of 61% (95% CI 47% to 71%). The absolute risk reduction for stroke with oral anticoagulants is about 3% per year. Aspirin has been shown in meta-analyses to have on average a 20-25% relative risk reduction, and is inferior to oral anticoagulants. In high risk patients with AF warfarin is a class I ACC/AHA indication unless there is a contraindication for anticoagulation. Unfortunately, this therapy requires frequent monitoring with blood samples and the interaction with food and several medications makes its use difficult and sometimes unreliable. It requires strict patient compliance and its use is also linked to potentially serious bleeding complications. In clinical practice, less than 60% of patients who do not have contraindications to oral anticoagulation are actually receiving them. Additionally, of those that receive oral anticoagulation, less than 50% are consistently within therapeutic targets. As such, the "real world" efficacy of a strategy towards prescribing oral anticoagulants is likely significantly lower than that demonstrated in clinical trials. As such, the need to discover other methods of anticoagulation with oral bioavailability, predictable pharmacokinetics, and minimal interactions with diet and other pharmacological agents is imperative. Low molecular weight heparin has a more predictable bioavailability and a longer half-life, but its subcutaneous mode of administration and long-term risks, in particular, osteoporosis makes the chronic use of this medication non-feasible. Antiplatelet agents such as clopidogrel have proven efficacy and superiority compared to aspirin to prevent systemic vascular events in at-risk patient populations, but currently they do not play an important role in the prevention of AF related thromboembolic events. The ACTIVE study is a randomized trial comparing the combination of clopidogrel and aspirin therapy to oral anticoagulation with warfarin in patients with AF, and was unfortunately terminated prematurely by the data safety and monitoring board because of increased events in the antiplatelet arm. Direct thrombin inhibitors, such as ximelagatran, may be as effective as warfarin for stroke-risk reduction in patients with AF. No anticoagulation monitoring is needed and it has excellent bioavailability, with a twice-daily oral dose. Elevation of liver enzymes was an initial concern regarding the use of this new drug, which is not available for general use. Ongoing pharmacological research and future clinical trials may one day leave the "warfarin days" behind. Unfortunately, the new therapies that are being tested seem to be at least several years away from being available on a widespread basis. In this review, we discuss the underlying pathophysiology of AF and stroke. We also provide a comprehensive discussion regarding various available therapies to treat AF.     

An unusual systemic presentation of gout

An elderly female presented with a systemic febrile illness and acute polyarthritis as the first manifestation of gout. She improved dramatically with anti-inflammatory therapy.     

The Accuracy of Colorectal Cancer Detection by Computed Tomography in the Unprepared Large Bowel in a Community-Based Hospital

Purpose

This retrospective study examined the performance of general radiologists in a community-based hospital in detecting colorectal cancer (CRC) with computed tomography (CT) in the unprepared large bowel.