Superparamagnetic iron oxide polyacrylic acid coated {\gamma}-Fe2O3 nanoparticles does not affect kidney function but causes acute effect on the cardiovascular function in healthy mice

This study describes the distribution of intravenously injected polyacrylic acid (PAA) coated {\gamma}-Fe2O3 NPs (10 mg kg-1) at the organ, cellular and subcellular levels in healthy BALB/cJ mice and in parallel addresses the effects of NP injection on kidney function, blood pressure and vascular contractility. Magnetic resonance imaging (MRI) and transmission electron microscopy (TEM) showed accumulation of NPs in the liver within 1h after intravenous infusion, accommodated by intracellular uptake in endothelial and Kupffer cells with subsequent intracellular uptake in renal cells, particularly the cytoplasm of the proximal tubule, in podocytes and mesangial cells. The renofunctional effects of NPs were evaluated by arterial acid-base status and measurements of glomerular filtration rate (GFR) after instrumentation with chronically indwelling catheters. Arterial pH was 7.46 and 7.41 in mice 0.5 h after injections of saline or NP, and did not change over the next 12h. In addition, the injections of NP did not affect arterial PCO2 or [HCO3-] either. Twenty-four and 96h after NP injections, the GFR averaged 11.0 and 13.0 ml min-1 g-1, respectively, values which were statistically comparable with controls (14.0 and 14.0 ml min-1 g-1). Mean arterial blood pressure (MAP) decreased 12-24h after NP injections (111 vs 123 min-1) associated with a decreased contractility of small mesenteric arteries revealed by myography to characterise endothelial function. In conclusion, our study demonstrates that accumulation of superparamagnetic iron oxide nanoparticles does not affect kidney function in healthy mice but temporarily decreases blood pressure.Comment: 21 pages, 12 figures, published in Toxicology and Applied Pharmacology 201

Constraints on the behavior of trace elements in the actively-forming TAG deposit, Mid-Atlantic Ridge, based on LA-ICP-MS analyses of pyrite

The distribution of trace ore elements in different paragenetic stages of pyrite has been documented for the first time in the sub-seafloor of the actively-forming TAG massive sulfide deposit. Trace element distributions have been determined by in-situ laser ablation inductively-coupled plasma mass spectrometry (LA-ICP-MS) of pyrite formed at different stages of mineralization, and at different temperatures constrained by previously published fluid inclusion analyses. The data reveal a strong dependence on paragenetic stage, with distinct low- and high-temperature enrichments. Porous pyrite (and marcasite) formed at low temperatures (350 °C) at the base of the hydrothermal mound and in the stockwork zone is enriched in Co, Se, Bi, Cu, Ni, and Sn. A number of different sub-types of pyrite also have characteristic trace element signatures; e.g., the earliest pyrite formed at the highest temperatures is always enriched in Co and Se compared to later stages. Ablation profiles for Co, Se, and Ni are smooth and indicate that these elements are present mainly in lattice substitutions rather than as inclusions of other sulfides. Profiles for As, Sb, Tl, and Cu can be either irregular or smooth, indicating both lattice substitutions and inclusions. Lead and Ag have mostly smooth profiles, but because Pb cannot substitute directly into the pyrite lattice, it is interpreted to be present as homogeneously distributed micro- or nano-scale particles. The behavior of the different trace elements mainly reflects their aqueous speciation in the hydrothermal fluids at different temperatures, and for some elements like Co and Se, strong partitioning into the pyrite lattice at elevated temperatures. Adsorption onto pyrite surfaces controls the distribution of a number of redox-sensitive elements (i.e., Mo, V, Ni, U), particularly in the upper part of the mound which is infiltrated by cold seawater. Where micro- or nano-scale inclusions of chalcopyrite, sphalerite, galena, or sulfosalts are present, there is still a strong temperature dependence on the inclusion population (e.g., more abundant chalcopyrite in the highest-temperature pyrite), suggesting that the inclusions were co-precipitated with pyrite rather than overgrown. However, at the deposit scale, the trace element distributions are also strongly controlled by remobilization and chemical zone refining, as previously documented in bulk geochemical profiles. The results show that pyrite chemistry is a remarkably good model of the chemistry of the entire hydrothermal system. For many trace elements, the concentrations in pyrite are highly predictive in terms of the conditions of mineral formation over a wide range of temperatures, from the stockwork zone to the cooler outer margins of the deposit. Calculated minimum concentrations of the trace elements in the fluids needed to account for the observed concentrations in pyrite show good agreement with measured vent fluid concentrations, particularly Pb, As, Mo, Ag, and Tl. However, significantly higher concentrations are indicated for Co (and Se) than have been measured in sampled fluids, confirming the strong partitioning of these elements into high-temperature pyrite

