Human Neutrophil Peptides Mediate Endothelial-Monocyte Interaction, Foam Cell Formation, and Platelet Activation

Objective—Neutrophils are involved in the inflammatory responses during atherosclerosis. Human neutrophil peptides (HNPs) released from activated neutrophils exert immune modulating properties. We hypothesized that HNPs play an important role in neutrophil-mediated inflammatory cardiovascular responses in atherosclerosis. Methods and Results—We examined the role of HNPs in endothelial-leukocyte interaction, platelet activation, and foam cell formation in vitro and in vivo. We demonstrated that stimulation of human coronary artery endothelial cells with clinically relevant concentrations of HNPs resulted in monocyte adhesion and transmigration; induction of oxidative stress in human macrophages, which accelerates foam cell formation; and activation and aggregation of human platelets. The administration of superoxide dismutase or anti-CD36 antibody reduced foam cell formation and cholesterol efflux. Mice deficient in double genes of low-density lipoprotein receptor and low-density lipoprotein receptor–related protein (LRP), and mice deficient in a single gene of LRP8, the only LRP phenotype expressed in platelets, showed reduced leukocyte rolling and decreased platelet aggregation and thrombus formation in response to HNP stimulation. Conclusion—HNPs exert proatherosclerotic properties that appear to be mediated through LRP8 signaling pathways, suggesting an important role for HNPs in the development of inflammatory cardiovascular diseases

Human neutrophil peptides mediate endothelial-monocyte interaction, foam cell formation, and platelet activation

Objective-: Neutrophils are involved in the inflammatory responses during atherosclerosis. Human neutrophil peptides (HNPs) released from activated neutrophils exert immune modulating properties. We hypothesized that HNPs play an important role in neutrophil-mediated inflammatory cardiovascular responses in atherosclerosis. Methods and results-: We examined the role of HNPs in endothelial-leukocyte interaction, platelet activation, and foam cell formation in vitro and in vivo. We demonstrated that stimulation of human coronary artery endothelial cells with clinically relevant concentrations of HNPs resulted in monocyte adhesion and transmigration; induction of oxidative stress in human macrophages, which accelerates foam cell formation; and activation and aggregation of human platelets. The administration of superoxide dismutase or anti-CD36 antibody reduced foam cell formation and cholesterol efflux. Mice deficient in double genes of low-density lipoprotein receptor and low-density lipoprotein receptor-related protein (LRP), and mice deficient in a single gene of LRP8, the only LRP phenotype expressed in platelets, showed reduced leukocyte rolling and decreased platelet aggregation and thrombus formation in response to HNP stimulation. Conclusion-: HNPs exert proatherosclerotic properties that appear to be mediated through LRP8 signaling pathways, suggesting an important role for HNPs in the development of inflammatory cardiovascular diseases. © 2011 American Heart Association. All rights reserved

Intravenous Immunoglobulin Prevents Murine Antibody-Mediated Acute Lung Injury at the Level of Neutrophil Reactive Oxygen Species (ROS) Production

Transfusion-related acute lung injury (TRALI) is a leading cause of transfusion-associated mortality that can occur with any type of transfusion and is thought to be primarily due to donor antibodies activating pulmonary neutrophils in recipients. Recently, a large prospective case controlled clinical study of cardiac surgery patients demonstrated that despite implementation of male donors, a high incidence of TRALI still occurred and suggested a need for additional interventions in susceptible patient populations. To examine if intravenous immunoglobulin (IVIg) may be effective, a murine model of antibody-mediated acute lung injury that approximates human TRALI was examined. When BALB/c mice were injected with the anti-major histocompatibility complex class I antibody 34-1-2s, mild shock (reduced rectal temperature) and respiratory distress (dyspnea) were observed and pre-treatment of the mice with 2 g/kg IVIg completely prevented these symptoms. To determine IVIg's usefulness to affect severe lung damage, SCID mice, previously shown to be hypersensitive to 34-1-2s were used. SCID mice treated with 34-1-2s underwent severe shock, lung damage (increased wet/dry ratios) and 40% mortality within 2 hours. Treatment with 2 g/kg IVIg 18 hours before 34-1-2s administration completely protected the mice from all adverse events. Treatment with IVIg after symptoms began also reduced lung damage and mortality. While the prophylactic IVIg administration did not affect 34-1-2s-induced pulmonary neutrophil accumulation, bone marrow-derived neutrophils from the IVIg-treated mice displayed no spontaneous ROS production nor could they be stimulated in vitro with fMLP or 34-1-2s. These results suggest that IVIg prevents murine antibody-mediated acute lung injury at the level of neutrophil ROS production and thus, alleviating tissue damage

