Extracorporeal membrane oxygenation (ECMO) is a technology capable of providing short-term mechanical support to the heart, lungs or both. Over the last decade, the number of centres offering ECMO ...has grown rapidly. At the same time, the indications for its use have also been broadened. In part, this trend has been supported by advances in circuit design and in cannulation techniques. Despite the widespread adoption of extracorporeal life support techniques, the use of ECMO remains associated with significant morbidity and mortality. A complication witnessed during ECMO is the inflammatory response to extracorporeal circulation. This reaction shares similarities with the systemic inflammatory response syndrome (SIRS) and has been well-documented in relation to cardiopulmonary bypass. The exposure of a patient's blood to the non-endothelialised surface of the ECMO circuit results in the widespread activation of the innate immune system; if unchecked this may result in inflammation and organ injury. Here, we review the pathophysiology of the inflammatory response to ECMO, highlighting the complex interactions between arms of the innate immune response, the endothelium and coagulation. An understanding of the processes involved may guide the design of therapies and strategies aimed at ameliorating inflammation during ECMO. Likewise, an appreciation of the potentially deleterious inflammatory effects of ECMO may assist those weighing the risks and benefits of therapy.
Optimal management of cardiogenic shock requiring extracorporeal membrane oxygenation (ECMO) is still an evolving area in which assessment and optimization of the microcirculation may be critically ...important. We hypothesized that the venous arterial carbon dioxide gap (P(v-a)CO2 gap); the ratio of this gap to arterio-venous oxygen content (P(v-a)CO2/C(a-v)O2 ratio) and the anion gap would be early indicators of microcirculatory status and useful parameters for outcome prediction during ECMO support. We retrospectively reviewed 31 cardiogenic shock patients requiring veno-arterial ECMO, calculating P(v-a)CO2 gap and P(v-a)CO2/C(a-v)O2 ratios in the first 36 hours and the final 24 hours of ECMO support. Sixteen patients (52%) survived and 15 (48%) died. After 24 hours of ECMO support, the P(v-a)CO2 gap (4.9 ± 1.5 vs. 6.8 ± 1.9 mm Hg; p = 0.004) and anion gap (5.2 ± 1.8 vs. 8.7 ± 2.7 mmol/L; p < 0.001) were significantly higher in non-survivors. In the final 24 hours of ECMO support, the P(v-a)CO2 gap (3.5 ± 1.6 vs. 10.5 ± 3.2 mm Hg; p < 0.001), P(v-a)CO2/C(a-v)O2 ratio (1.1 ± 0.5 vs. 2.7 ± 1.0; p < 0.001), anion gap (5.1 ± 3.0 vs. 9.3 ± 5.9 mmol/L; p = 0.02), and lactate (median 1.0 interquartile range {IQR}0.7–1.5 vs. 2.8 IQR1.7–7.7 mmol/L; p = <0.001) were all significantly lower in survivors. Increasing P(v-a)CO2 gap and increasing anion gap were significantly associated with increased risk of mortality. Optimum cut-points for prediction of mortality were 6 mm Hg for P(v-a)CO2 gap in combination with an anion gap above 6 mmol/L in the first 24 hours of ECMO in patients with cardiogenic shock requiring ECMO.
In 2015, Spain approved a law that offered citizenship to the descendants of Sephardi Jews expelled in 1492. Drawing on archival, ethnographic, and historical sources, I show that this law belongs to ...a political genealogy of philosephardism in which the “return” of Sephardi Jews has been imagined as a way to usher in a deferred Spanish modernity. Borrowing from anthropological theories of “racial fusion,” philosephardic thinkers at the turn of the twentieth century saw Sephardi Jews as inheritors of a racial mixture that made them living repositories of an earlier moment of national greatness. The senator Ángel Pulido, trained as an anthropologist, channeled these intellectual currents into an international campaign advocating the repatriation of Sephardi Jews. Linking this racial logic to an affective one, Pulido asserted that Sephardi Jews did not “harbor rancor” for the Expulsion, but instead felt love and nostalgia toward Spain, and could thus be trusted as loyal subjects who would help resurrect its empire. Today, affective criteria continue to be enmeshed in debates about who qualifies for inclusion and are inextricable from the histories of racial thought that made earlier exclusions possible. Like its precursors, the 2015 Sephardic citizenship law rhetorically fashioned Sephardi Jews as fundamentally Spanish, not only making claims about Sephardi Jews, but also making claims on them. Reckoning with how rancor and other sentiments have helped buttress such claims exposes the recalcitrant hold that philosephardic thought has on Spain's present, even those “progressive” political projects that promise to “return” what has been lost.