Serial intravital 2-photon microscopy and analysis of the kidney using upright microscopes

Serial intravital 2-photon microscopy of the kidney and other abdominal organs is a powerful technique to assess tissue function and structure simultaneously and over time. Thus, serial intravital microscopy can capture dynamic tissue changes during health and disease and holds great potential to characterize (patho-) physiological processes with subcellular resolution. However, successful image acquisition and analysis require significant expertise and impose multiple potential challenges. Abdominal organs are rhythmically displaced by breathing movements which hamper high-resolution imaging. Traditionally, kidney intravital imaging is performed on inverted microscopes where breathing movements are partly compensated by the weight of the animal pressing down. Here, we present a custom and easy-to-implement setup for intravital imaging of the kidney and other abdominal organs on upright microscopes. Furthermore, we provide image processing protocols and a new plugin for the free image analysis software FIJI to process multichannel fluorescence microscopy data. The proposed image processing pipelines cover multiple image denoising algorithms, sample drift correction using 2D registration, and alignment of serial imaging data collected over several weeks using landmark-based 3D registration. The provided tools aim to lower the barrier of entry to intravital microscopy of the kidney and are readily applicable by biomedical practitioners

Mild cognitive impairment and kidney disease: clinical aspects.

Chronic kidney disease (CKD) is now seen as a systemic disease involving also the central nervous system [1], but the link between the kidney and different organ systems and disease went unnoticed for a long time. The king of Poland, Stephen Bathory (1533-86), suffered from CKD due to polycystic kidney disease and depression [2]. Similarly, Wolfgang Amadeus Mozart was also thought to have had CKD [3] and depression [4]. A list of 'Famous People Who Have Died from Kidney Disease' [5] includes many who suffered from both CKD and depression or other signs of mental illness. Is this a coincidence or actually evidence of a link between kidney disease and brain dysfunction? This is not merely an academic question because all forms of mental illness can seriously impair an individual's quality of life, and are frequently associated with progression of diseases and premature mortality, so it is worth the effort of trying to answer it. Europe and much of the industrialized countries are experiencing growing numbers of patients with CKD within their ageing populations [6]. CKD is complex and potentially fatal: (i) all organs are affected, sooner or later; (ii) the balance of plasma volume, electrolytes, acid-base and minerals, metabolites, hormones and proteins is disturbed; and (iii) patients often need a multidisciplinary team approach managing complex comorbidities, drug regimens and special diets. Although the prognosis of patients with CKD remains poor, their increasing life expectancy has shifted medical attention from life-threatening emergencies to long-term complications and sequelae, and how to improve quality of life [7]. Indeed, kidney failure has detrimental effects on health-related quality of life (HRQoL), reaching levels similar to those seen in patients with metastatic cancer [8]. This might be due to psychological factors, both kidney disease and cancer being chronic diseases with a bad prognosis. However, although the effect of CKD on quality of life is more evident in advanced stages (stage G4P) and in older patients [9, 10], a large study has shown a significant decrease in HRQoL as early as CKD stage G2 [11]. Notably, neurological and cognitive impairments [12], and depression [13] are among the most debilitating consequences of CKD contributing to the significantly reduced HRQoL [14]