Prediction of Opioid-Induced Respiratory Depression on Inpatient Wards Using Continuous Capnography and Oximetry: An International Prospective, Observational Trial.

BACKGROUND: Opioid-related adverse events are a serious problem in hospitalized patients. Little is known about patients who are likely to experience opioid-induced respiratory depression events on the general care floor and may benefit from improved monitoring and early intervention. The trial objective was to derive and validate a risk prediction tool for respiratory depression in patients receiving opioids, as detected by continuous pulse oximetry and capnography monitoring. METHODS: PRediction of Opioid-induced respiratory Depression In patients monitored by capnoGraphY (PRODIGY) was a prospective, observational trial of blinded continuous capnography and oximetry conducted at 16 sites in the United States, Europe, and Asia. Vital signs were intermittently monitored per standard of care. A total of 1335 patients receiving parenteral opioids and continuously monitored on the general care floor were included in the analysis. A respiratory depression episode was defined as respiratory rate ≤5 breaths/min (bpm), oxygen saturation ≤85%, or end-tidal carbon dioxide ≤15 or ≥60 mm Hg for ≥3 minutes; apnea episode lasting \u3e30 seconds; or any respiratory opioid-related adverse event. A risk prediction tool was derived using a multivariable logistic regression model of 46 a priori defined risk factors with stepwise selection and was internally validated by bootstrapping. RESULTS: One or more respiratory depression episodes were detected in 614 (46%) of 1335 general care floor patients (43% male; mean age, 58 ± 14 years) continuously monitored for a median of 24 hours (interquartile range [IQR], 17-26). A multivariable respiratory depression prediction model with area under the curve of 0.740 was developed using 5 independent variables: age ≥60 (in decades), sex, opioid naivety, sleep disorders, and chronic heart failure. The PRODIGY risk prediction tool showed significant separation between patients with and without respiratory depression (P \u3c .001) and an odds ratio of 6.07 (95% confidence interval [CI], 4.44-8.30; P \u3c .001) between the high- and low-risk groups. Compared to patients without respiratory depression episodes, mean hospital length of stay was 3 days longer in patients with ≥1 respiratory depression episode (10.5 ± 10.8 vs 7.7 ± 7.8 days; P \u3c .0001) identified using continuous oximetry and capnography monitoring. CONCLUSIONS: A PRODIGY risk prediction model, derived from continuous oximetry and capnography, accurately predicts respiratory depression episodes in patients receiving opioids on the general care floor. Implementation of the PRODIGY score to determine the need for continuous monitoring may be a first step to reduce the incidence and consequences of respiratory compromise in patients receiving opioids on the general care floor

An electromyographical analysis of the role of dorsiflexors on the gait transition during human locomotion

Etude EMG de l'activité de plusieurs muscles des membres inférieurs lors de la transition marche-course chez des jeunes adulte

Experimental Inoculation of Egyptian Fruit Bats (Rousettus aegyptiacus) with Ebola Virus

