Citations

The objective of the present study was to examine the effect of direct expansion of the renal interstitial volume on sodium reabsorption by proximal tubules of superficial and deep nephrons in the absence of systemic extracellular volume expansion. Renal interstitial volume expansion was achieved by injection of 50 microliter of 2.5% albumin in 0.9% saline into the renal interstitium via a polyethylene matrix that was chronically implanted in the interstitium of the rat kidney. Renal interstitial volume expansion increased renal interstitial hydrostatic pressure from 3.8 +/- 0.5 to 6.8 +/- 1.1 mmHg, P less than 0.05 (n = 5 rats). Fractional reabsorption of sodium by the superficial late proximal tubule decreased from 45.7 +/- 5.6 to 34.2 +/- 5.4%, P less than 0.05, and by the proximal tubule and descending limb of Henle's loop of deep nephrons it decreased from 73.9 +/- 2.9 to 57.2 +/- 6.3%, P less than 0.05 (n = 8 rats). Thus expansion of the renal interstitial volume increased renal interstitial hydrostatic pressure and decreased sodium reabsorption by the proximal tubules of superficial and deep nephrons.

The purpose of this study was to investigate the hypothesis that changes in renal perfusion pressure may be transmitted to the renal interstitium and cause alterations in renal interstitial hydrostatic pressure and sodium excretion. A method that utilizes a chronically implanted polyethylene matrix that allows for direct continuous measurement of renal interstitial hydrostatic pressure, and agrees well with subcapsular measurement in rats, was developed. Renal interstitial hydrostatic pressure, fractional excretion of sodium, and urine flow rate were 3.0 +/- 0.3 mmHg, 0.35 +/- 0.13%, and 19.44 +/- 3.00 microliter/min, respectively, when renal perfusion pressure was 101 +/- 0.8 mmHg. When renal perfusion pressure was increased to 123 +/- 0.9 mmHg renal interstitial hydrostatic pressure, fractional excretion of sodium, and urine flow rate increased significantly to 5.8 +/- 0.6 mmHg, 1.29 +/- 0.29%, and 50.76 +/- 8.83 microliter/min, respectively, in anesthetized male Sprague-Dawley rats. These changes occur despite a well-autoregulated glomerular filtration rate and renal blood flow. In conclusion, increasing renal perfusion pressure caused a significant increase in renal interstitial hydrostatic pressure as measured directly by the implanted polyethylene matrix method and was associated with a significant increase in sodium excretion.

Abstract Aims This study was designed to evaluate the safety, tolerability and haemodynamic effects of BMS-986231, a novel second-generation nitroxyl donor with potential inotropic, lusitropic and vasodilatory effects in patients hospitalized with decompensated heart failure and reduced ejection fraction (HFrEF). Methods and results Forty-six patients hospitalized with decompensated HFrEF were enrolled into four sequential dose-escalation cohorts in this double-blind, randomized, placebo-controlled Phase 2a study. Patients with baseline pulmonary capillary wedge pressure (PCWP) of ≥20 mmHg and a cardiac index of ≤2.5 L/min/m2 received one 6-h i.v. infusion of BMS-986231 (at 3, 5, 7 or 12 µg/kg/min) or placebo. BMS-986231 produced rapid and sustained reductions in PCWP, as well as consistent reductions in time-averaged pulmonary arterial systolic pressure, pulmonary arterial diastolic pressure and right atrial pressure. BMS-986231 increased non-invasively measured time-averaged stroke volume index, cardiac index and cardiac power index values, and decreased total peripheral vascular resistance. There was no evidence of increased heart rate, drug-related arrhythmia or symptomatic hypotension with BMS-986231. Analyses of adverse events throughout the 30-day follow-up did not identify any toxicities specific to BMS-986231, with the potential exception of infrequent mild-to-moderate headaches during infusion. There were no treatment-related serious adverse events. Conclusions BMS-986231 demonstrated a favourable safety and haemodynamic profile in patients hospitalized with advanced heart failure. Based on preclinical data and these study's findings, it is possible that the haemodynamic benefits may be mediated by inotropic and/or lusitropic as well as vasodilatory effects. The therapeutic potential of BMS-986231 should be further assessed in patients with heart failure.

Instability after total knee replacement (TKR) accounts for 10% to 22% of revision procedures. All patients who present for evaluation of instability require a thorough history to be taken and physical examination, as well as appropriate imaging. Deep periprosthetic infection must be ruled out by laboratory testing and an aspiration of the knee must be carried out. The three main categories of instability include flexion instability, extension instability (symmetric and asymmetric), and genu recurvatum. Most recently, the aetiologies contributing to, and surgical manoeuvres required to correct, flexion instability have been elucidated. While implant design and patient-related factors may certainly contribute to the aetiology, surgical technique is also a significant factor in all forms of post-operative instability.Cite this article: Bone Joint J 2014;96-B(11 Suppl A):112–4.

AbstractWith increasing numbers of people with Alzheimer's and other dementias across the globe, many countries have developed national plans to deal with the resulting challenges. In the United States, the National Alzheimer's Project Act, signed into law in 2011, required the creation of such a plan with annual updates thereafter. Pursuant to this, the US Department of Health and Human Services (HHS) released the National Plan to Address Alzheimer's Disease in 2012, including an ambitious research goal of preventing and effectively treating Alzheimer's disease by 2025. To guide investments, activities, and the measurement of progress toward achieving this 2025 goal, in its first annual plan update (2013) HHS also incorporated into the plan a set of short, medium and long‐term milestones. HHS further committed to updating these milestones on an ongoing basis to account for progress and setbacks, and emerging opportunities and obstacles. To assist HHS as it updates these milestones, the Alzheimer's Association convened a National Plan Milestone Workgroup consisting of scientific experts representing all areas of Alzheimer's and dementia research. The workgroup evaluated each milestone and made recommendations to ensure that they collectively constitute an adequate work plan for reaching the goal of preventing and effectively treating Alzheimer's by 2025. This report presents these Workgroup recommendations.

Abstract—Chronic intravenous infusion of subpressor doses of angiotensin II causes blood pressure to increase progressively over the course of several days. The mechanisms underlying this response, however, are poorly understood. Because high-dose angiotensin II increases oxidative stress, and some compounds that result from the increased oxidative stress (eg, isoprostanes) produce vasoconstriction and antinatriuresis, we tested the hypothesis that a subpressor dose of angiotensin II also increases oxidative stress, as measured by 8-epi-prostaglandin F2α(isoprostanes), which may contribute to the slow pressor response to angiotensin II. To test this hypothesis, we infused angiotensin II (10 ng/kg per minute for 28 days via an osmotic pump) into 6 conscious normotensive female pigs (30 to 35 kg). We recorded mean arterial pressure continuously with a telemetry system and measured plasma isoprostanes before starting the angiotensin II infusion (baseline) and again after 28 days with an enzyme immunoassay. Angiotensin II infusion significantly increased mean arterial pressure from 121±4 to 153±7 mm Hg (P<0.05) without altering total plasma isoprostane levels (180.0±24.3 versus 147.0±29.2 pg/mL;P=NS). However, the plasma concentrations of free isoprostanes increased significantly, from 38.3±5.8 to 54.7±10.4 pg/mL (P<0.05). These results suggest that subpressor doses of angiotensin II increase oxidative stress, as implied by the increased concentration of free isoprostanes, which accompany the elevation in mean arterial pressure elevation. Thus, isoprostane-induced vasoconstriction and antinatriuresis may contribute to the hypertension induced by the slow pressor responses of angiotensin II.