Drugs with a negative impact on cognitive function (Part 1): chronic kidney disease as a risk factor

People living with chronic kidney disease (CKD) frequently suffer from mild cognitive impairment and/or other neurocognitive disorders. This review in two parts will focus on adverse drug reactions resulting in cognitive impairment as a potentially modifiable risk factor in CKD patients. Many patients with CKD have a substantial burden of comorbidities leading to polypharmacy. A recent study found that patients seen by nephrologists were the most complex to treat because of their high number of comorbidities and medications. Due to polypharmacy, these patients may experience a wide range of adverse drug reactions. Along with CKD progression, the accumulation of uremic toxins may lead to blood–brain barrier (BBB) disruption and pharmacokinetic alterations, increasing the risk of adverse reactions affecting the central nervous system (CNS). In patients on dialysis, the excretion of drugs that depend on kidney function is severely reduced such that adverse and toxic levels of a drug or its metabolites may be reached at relatively low doses, unless dosing is adjusted. This first review will discuss how CKD represents a risk factor for adverse drug reactions affecting the CNS via (i) BBB disruption associated with CKD and (ii) the impact of reduced kidney function and dialysis itself on drug pharmacokinetics

Operational Research: Methods and Applications

Throughout its history, Operational Research has evolved to include a variety of methods, models and algorithms that have been applied to a diverse and wide range of contexts. This encyclopedic article consists of two main sections: methods and applications. The first aims to summarise the up-to-date knowledge and provide an overview of the state-of-the-art methods and key developments in the various subdomains of the field. The second offers a wide-ranging list of areas where Operational Research has been applied. The article is meant to be read in a nonlinear fashion. It should be used as a point of reference or first-port-of-call for a diverse pool of readers: academics, researchers, students, and practitioners. The entries within the methods and applications sections are presented in alphabetical order

Circulating microRNAs in sera correlate with soluble biomarkers of immune activation but do not predict mortality in ART treated individuals with HIV-1 infection: A case control study

Introduction: The use of anti-retroviral therapy (ART) has dramatically reduced HIV-1 associated morbidity and mortality. However, HIV-1 infected individuals have increased rates of morbidity and mortality compared to the non-HIV-1 infected population and this appears to be related to end-organ diseases collectively referred to as Serious Non-AIDS Events (SNAEs). Circulating miRNAs are reported as promising biomarkers for a number of human disease conditions including those that constitute SNAEs. Our study sought to investigate the potential of selected miRNAs in predicting mortality in HIV-1 infected ART treated individuals. Materials and Methods: A set of miRNAs was chosen based on published associations with human disease conditions that constitute SNAEs. This case: control study compared 126 cases (individuals who died whilst on therapy), and 247 matched controls (individuals who remained alive). Cases and controls were ART treated participants of two pivotal HIV-1 trials. The relative abundance of each miRNA in serum was measured, by RTqPCR. Associations with mortality (all-cause, cardiovascular and malignancy) were assessed by logistic regression analysis. Correlations between miRNAs and CD4+ T cell count, hs-CRP, IL-6 and D-dimer were also assessed. Results: None of the selected miRNAs was associated with all-cause, cardiovascular or malignancy mortality. The levels of three miRNAs (miRs -21, -122 and -200a) correlated with IL-6 while miR-21 also correlated with D-dimer. Additionally, the abundance of miRs -31, -150 and -223, correlated with baseline CD4+ T cell count while the same three miRNAs plus miR- 145 correlated with nadir CD4+ T cell count. Discussion: No associations with mortality were found with any circulating miRNA studied. These results cast doubt onto the effectiveness of circulating miRNA as early predictors of mortality or the major underlying diseases that contribute to mortality in participants treated for HIV-1 infection