Colonized Egyptian fruit bats (Rousettus aegyptiacus), originating in South Africa, were inoculated subcutaneously with Ebola virus (EBOV). No overt signs of morbidity, mortality, or gross lesions were noted. Bats seroconverted by Day 10–16 post inoculation (p.i.), with the highest mean anti-EBOV IgG level on Day 28 p.i. EBOV RNA was detected in blood from one bat. In 16 other tissues tested, viral RNA distribution was limited and at very low levels. No seroconversion could be demonstrated in any of the control bats up to 28 days after in-contact exposure to subcutaneously-inoculated bats. The control bats were subsequently inoculated intraperitoneally, and intramuscularly with the same dose of EBOV. No mortality, morbidity or gross pathology was observed in these bats. Kinetics of immune response was similar to that in subcutaneously-inoculated bats. Viral RNA was more widely disseminated to multiple tissues and detectable in a higher proportion of individuals, but consistently at very low levels. Irrespective of the route of inoculation, no virus was isolated from tissues which tested positive for EBOV RNA. Viral RNA was not detected in oral, nasal, ocular, vaginal, penile and rectal swabs from any of the experimental groups.Janusz T. Paweska was supported by the South African Poliomyelitis Research Foundation grant No. 13/15.http://www.mdpi.com/journal/virusesam2016Microbiology and Plant Patholog

IVIg prevents 34-1-2s-induced hypothermia in BALB/c and SCID mice.

<p>Systemic shock was measured by rectal temperatures in A) BALB/c mice or B) SCID mice. In both panels, mice were either not-treated (○) or administered 34-1-2s (•, 9 mg/kg for BALB/c mice and 2 mg/kg for SCID mice iv) or treated prophylactically with 2 g/kg of IVIg 18 hours before 34-1-2s infusion (▵). Some SCID mice in panel B were also treated with 1 g/kg of IVIg 18 hours before 34-1-2s infusion (▿), 1 g/kg of IVIg within 3 minutes after 34-1-2s infusion (□) or 2 g/kg HSA (). Rectal temperatures were monitored at the indicated times after TRALI induction. There were at least 5 mice per group. The data is expressed as mean ±SEM rectal temperatures. Significance was determined by Student's t test at each time point between 34-1-2s infused mice (•) and IVIg treated (▵) mice (★, p<0.02; ★★, p<0.01; ★★★ p<0.0001).</p

IVIg has a modest protective effect in acid-induced lung injury.

<p>IVIg partially protects from arterial hypoxemia, but not changes in lung mechanics and edema formation in acid-induced lung injury. SCID mice were pretreated with either saline (White bars) or 2 g/kg of IVIg (Black bars) 18 hours before acid induced lung injury was induced by intratracheal instillation of HCl (2 mL/kg bw at pH 1.0) (A) Arterial oxygen saturation (SaO₂) levels and (B) peak inspiratory pressure were determined at baseline and 2 hours after instillation of HCl. Wet-to-dry lung weight ratios (C) were determined 2 h after HCl instillation. Data are expressed as means±SEM from n = 5 animals in each group. The ★ indicates significance (p<0.05) between baseline and the treatment groups determined by Student's t test.</p

IVIg prevents 34-1-2s-induced TRALI mortality in SCID mice.

<p>Kaplan-Meier survival plots of SCID mice (N = 10 for each dose group). SCID mice were not treated (○) or administered 34-1-2s (•, 2 mg/kg). Some mice were treated prophylactically 18 hours before 34-1-2s infusion with either a control infusion of 2 g/kg HSA () or 2 g/kg of IVIg (▵) or 1 g/kg of IVIg (▿). The other mice were treated within 3 minutes after TRALI induction with 1 g/kg of IVIg (□). The data is expressed as percentage of mice surviving at the indicated times after TRALI induction. No BALB/c mice treated with 9 mg/kg 34-1-2s died during the experimental protocol. Significance was determined by a Log ranked Mantel-Cox test between 34-1-2s infused mice (•) and prophylactically IVIg treated (▵, 2 g/kg) mice); p = 0.0289 (the survival curves are significantly different.</p