Principles of Quantitative Fluid and Cation Replacement in Extreme Hyperglycemia

Hyperglycemia may cause profound deficits of water, sodium and potassium through osmotic diuresis, which continues during treatment as long as there is glucosuria. Replacement fluids should cover both the deficits at presentation and the ongoing losses during treatment. At presentation with hyperglycemia, quantitative estimates of the deficits in water, sodium and potassium are based on rapid body weight changes, which indicate changes in body water, and on the serum sodium concentration corrected to a normal serum glucose level. The corrected serum sodium concentration provides a measure of the water deficit relative to the cation deficit (sodium, plus potassium) that is useful in guiding the choice of monovalent cation concentration in the initial replacement fluids. Monitoring clinical status, serum chemistries (glucose, sodium, potassium, total carbon dioxide), urine flow rate, and urine chemistries (sodium and potassium) during the course of fluid and cation replacement therapy is critical. This monitoring guides the volume and composition of replacement solutions for deficits developing during treatment and the management of potassium balance and acid-base abnormalities, including metabolic acidosis, respiratory acidosis, rarely, and others

Principles of Management of Severe Hyponatremia

Hyponatremia represents a serious health hazard.1 Hospitalized patients,2 nursing home residents,3 women,4,5 and children6 exhibit high frequency and/or severity of hyponatremia. Hyponatremia developing during the course of other morbid conditions increases their severity.7–10 Estimates of direct costs for treating hyponatremia in the United States ranged between $1.61 and$3.6 billion.11 Clinical manifestations of hyponatremia are universal12,13 and range from subtle (disturbances of balance, problems in cognition detected only during specific testing) to life-threatening manifestations of increased intracranial pressure with life-threatening hypoxia14–16 and noncardiac pulmonary edema.17 Although the treating physicians must make an accurate diagnosis based on well-established and described clinical criteria,1 treatment is also guided by the severity of these manifestations. The magnitude and rate of increase in serum sodium concentration ([Na]) during treatment are critical. Overcorrection of chronic hyponatremia may lead to osmotic myelinolysis,18–21 whereas undercorrection may fail to prevent life-threatening manifestations.1,2

Reduction of Na/K-ATPase potentiates marinobufagenin-induced cardiac dysfunction and myocyte apoptosis

Background: Na/K-ATPase decrease has been reported in patients with heart failure and is related to cardiac dysfunction. Results: Reducing Na/K-ATPase activates caspase 9 and induces cardiac dilation when treated with marinobufagenin. Conclusion: Reduction of Na/K-ATPase potentiates marinobufagenin-induced cardiac myocyte apoptosis. Significance: Decreased Na/K-ATPase content together with increased cardiotonic steroids levels is a novel mechanism that may account for cardiac dysfunction

Protein Carbonylation of an Amino Acid Residue of the Na/K‐ATPase α1 Subunit Determines Na/K‐ATPase Signaling and Sodium Transport in Renal Proximal Tubular Cells

Background We have demonstrated that cardiotonic steroids, such as ouabain, signaling through the Na/K‐ATPase, regulate sodium reabsorption in the renal proximal tubule. By direct carbonylation modification of the Pro222 residue in the actuator (A) domain of pig Na/K‐ATPase α1 subunit, reactive oxygen species are required for ouabain‐stimulated Na/K‐ATPase/c‐Src signaling and subsequent regulation of active transepithelial 22Na+ transport. In the present study we sought to determine the functional role of Pro222 carbonylation in Na/K‐ATPase signaling and sodium handling. Methods and Results Stable pig α1 knockdown LLC‐PK1‐originated PY‐17 cells were rescued by expressing wild‐type rat α1 and rat α1 with a single mutation of Pro224 (corresponding to pig Pro222) to Ala. This mutation does not affect ouabain‐induced inhibition of Na/K‐ATPase activity, but abolishes the effects of ouabain on Na/K‐ATPase/c‐Src signaling, protein carbonylation, Na/K‐ATPase endocytosis, and active transepithelial 22Na+ transport. Conclusions Direct carbonylation modification of Pro224 in the rat α1 subunit determines ouabain‐mediated Na/K‐ATPase signal transduction and subsequent regulation of renal proximal tubule sodium transport

Triple-GEM discharge probability studies at CHARM: Simulations and experimental results

