Leukocyte filtration and leukocyte modulation therapy during extracorporeal cardiopulmonary resuscitation in a porcine model of prolonged cardiac arrest.

Extracorporeal cardiopulmonary resuscitation (ECPR) is emerging as a feasible and effective rescue strategy for prolonged cardiac arrest (CA). However, prolonged total body ischemia and reperfusion can cause microvascular occlusion that prevents organ reperfusion and recovery of function. One hypothesized mechanism of microvascular "no-reflow" is leukocyte adhesion and formation of neutrophil extracellular traps. In this study we tested the hypothesis that a leukocyte filter (LF) or leukocyte modulation device (L-MOD) could reduce NETosis and improve recovery of heart and brain function in a swine model of prolonged cardiac arrest treated with ECPR. Thirty-six swine (45.5 ± 2.5 kg, evenly distributed sex) underwent 8 min of untreated ventricular fibrillation CA followed by 30 min of mechanical CPR with subsequent 8 h of ECPR. Two females were later excluded from analysis due to CPR complications. Swine were randomized to standard care (Control group), LF, or L-MOD at the onset of CPR. NET formation was quantified by serum dsDNA and citrullinated histone as well as immunofluorescence staining of the heart and brain for citrullinated histone in the microvasculature. Primary outcomes included recovery of cardiac function based on cardiac resuscitability score (CRS) and recovery of neurologic function based on the somatosensory evoked potential (SSEP) N20 cortical response. In this model of prolonged CA treated with ECPR we observed significant increases in serum biomarkers of NETosis and immunohistochemical evidence of microvascular NET formation in the heart and brain that were not reduced by LF or L-MOD therapy. Correspondingly, there were no significant differences in CRS and SSEP recovery between Control, LF, and L-MOD groups 8 h after ECPR onset (CRS = 3.1 ± 2.7, 3.7 ± 2.6, and 2.6 ± 2.6 respectively; p = 0.606; and SSEP = 27.9 ± 13.0%, 36.7 ± 10.5%, and 31.2 ± 9.8% respectively, p = 0.194). In this model of prolonged CA treated with ECPR, the use of LF or L-MOD therapy during ECPR did not reduce microvascular NETosis or improve recovery of myocardial or brain function. The causal relationship between microvascular NETosis, no-reflow, and recovery of organ function after prolonged cardiac arrest treated with ECPR requires further investigation.

Resource availability hypothesis: Perceived financial and caloric status affect individuals' height preferences for potential partners.

Height is an important concern in human mate choices. Prior research indicates that people who live in areas with abundant resources differ from those who live in areas with scarce resources regarding height preferences. Based on a health-maximizing principle, we propose a resource availability account for such differences. Compared with women's height preferences, men's height preferences are hypothesized to be more dependent on either financial or caloric resource availability. Specifically, taller females would be more preferred by males who are poor in resources than those who are rich in resources. Results from three studies supported these hypotheses. In Study 1, men from remote areas of China who had lower family income preferred taller women more than those from eastern China who had higher family income. In Study 2, men who were financially dissatisfied preferred taller women more than those who were financially satisfied. In Study 3, men with low caloric status preferred taller women more than men with high caloric status. In addition, women's height preferences in Studies 1, 2 and 3 were less determined by resource availability. These findings suggest that height preferences are changeable, depending on financial or caloric status.

Different timing features in brain processing of core and moral disgust pictures: an event-related potentials study.

Disgust, an emotion motivating withdrawal from offensive stimuli, protects us from the risk of biological pathogens and sociomoral violations. Homogeneity of its two types, namely, core and moral disgust has been under intensive debate. To examine the dynamic relationship between them, we recorded event-related potentials (ERPs) for core disgust, moral disgust and neutral pictures while participants performed a modified oddball task. ERP analysis revealed that N1 and P2 amplitudes were largest for the core disgust pictures, indicating automatic processing of the core disgust-evoking pictures. N2 amplitudes were higher for pictures evoking moral disgust relative to core disgust and neutral pictures, reflecting a violation of social norms. The core disgust pictures elicited larger P3 and late positive potential (LPP) amplitudes in comparison with the moral disgust pictures which, in turn, elicited larger P3 and LPP amplitudes when compared to the neutral pictures. Taken together, these findings indicated that core and moral disgust pictures elicited different neural activities at various stages of information processing, which provided supporting evidence for the heterogeneity of disgust.

