Anti-Human Tissue Factor Antibody Ameliorated Intestinal Ischemia Reperfusion-Induced Acute Lung Injury in Human Tissue Factor Knock-In Mice

BACKGROUND: Interaction between the coagulation and inflammation systems plays an important role in the development of acute respiratory distress syndrome (ARDS). Anti-coagulation is an attractive option for ARDS treatment, and this has promoted development of new antibodies. However, preclinical trials for these antibodies are often limited by the high cost and availability of non-human primates. In the present study, we developed a novel alternative method to test the role of a humanized anti-tissue factor mAb in acute lung injury with transgenic mice. METHODOLOGY/PRINCIPAL FINDINGS: Human tissue factor knock-in (hTF-KI) transgenic mice and a novel humanized anti-human tissue factor mAb (anti-hTF mAb, CNTO859) were developed. The hTF-KI mice showed a normal and functional expression of hTF. The anti-hTF mAb specifically blocked the pro-coagulation activity of brain extracts from the hTF-KI mice and human, but not from wild type mice. An extrapulmonary ARDS model was used by intestinal ischemia-reperfusion. Significant lung tissue damage in hTF-KI mice was observed after 2 h reperfusion. Administration of CNTO859 (5 mg/kg, i.v.) attenuated the severity of lung tissue injury, decreased the total cell counts and protein concentration in bronchoalveolar lavage fluid, and reduced Evans blue leakage. In addition, the treatment significantly reduced alveolar fibrin deposition, and decreased tissue factor and plasminogen activator inhibitor-1 activity in the serum. This treatment also down-regulated cytokine expression and reduced cell death in the lung. CONCLUSIONS: This novel anti-hTF antibody showed beneficial effects on intestinal ischemia-reperfusion induced acute lung injury, which merits further investigation for clinical usage. In addition, the use of knock-in transgenic mice to test the efficacy of antibodies against human-specific proteins is a novel strategy for preclinical studies

Journal of clinical monitoring and computing 2016 end of year summary:monitoring cerebral oxygenation and autoregulation

In the perioperative and critical care setting, monitoring of cerebral oxygenation (ScO2) and cerebral autoregulation enjoy increasing popularity in recent years, particularly in patients undergoing cardiac surgery. Monitoring ScO2 is based on near infrared spectroscopy, and attempts to early detect cerebral hypoperfusion and thereby prevent cerebral dysfunction and postoperative neurologic complications. Autoregulation of cerebral blood flow provides a steady flow of blood towards the brain despite variations in mean arterial blood pressure (MAP) and cerebral perfusion pressure, and is effective in a MAP range between approximately 50-150 mmHg. This range of intact autoregulation may, however, vary considerably between individuals, and shifts to higher thresholds have been observed in elderly and hypertensive patients. As a consequence, intraoperative hypotension will be poorly tolerated, and might cause ischemic events and postoperative neurological complications. This article summarizes research investigating technologies for the assessment of ScO2 and cerebral autoregulation published in the Journal of Clinical Monitoring and Computing in 2016

Mitogen- and Stress-Activated Kinase 1 (MSK1) Regulates Cigarette Smoke-Induced Histone Modifications on NF-κB-dependent Genes

Cigarette smoke (CS) causes sustained lung inflammation, which is an important event in the pathogenesis of chronic obstructive pulmonary disease (COPD). We have previously reported that IKKα (I kappaB kinase alpha) plays a key role in CS-induced pro-inflammatory gene transcription by chromatin modifications; however, the underlying role of downstream signaling kinase is not known. Mitogen- and stress-activated kinase 1 (MSK1) serves as a specific downstream NF-κB RelA/p65 kinase, mediating transcriptional activation of NF-κB-dependent pro-inflammatory genes. The role of MSK1 in nuclear signaling and chromatin modifications is not known, particularly in response to environmental stimuli. We hypothesized that MSK1 regulates chromatin modifications of pro-inflammatory gene promoters in response to CS. Here, we report that CS extract activates MSK1 in human lung epithelial (H292 and BEAS-2B) cell lines, human primary small airway epithelial cells (SAEC), and in mouse lung, resulting in phosphorylation of nuclear MSK1 (Thr581), phospho-acetylation of RelA/p65 at Ser276 and Lys310 respectively. This event was associated with phospho-acetylation of histone H3 (Ser10/Lys9) and acetylation of histone H4 (Lys12). MSK1 N- and C-terminal kinase-dead mutants, MSK1 siRNA-mediated knock-down in transiently transfected H292 cells, and MSK1 stable knock-down mouse embryonic fibroblasts significantly reduced CS extract-induced MSK1, NF-κB RelA/p65 activation, and posttranslational modifications of histones. CS extract/CS promotes the direct interaction of MSK1 with RelA/p65 and p300 in epithelial cells and in mouse lung. Furthermore, CS-mediated recruitment of MSK1 and its substrates to the promoters of NF-κB-dependent pro-inflammatory genes leads to transcriptional activation, as determined by chromatin immunoprecipitation. Thus, MSK1 is an important downstream kinase involved in CS-induced NF-κB activation and chromatin modifications, which have implications in pathogenesis of COPD

Preliminary-Observations On Blood-Flow in the Coronary-Arteries of 2 School Sharks (Galeorhinus-Australis)