The CMS muon system in the region with 2.03<|η|<2.82 is characterized by a very harsh radiation environment which can generate hit rates up to 144 kHz/cm$^{2}$ and an integrated charge of 8 C/cm$^{2}$ over ten years of operation. In order to increase the detector performance and acceptance for physics events including muons, a new muon station (ME0) has been proposed for installation in that region. The technology proposed is Triple—Gas Electron Multiplier (Triple-GEM), which has already been qualified for the operation in the CMS muon system. However, an additional set of studies focused on the discharge probability is necessary for the ME0 station, because of the large radiation environment mentioned above. A test was carried out in 2017 at the Cern High energy AcceleRator Mixed (CHARM) facility, with the aim of giving an estimation of the discharge probability of Triple-GEM detectors in a very intense radiation field environment, similar to the one of the CMS muon system. A dedicated standalone Geant4 simulation was performed simultaneously, to evaluate the behavior expected in the detector exposed to the CHARM field. The geometry of the detector has been carefully reproduced, as well as the background field present in the facility. This paper presents the results obtained from the Geant4 simulation, in terms of sensitivity of the detector to the CHARM environment, together with the analysis of the energy deposited in the gaps and of the processes developed inside the detector. The discharge probability test performed at CHARM will be presented, with a complete discussion of the results obtained, which turn out to be consistent with measurements performed by other groups

Detector Control System for the GE1/1 slice test

Gas Electron Multiplier (GEM) technology, in particular triple-GEM, was selected for the upgrade of the CMS endcap muon system following several years of intense effort on R&D. The triple-GEM chambers (GE1/1) are being installed at station 1 during the second long shutdown with the goal of reducing the Level-1 muon trigger rate and improving the tracking performance in the harsh radiation environment foreseen in the future LHC operation [1]. A first installation of a demonstrator system started at the beginning of 2017: 10 triple-GEM detectors were installed in the CMS muon system with the aim of gaining operational experience and demonstrating the integration of the GE1/1 system into the trigger. In this context, a dedicated Detector Control System (DCS) has been developed, to control and monitor the detectors installed and integrating them into the CMS operation. This paper presents the slice test DCS, describing in detail the different parts of the system and their implementation

Physician privacy concerns when disclosing patient data for public health purposes during a pandemic influenza outbreak

Background: Privacy concerns by providers have been a barrier to disclosing patient information for public health\ud purposes. This is the case even for mandated notifiable disease reporting. In the context of a pandemic it has been\ud argued that the public good should supersede an individual’s right to privacy. The precise nature of these provider\ud privacy concerns, and whether they are diluted in the context of a pandemic are not known. Our objective was to\ud understand the privacy barriers which could potentially influence family physicians’ reporting of patient-level\ud surveillance data to public health agencies during the Fall 2009 pandemic H1N1 influenza outbreak.\ud Methods: Thirty seven family doctors participated in a series of five focus groups between October 29-31 2009.\ud They also completed a survey about the data they were willing to disclose to public health units. Descriptive\ud statistics were used to summarize the amount of patient detail the participants were willing to disclose, factors that\ud would facilitate data disclosure, and the consensus on those factors. The analysis of the qualitative data was based\ud on grounded theory.\ud Results: The family doctors were reluctant to disclose patient data to public health units. This was due to concerns\ud about the extent to which public health agencies are dependable to protect health information (trusting beliefs),\ud and the possibility of loss due to disclosing health information (risk beliefs). We identified six specific actions that\ud public health units can take which would affect these beliefs, and potentially increase the willingness to disclose\ud patient information for public health purposes.\ud Conclusions: The uncertainty surrounding a pandemic of a new strain of influenza has not changed the privacy\ud concerns of physicians about disclosing patient data. It is important to address these concerns to ensure reliable\ud reporting during future outbreaks.University of Ottawa Open Access Author Fun

Putting the treatment of paediatric schistosomiasis into context

Abstract Despite increased international efforts to control schistosomiasis using preventive chemotherapy, several challenges still exist in reaching the target populations. Until recently, preschool-aged children had been excluded from the recommended target population for mass drug administration, i.e. primary school children aged 6–15 years. Our studies and those of others provided the evidence base for the need to treat preschool-aged children that led to recommendations by the World Health Organization to include preschool-aged children in treatment programmes in 2010. The major challenge now lies in the unavailability of a child-size formulation of the appropriate anthelmintic drug, praziquantel. The currently available formulation of praziquantel presents several problems. First, it is a large tablet, making it difficult for young children and infants to swallow it and thus requires its breaking/crushing to allow for safe uptake. Second, it is bitter so it is often mixed with a sweetener to make it palatable for young children. Third, the current formulation of 600 mg does not allow for flexible dose adjustments for this age group. Thus, there is a need to formulate a child-appropriate praziquantel tablet. This paper discusses the target product profile for paediatric praziquantel, as well as knowledge gaps pertinent to the successful control of schistosome infection and disease in preschool-aged children