Selective cytopheretic inhibitory device with regional citrate anticoagulation and portable sorbent dialysis.

Selective cytopheretic inhibitory device (SCD) therapy is an immunomodulatory treatment provided by a synthetic biomimetic membrane in an extracorporeal circuit, which has shown promise in preclinical large animal models of severe sepsis as well as in clinical trials treating patients with acute kidney injury and multiple organ failure. During SCD therapy, citrate is administered to lower ionized calcium levels in blood for anticoagulation and inhibition of leukocyte activation. Historically, citrate has been known to interfere with sorbent dialysis, therefore, posing a potential issue for the use of SCD therapy with a portable dialysis system. This sorbent dialysis SCD (sorbent SCD) would be well suited for battlefield and natural disaster applications where the water supply for standard dialysis is limited, and the types of injuries in those settings would benefit from SCD therapy. In order to explore the compatibility of sorbent and SCD technologies, a uremic porcine model was tested with the Allient sorbent dialysis system (Renal Solutions Incorporated, Fresenius Medical Care, Warrendale, PA, USA) and concurrent SCD therapy with regional citrate anticoagulation. The hypothesis to be assessed was whether the citrate load required by the SCD could be metabolized prior to recirculation from systemic blood back into the therapeutic circuit. Despite the fact that the sorbent SCD maintained urea clearance without any adverse hematologic events, citrate load for SCD therapy caused an interaction with the sorbent column resulting in elevated, potentially toxic aluminum levels in dialysate and in systemic blood. Alternative strategies to implement sorbent-SCD therapy will be required, including development of alternate urease-sorbent column binding chemistry or further changes to the sorbent-SCD therapeutic circuit along with determining the minimum citrate concentration required for efficacious SCD treatment.

A biomimetic membrane device that modulates the excessive inflammatory response to sepsis.

OBJECTIVE: Septic shock has a clinical mortality rate approaching fifty percent. The major clinical manifestations of sepsis are due to the dysregulation of the host's response to infection rather than the direct consequences of the invading pathogen. Central to this initial immunologic response is the activation of leukocytes and microvascular endothelium resulting in cardiovascular instability, lung injury and renal dysfunction. Due to the primary role of leukocyte activation in the sepsis syndrome, a synthetic biomimetic membrane, called a selective cytopheretic device (SCD), was developed to bind activated leukocytes. The incorporation of the SCD along an extracorporeal blood circuit coupled with regional anticoagulation with citrate to lower blood ionized calcium was devised to modulate leukocyte activation in sepsis. DESIGN: Laboratory investigation. SETTING: University of Michigan Medical School. SUBJECTS: Pigs weighing 30-35 kg. INTERVENTIONS: To assess the effect of the SCD in septic shock, pigs were administered 30×10(10) bacteria/kg body weight of Escherichia coli into the peritoneal cavity and within 1 hr were immediately placed in an extracorporeal circuit containing SCD. MEASUREMENTS AND MAIN RESULTS: In this animal model, the SCD with citrate compared to control groups without the SCD or with heparin anticoagulation ameliorated the cardiovascular instability and lung sequestration of activated leukocytes, reduced renal dysfunction and improved survival time compared to various control groups. This effect was associated with minimal elevations of systemic circulating neutrophil activation. CONCLUSIONS: These preclinical studies along with two favorable exploratory clinical trials form the basis of an FDA-approved investigational device exemption for a pivotal multicenter, randomized control trial currently underway.

Cell therapy with a tissue-engineered kidney reduces the multiple-organ consequences of septic shock.

