The atypical chemokine receptor Ackr2 constrains NK cell migratory activity and promotes metastasis

Chemokines have been shown to be essential players in a range of cancer contexts. In this study, we demonstrate that mice deficient in the atypical chemokine receptor Ackr2 display impaired development of metastasis in vivo in both cell line and spontaneous models. Further analysis reveals that this relates to increased expression of the chemokine receptor CCR2, specifically by KLRG1+ NK cells from the Ackr2−/− mice. This leads to increased recruitment of KLRG1+ NK cells to CCL2-expressing tumors and enhanced tumor killing. Together, these data indicate that Ackr2 limits the expression of CCR2 on NK cells and restricts their tumoricidal activity. Our data have important implications for our understanding of the roles for chemokines in the metastatic process and highlight Ackr2 and CCR2 as potentially manipulable therapeutic targets in metastasis

Variably protease-sensitive prionopathy, a unique prion variant with inefficient transmission properties

Variably protease-sensitive prionopathy (VPSPr) can occur in persons of all codon 129 genotypes in the human prion protein gene (PRNP) and is characterized by a unique biochemical profile when compared with other human prion diseases. We investigated transmission properties of VPSPr by inoculating transgenic mice expressing human PRNP with brain tissue from 2 persons with the valine-homozygous (VV) and 1 with the heterozygous methionine/valine codon 129 genotype. No clinical signs or vacuolar pathology were observed in any inoculated mice. Small deposits of prion protein accumulated in the brains of inoculated mice after challenge with brain material from VV VPSPr patients. Some of these deposits resembled microplaques that occur in the brains of VPSPr patients. Comparison of these transmission properties with those of sporadic Creutzfeldt-Jakob disease in the same lines of mice indicated that VPSPr has distinct biological properties. Moreover, we established that VPSPr has limited potential for human-to-human transmission

Phenotypic and functional characterization of macrophages with therapeutic potential generated from human cirrhotic monocytes in a cohort study

AbstractBackground aimsMacrophages have complex roles in the liver. The aim of this study was to compare profiles of human monocyte-derived macrophages between controls and cirrhotic patients, to determine whether chronic inflammation affects precursor number or the phenotype, with the eventual aim to develop a cell therapy for cirrhosis.MethodsInfusion of human macrophages in a murine liver fibrosis model demonstrated a decrease in markers of liver injury (alanine transaminase, bilirubin, aspartate transaminase) and fibrosis (transforming growth factor-β, α-smooth muscle actin, phosphatidylserine receptor) and an increase in markers of liver regeneration (matrix metalloproteinases [MMP]-9, MMP-12 and TNF-related weak inducer of apoptosis). CD14+ monocytes were then isolated from controls. Monocytes were matured into macrophages for 7 days using a Good Manufacturing Practice–compatible technique.ResultsThere was no significant difference between the mean number of CD14+ monocytes isolated from cirrhotic patients (n = 9) and controls (n = 10); 2.8 ± SEM 0.54 × 108 and 2.5 ± 0.56 × 108, respectively. The mean yield of mature macrophages cultured was also not significantly different between cirrhotic patients and controls (0.9 × 108 ± 0.38 × 108, with more than 90% viability and 0.65 × 108 ± 0.16 × 108, respectively. Maturation to macrophages resulted in up-regulation of a number of genes (MMP-9, CCL2, interleukin [IL]-10 and TNF-related weak inducer of apoptosis). A cytokine and chemokine polymerase chain reaction array, comparing the control and cirrhotic macrophages, revealed no statistically significant differences.ConclusionsMacrophages can be differentiated from cirrhotic patients' apheresis-derived CD14 monocytes and develop the same pro-resolution phenotype as control macrophages, indicating their suitability for clinical therapy

How well do pediatric anesthesiologists agree when assigning ASA physical status classifications to their patients?