Effects of enhanced oxygen release from hemoglobin by RSR13 in an acute renal failure model

Background: Acute renal failure is believed to be caused, in some circumstances, by impaired oxygen delivery to the outer medulla. This study examined the effect of RSR13, a synthetic allosteric modifier of hemoglobin oxygen-binding affinity, on renal function in a setting of acute renal failure in rats. Methods: An in vivo model of acute renal failure in the rat produced by reduced renal mass, salt restriction, volume depletion, prostaglandin inhibition, and radiocontrast administration was used. A computer-based simulation of oxygen tensions along the nephron was utilized to interpret the findings. Mechanistic studies were subsequently performed using oxygen-sensitive electrodes and 31P nuclear magnetic resonance (NMR) spectroscopy to define the effect of RSR13 on renal function in the setting of compromised acute renal failure. Results: RSR13 did not attenuate acute renal failure in this model; rather, serum creatinine increased to a greater degree in the RSR13-treated rats than in rats receiving saline vehicle as the control (P \u3c 0.05). Simulations explained this finding under conditions of severe medullary hypoxia. Mechanistic studies demonstrated marked worsening of medullary hypoxia following RSR13 under conditions similar to our experimental model. Furosemide pretreatment to reduce the imbalance between oxygen supply and demand markedly attenuated the basal-medullary hypoxia produced in the presence of indomethacin and RSR13 (P \u3c 0.01). Additionally, 31P NMR studies demonstrated renal adenosine 5\u27-triphosphate (ATP) depletion in rats with acute renal failure treated with RSR13 (45% decrease, P \u3c 0.01); again, this effect of RSR13 was completely prevented by pretreatment with furosemide. Conclusions: Under conditions of severe renal medullary hypoxia, induced in part by indomethacin-mediated reductions in outer medullary blood flow, the administration of RSR13 can exacerbate acute renal dysfunction. However, reducing the rate of oxygen consumption by inhibiting sodium transport with furosemide pretreatment or post-treatment appears to be functionally protective

Ouabain Induces Endocytosis of Plasmalemmal Na/K-ATPase in LLC-PK1 Cells by a Clathrin-dependent Mechanism

Background: We have demonstrated that ouabain causes dose- and time-dependent decreases in 86Rb uptake in porcine proximal tubular (LLC-PK1) cells. The present study addresses the molecular mechanisms involved in this process. Methods: Studies were performed with cultured LLC-PK1 and Src family kinase deficient (SYF) cells. Results: We found that 50 nmol/L ouabain applied to the basal, but not apical, aspect for 12 hours caused decreases in the plasmalemmal Na/K-ATPase. This loss of plasmalemmal Na/K-ATPase reverses completely within 12 to 24 hours after removal of ouabain. Ouabain also increased the Na/K-ATPase content in both early and late endosomes, activated phosphatidylinositol 3-kinase (PI(3)K), and also caused a translocation of some Na/K-ATPase to the nucleus. Immunofluorescence demonstrated that the Na/K-ATPase colocalized with clathrin both before and after exposure to ouabain, and immunoprecipitation experiments confirmed that ouabain stimulated interactions among the Na/K-ATPase, adaptor protein-2 (AP-2), and clathrin. Potassium (K) depletion, chlorpromazine, or PI(3)K inhibition all significantly attenuated this ouabain-induced endocytosis. Inhibition of the ouabain-activated signaling process through Src by 4-Amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2) significantly attenuated ouabain-induced endocytosis. Moreover, experiments performed in SYF cells demonstrated that ouabain induced increases in the endocytosis of the Na/K-ATPase when Src was reconstituted (SYF+), but not in the Src-deficient (SYF-) cells. Conclusion: These data demonstrate that ouabain stimulates a clathrin-dependent endocytosis pathway that translocates the Na/K-ATPase to intracellular compartments, thus suggesting a potential role of endocytosis in ouabain-induced signal transduction as well as proximal tubule sodium handling