Vital drugs may be degraded or sequestered in extracorporeal membrane oxygenation (ECMO) circuits, with lipophilic drugs considered to be particularly vulnerable. However, the circuit effects on ...protein-bound drugs have not been fully elucidated. The aim of this experimental study was to investigate the influence of plasma protein binding on drug disposition in ex vivo ECMO circuits.
Four identical ECMO circuits comprising centrifugal pumps and polymethylpentene oxygenators and were used. The circuits were primed with crystalloid, albumin and fresh human whole blood and maintained at a physiological pH and temperature for 24 hours. After baseline sampling, known quantities of study drugs (ceftriaxone, ciprofloxacin, linezolid, fluconazole, caspofungin and thiopentone) were injected into the circuit to achieve therapeutic concentrations. Equivalent doses of these drugs were also injected into four polypropylene jars containing fresh human whole blood for drug stability testing. Serial blood samples were collected from the controls and the ECMO circuits over 24 hours, and the concentrations of the study drugs were quantified using validated chromatographic assays. A regression model was constructed to examine the relationship between circuit drug recovery as the dependent variable and protein binding and partition coefficient (a measure of lipophilicity) as explanatory variables.
Four hundred eighty samples were analysed. There was no significant loss of any study drugs in the controls over 24 hours. The average drug recoveries from the ECMO circuits at 24 hours were as follows: ciprofloxacin 96%, linezolid 91%, fluconazole 91%, ceftriaxone 80%, caspofungin 56% and thiopentone 12%. There was a significant reduction of ceftriaxone (P = 0.01), caspofungin (P = 0.01) and thiopentone (P = 0.008) concentrations in the ECMO circuit at 24 hours. Both protein binding and partition coefficient were highly significant, with the model possessing a high coefficient of determination (R (2) = 0.88, P <0.001).
Recovery of the highly protein-bound drugs ceftriaxone, caspofungin and thiopentone was significantly lower in the ECMO circuits at 24 hours. For drugs with similar lipophilicity, the extent of protein binding may determine circuit drug loss. Future clinical population pharmacokinetic studies should initially be focused on drugs with greater lipophilicity and protein binding, and therapeutic drug monitoring should be strongly considered with the use of such drugs.
Abstract
Background
Advanced chronic obstructive pulmonary disease (COPD) often leads to hospitalisation and invasive aspergillosis (IA) is a serious complication.
Aspergillus
sensitisation may ...worsen symptoms in COPD.
Methods
We identified published papers between January 2000 and May 2019 with > 50 subjects and GOLD criteria for grade II, III or IV (FEV1/FVC < 70% and FEV1 < 80%) using standardised criteria in multiple countries, to re-estimate the prevalence of COPD. Hospitalised COPD patients develop IA in 1.3–3.9%, based on positive cultures of
Aspergillus
spp. and radiological findings. Given limited data on per-patient annual hospitalisation rates, we assumed a conservative 10.5% estimate. Annual IA mortality in COPD was estimated using the literature rates of 43–72%. A separate literature search assessed the impact of
Aspergillus
sensitisation on severity of COPD (by FEV1).
Results
We re-estimated the global prevalence of COPD GOLD stages II-IV at 552,300,599 people (7.39% of the population) with 339,206,893 (8.58%) in Asia, 85,278,783 (8.52%) in the Americas, 64,298,051 (5.37%) in Africa, 59,484,329 (7.77%) in Europe and 4,032,543 (10.86%) in Oceania. An estimated 57,991,563 (10.5%) people with COPD are admitted to hospital annually and of these 753,073 (1.3%) – 2,272,322 (3.9%) develop IA and 540,451–977,082 deaths are predicted annually.
Aspergillus
sensitisation prevalence in COPD was 13.6% (7.0–18.3%) and not related to lower predicted FEV1% (
P
> 0.05).
Conclusions
The prevalence of COPD is much higher than previously estimated. Overall COPD mortality may be higher than estimated and IA probably contributes to many deaths. Improved rapid diagnosis of IA using culture and non-culture based techniques is required in COPD hospital admissions to reduce mortality.