Background: The scope and application of the American Society of Anesthesiologists Physical Status (ASA PS) classification has been called into question and interobserver consistency even by specialist anesthesiologists has been described as only fair. Our purpose was to evaluate the consistency of the application of the ASA PS amongst a group of pediatric anesthesiologists. Methods: We randomly selected 400 names from the active list of specialist members of the Society for Pediatric Anesthesia. Respondents were asked to rate 10 hypothetical pediatric patients and answer four demographic questions. Results: We received 267 surveys, yielding a response rate of 66.8% and the highest number of responses in any study of this nature. The spread of answers was wide across almost all cases. Only one case had a response spread of only two classifications, with the remaining cases having three or more different ASA PS classifications chosen. The most variability was found for a hypothetical patient with severe trauma, who received five different ASA PS classifications. The Modified Kappa Statistic was 0.5, suggesting moderate agreement. No significant difference between the private and academic anesthesiologists was found (P = 0.26). Conclusions: We present the largest evaluation of interobserver consistency in ASA PS in pediatric patients by pediatric anesthesiologists. We conclude that agreement between anesthesiologists is only moderate and suggest standardizing assessment, so that it reflects the patient status at the time of anesthesia, including any acute medical or surgical conditions. © 2007 The Authors

Prospective randomized crossover evaluation of three anesthetic regimens for painful procedures in children with cancer

Objective: To identify the most effective sedation regimen for bone marrow aspiration and lumbar puncture procedures with a prospective trial of 3 combinations of sedation/analgesia. Study design: In this double-blind crossover study, we randomly assigned 162 children with acute lymphoblastic leukemia or lymphoblastic lymphoma to receive fentanyl 1 mcg/kg, fentanyl 0.5 mcg/kg, or placebo, in addition to propofol and topical anesthetic for 355 procedures. Results: We found no significant differences among the 3 regimens in the frequency of pain (pain score \u3e 0) or severe pain (pain score ≥ 5) during recovery, or a \u3e20% increase in hemodynamic/respiratory variables during anesthesia. Treatment with fentanyl 1 mcg/kg was associated with a lower frequency of movement during procedure compared with treatment with fentanyl 0.5 mcg/kg (P =.0476) or treatment with placebo (P =.0545). The placebo group required longer time to recover (median, 18 minutes) compared with the fentanyl 0.5 mcg/kg group (median, 9 minutes) (median difference 2.0, P =.007) and the fentanyl 1 mcg/kg (median 8 minutes), (median difference 2.0, P =.15). The placebo group also required larger total dose of propofol (median 5 mg/kg) compared with that of the fentanyl 1 mcg/kg group (median, 3.5 mg/kg) and the fentanyl 0.5 mcg/kg group (median 3.5 mg/kg) (median differences 1.5, P \u3c.00005, in both comparisons). Conclusion: The addition of fentanyl 1 mcg/kg to propofol for brief painful procedures reduces movement, propofol dose, and recovery time. Copyright © 2013 Mosby Inc

Talking to Teens about Pain:A Modified Delphi Study of Adolescent Pain Science Education

Background: Persistent pain is a prevalent condition that negatively influences physical, emotional, social and family functioning in adolescents. Pain science education is a promising therapy for adults, yet to be thoroughly investigated for persistent pain in adolescents. There is a need to develop suitable curricula for adolescent pain science education. Methods: An interdisciplinary meeting of 12 clinicians and researchers was held during March 2018 in Adelaide, South Australia. An a priori objective of the meeting was to identify and gain consensus on key learning objectives for adolescent pain science education using a modified-Delphi process. Results and Conclusion: Consensus was reached via a modified Delphi process for seven learning objectives to form the foundation of a curriculum: 1) Pain is a protector; 2) The pain system can become overprotective; 3) Pain is a brain output; 4) Pain is not an accurate marker of tissue state; 5) There are many potential contributors to anyone’s pain; 6) We are all bioplastic and; 7) Pain education is treatment. Recommendations are made for promising areas for future research in adolescent pain science education