Coronary arterial blood flow and pressure, intraventricular blood pressure, and ventral aortic blood velocity were measured in two anaesthetized school sharks (Galeorhinus australis) in order to examine the phasic relationships between these flows and pressures. Maximum instantaneous flow recorded in the ventral coronary artery was 0.37 mL . min-1 . kg-1 body mass (estimated 0.63 mL . min-1 .g-1 ventricular mass). The average mean coronary blood flow was estimated as 0.28 mL . min-1 . g-1 ventricular mass during periods of high coronary blood flow. On average, 86% of coronary flow occurred during diastole. Coronary arterial flow began during the last quarter of ventricular systole. Coronary blood flow peaked when intraventricular pressure fell to just below zero immediately after ventricular systole. Coronary blood flow fell slightly as diastole continued and reflected the small fall in coronary arterial pressure. Coronary flow reversed briefly during isovolumic ventricular contraction. Increases in the proportion of the cardiac cycle occupied by ventricular diastole, which occur during hypoxic bradycardia, have the potential to more than double coronary blood flow provided coronary arterial pressure is maintained

Cardiac Physiology in Tunas .1. Invitro Perfused Heart Preparations From Yellowfin and Skipjack Tunas

An in situ heart preparation perfused with oxygenated saline was used to examine cardiac performance at 25-degrees-C in yellowfin tuna (Thunnus albacares) and skipjack tuna (Katsuwonus pelamis). Heart rates (91-172 bpm in skipjack tuna and 101 - 157 bpm in yellowfin tuna) were comparable to those measured in vivo, and physiological stroke volumes were possible in yellowfin tuna with subambient filling pressures. In yellowfin tuna, maximum stroke volume and cardiac output were similar to the values obtained in vivo with spinally blocked animals; mean output pressures (up to 145 cmH2O, 1 cmH2O = 0.098 kPa) could exceed in vivo values without a major decrease in the resting cardiac output (homeometric regulation). In contrast, saline-perfused skipjack tuna hearts could not develop physiological output pressures without compromising cardiac output, with cardiac output being only 63% of the in vivo value at an output pressure near the in vivo ventral aortic pressure. The poor performance of the skipjack tuna heart is attributed to limited oxygen diffusion through the thicker walled ventricle. We conclude that the tuna heart is more dependent on its coronary circulation for normal function than the hearts of other fishes examined thus far. The coronary circulation was perfused with saline at various flow rates in isolated hearts from skipjack tuna to develop a pressure-flow relationship for the intact circulation. Coronary resistance reached a minimum of 24 cmH2O . min . g ventricular mass/mL at a flow rate of 2 mL/(min . g ventricular mass) with perfusion pressure about 40 cmH2O. In vivo coronary blood flow was estimated from the pressure-flow relationship as 0.67 mL/(min . g ventricular mass). Injections of adrenaline, noradrenaline, and phenylephrine into coronary circulation under constant flow conditions increased perfusion pressure, indicating the possibility of alpha-adrenergic vasoconstriction

Prevalence of spinal abnormalities in Chinook salmon smolt and influence of early rearing temperature and growth rates

"This is the peer reviewed version of the following article: Munday, J. S., et al. (2018). "Prevalence of spinal abnormalities in Chinook salmon smolt and influence of early rearing temperature and growth rates." Journal of Fish Diseases 41(7): 1111-1116, which has been published in final form at https://onlinelibrary.wiley.com/doi/full/10.1111/jfd.12804. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.Publishe

H-1 magnetic resonance spectroscopy of chronic cerebral white matter lesions and normal appearing white matter in multiple sclerosis

Objectives-To test the hypothesis that irrecoverable neurological deficit in multiple sclerosis is associated with axonal loss.Methods-H-1 magnetic resonance spectroscopy (MRS) was carried out in a group of patients with clinically definite multiple sclerosis (n=31).Using this technique, the apparent concentration of NA ([NA] the sum of N-acetyl aspartate (NAA), a neuronal marker, and N-acetylaspartylglutamate has been compared in four groups of patients with multiple sclerosis classified as relapsing-remitting, secondary progressive, primary progressive, benign, and a control group.Results-In the patients with relapsing-remitting disease (n=9) there was a highly significant reduction of apparent NA (median 8.73 mM, range 6.86 MM-10.74 mM, P=0.0008) from an area of high signal compared with the control group (median 11.97 mM, range 10.55 mM-14.5 mM). In the patients with secondary progressive disease (n=10), there was again a highly significant reduction of apparent NA (median 7.82 mM, range 3.5 mM-10.3 mM, P=0.0003) from an area of high signal compared with the control group. In the patients with primary progressive disease (n=6) there was once again a highly significant reduction of apparent NA (median 8.83 mM, range 6.95 mM-9.89 mM, P<0.002) from an area of high signal compared with the control group. In the patients with benign disease, however, there was no significant difference in the apparent NA (median 10.5 mM, range 8.53 mM-12.8 mM, P>0.05) from an area of high signal compared with the control group. In the patients with benign disease (n=5) there was also no significant difference in the apparent NA (median 10.74 mM, range 8.58 mM-13.4 mM, P>0.3) from an area of normal appearing white matter compared with the control group. In the patients with primary progressive disease, however, there was a significant reduction of apparent NA from an area of normal appearing white matter (median 8.78 mM, range 8.7 mM-12.38 mM, P< 0.025) compared with the control group.There was a significant inverse correlation between [NA] from lesions in the patients with multiple sclerosis and disability as measured on the Kurtzke expanded disability scale score (r= -0.364, 0.05>P> 0.02).Conclusion-These findings support the hypothesis that axonal loss is important in the development of disability in multiple sclerosis. They also provide evidence for axonal loss in normal appearing white matter in patients with primary progressive disease