Tau has been implicated in many neurogenerative diseases called “tauopathies” where tau self‐assembles into neurofibrillary tangles. Alzheimer’s disease, the most common tauopathy, affects over 50 ...million people causing a dire need for therapeutics to be generated. However, the cellular mechanism of Alzheimer’s disease and related tauopathies remains poorly understood. Tau has recently been discovered to phase separate into liquid‐like droplets, or condensates, a phenomenon with growing significance in biology with the potential to inspire new therapeutic avenues. To gain insight into the putative role of phase separation in tau pathology, here we quantify the impact of pathological tau mutations on the phase behavior and material properties of tau condensates. We combine DIC and confocal microscopy with particle tracking microrheology measurements in order to characterize droplet morphology and quantify droplet viscoelasticity, respectively. We find that WT full‐length tau readily phase separates with polyU RNA to form condensed viscous fluids. Interestingly, while some pathological mutations have a pronounced effect on droplet viscosity and droplet aging dynamics, others display no significant effect on droplet properties. These results demonstrate an important, albeit complex relationship between tau phase separation, aggregation and pathology. Continued parsing of the complex landscape of tau assembly states, coupled with genetic and cellular analysis has the potential to reveal the roots of tau pathology and its ultimate therapeutic targeting.
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Phase separation has emerged as a new paradigm currently revolutionizing our understanding of cell biology and intracellular organization. Disordered protein domains have recently been demonstrated ...as integral drivers of phase separation into condensed liquids with emergent material properties. Using in vitro model systems employing purified protein components is necessary to interrogate the molecular mechanisms underlying phase separation; however, these systems pose many experimental challenges. In this chapter we describe general strategies for purifying, handling, imaging, and characterizing the phase behavior of disordered proteins. We further outline methods for the purification of the model P granule protein LAF-1, the construction of phase diagrams, and the quantification of liquid droplet fusion or coalescence.
Extracorporeal membrane oxygenation (ECMO) is a supportive therapy, with its success dependent on effective drug therapy that reverses the pathology and/or normalizes physiology. However, the circuit ...that sustains life can also sequester life-saving drugs, thereby compromising the role of ECMO as a temporary support device. This ex vivo study was designed to determine the degree of sequestration of commonly used antibiotics, sedatives and analgesics in ECMO circuits.
Four identical ECMO circuits were set up as per the standard protocol for adult patients on ECMO. The circuits were primed with crystalloid and albumin, followed by fresh human whole blood, and were maintained at a physiological pH and temperature for 24 hours. After baseline sampling, fentanyl, morphine, midazolam, meropenem and vancomycin were injected into the circuit at therapeutic concentrations. Equivalent doses of these drugs were also injected into four polyvinylchloride jars containing fresh human whole blood for drug stability testing. Serial blood samples were collected from the ECMO circuits and the controls over 24 hours and the concentrations of the study drugs were quantified using validated assays.
Four hundred samples were analyzed. All study drugs, except meropenem, were chemically stable. The average drug recoveries from the ECMO circuits and the controls at 24 hours relative to baseline, respectively, were fentanyl 3% and 82%, morphine 103% and 97%, midazolam 13% and 100%, meropenem 20% and 42%, vancomycin 90% and 99%. There was a significant loss of fentanyl (p = 0.0005), midazolam (p = 0.01) and meropenem (p = 0.006) in the ECMO circuit at 24 hours. There was no significant circuit loss of vancomycin at 24 hours (p = 0.26).
Sequestration of drugs in the circuit has implications on both the choice and dosing of some drugs prescribed during ECMO. Sequestration of lipophilic drugs such as fentanyl and midazolam appears significant and may in part explain the increased dosing requirements of these drugs during ECMO. Meropenem sequestration is also problematic and these data support a more frequent administration during ECMO.
Methylation of arginine (Arg) and lysine residues in histones has been correlated with epigenetic forms of gene regulation. Although histone methyltransferases are known, enzymes that demethylate ...histones have not been identified. Here, we demonstrate that human peptidylarginine deiminase 4 (PAD4) regulates histone Arg methylation by converting methyl-Arg to citrulline and releasing methylamine. PAD4 targets multiple sites in histones H3 and H4, including those sites methylated by coactivators CARM1 (H3$Arg^{17}$) and PRMT1 (H4$Arg^3$). A decrease of histone Arg methylation, with a concomitant increase of citrullination, requires PAD4 activity in human HL-60 granulocytes. Moreover, PAD4 activity is linked with the transcriptional regulation of estrogen-responsive genes in MCF-7 cells. These data suggest that PAD4 mediates gene expression by regulating Arg methylation and citrullination in histones.
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