OBJECTIVE: Gram-negative septic shock has a clinical mortality rate approaching 50%. The cause of death is secondary to a systemic inflammatory response syndrome with resulting cardiovascular collapse, ischemic damage to vital organs, and multiple-organ systems failure. Renal tubule cell injury occurs early in septic shock but is not clinically appreciated. Since renal tubule cells appear to play a critical role in the immunoregulation of stress states, renal cell therapy during septic shock may alter the detrimental multiple-organ consequences of systemic Gram-negative infection. The development of a tissue-engineered bioartificial kidney consisting of a conventional hemofiltration cartridge in series with a renal tubule assist device (RAD) containing 109 renal proximal tubule cells may be a new therapeutic approach to this clinical disorder. DESIGN: Laboratory study. SETTING: University medical school. SUBJECTS: Pigs weighing 30-35 kg. INTERVENTIONS: To assess the effect of the bioartificial kidney and the RAD in septic shock, pigs were administered 30 x 10(10) bacteria/kg body weight of Escherichia coli into the peritoneal cavity and within 1 hr were immediately placed in a continuous venovenous hemofiltration extracorporeal circuit with either a sham RAD without cells or a RAD with cells. MEASUREMENTS AND MAIN RESULTS: In this animal model, septic shock resulted within hours in acute tubule necrosis in the kidneys of all animals. Renal cell therapy resulted in significantly higher cardiac outputs and renal blood flow rates in treated animals compared with sham controls. RAD treatment also was associated with significantly lower plasma circulating concentrations of interleukin-6 and interferon-gamma compared with sham-treated animals. IL-6 release rates from peripheral blood mononuclear cells isolated from RAD-treated animals were significantly higher after endotoxin stimulation than those isolated from control animals. These physiologic and molecular alterations were associated with nearly a doubling of the average survival time in the RAD-treated group compared with the sham control group. CONCLUSION: These results demonstrate that renal cell therapy ameliorates cardiac and vascular dysfunction, alters systemic cytokine abnormalities, and improves survival time in a large animal model of Gram-negative septic shock. A cell therapeutic approach with a tissue-engineered bioartificial kidney may be a new treatment modality for this current unmet medical need.

Bioartificial kidney ameliorates gram-negative bacteria-induced septic shock in uremic animals.

The bioartificial kidney (BAK) consists of a conventional hemofiltration cartridge in series with a renal tubule assist device (RAD) containing 10(9) porcine renal proximal tubule cells. BAK replaces filtration, transport, and metabolic and endocrinologic activities of a kidney. Previous work in an acutely uremic dog model demonstrated that BAK ameliorated endotoxin (lipopolysaccharide [LPS])-induced hypotension and altered plasma cytokine levels. To further assess the role of BAK in sepsis in acute renal failure, dogs were nephrectomized and 48 h later administered intraperitoneally with 30 x 10(10) bacteria/kg of E. coli. One hour after bacterial administration, animals were placed in a continuous venovenous hemofiltration circuit with either a sham RAD without cells (n = 6) or a RAD with cells (n = 6). BP, cardiac output, heart rate, pulmonary capillary wedge pressure, and systemic vascular resistance were measured throughout the study. All animals tested were in renal failure, with blood urea nitrogen and serum creatinine concentrations greater than 60 and 6 mg/dl, respectively. RAD treatment maintained significantly better cardiovascular performance, as determined by arterial BP (P < 0.05) and cardiac output (P < 0.02), for longer periods than sham RAD therapy. Consistently, all sham RAD-treated animals, except one, expired within 2 to 9 h after bacterial administration, whereas all RAD-treated animals survived more than 10 h. Plasma levels of TNF-alpha, IL-10, and C-reactive protein (CRP) were measured during cell RAD and sham RAD treatment. IL-10 levels were significantly higher (P < 0.01) during the entire treatment interval in the RAD animals compared with sham controls. These data demonstrated in a pilot large animal experiment that the BAK with RAD altered plasma cytokine levels in acutely uremic animals with septic shock. This change was associated with improved cardiovascular performance and increased survival time. These results demonstrate that the addition of cell therapy to hemofiltration in an acutely uremic animal model with septic shock ameliorates cardiovascular dysfunction, alters systemic cytokine balance, and improves survival time.