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Chronic inflammation is frequently invoked as a mechanism of neurodegeneration and yet inflammatory cell infiltrates are seldom seen in brains of these disorders. Different disciplines utilize different technologies and methodologies to describe what is immunologically defined as the innate immune response (IIR). We examined murine models of the human neurodegenerative disease Aicardi‐Goutières Syndrome, where an IIR is initiated by aberrant RNA metabolism secondary to a mutation in adenosine deaminase acting on RNA gene (ADAR1). We previously showed that these mice demonstrated a deficit in RNA editing that lead to MDA‐5 mediated RNA sensing pathway activation of the IIR with massive interferon stimulated gene transcription and translation. As early as 2 weeks of age, in situ hybridization demonstrated that different central nervous system (CNS) cell lineages expressed very high levels of distinct interferon stimulated genes (ISGs) in the absence of interferon and absence of immune cell infiltrates. We have expanded these studies to more completely describe the breadth of ISG expression systemically and in CNS using double label in situ hybridization. Within the CNS aberrant ISG expression was mostly limited to neurons, microglia, ependyma, choroid plexus, and endothelial cells with little expression in oligodendroglia and astrocytes except for STAT1. Wild type controls showed a similar pattern of ISG expression but only in aged mice and at levels minimally detectable by in situ hybridization. Despite months of elevated ISG expression in mutant mice, there was essentially no inflammatory infiltrate, no interferon production and minimal glial reaction. Histomorphological neurodegenerative pathology of ventricular dilatation and deep gray matter mineralization were evident in mutant mice 8–13 months of age but this did not show a spatial relationship to ISG expression. This IIR without immune cell infiltration leads to neurodegeneration through non‐canonical pathways that may accentuate normal aging pathways. [ABSTRACT FROM AUTHOR]

Aim: There is limited information on the outcomes after primary prevention implantable cardioverter-defibrillator (ICD) implantation in patients with heart failure (HF) and diabetes. This analysis evaluates the effectiveness of a strategy of ICD plus medical therapy vs. medical therapy alone among patients with HF and diabetes.Methods and Results: A patient-level combined-analysis was conducted from a combined dataset that included four primary prevention ICD trials of patients with HF or severely reduced ejection fractions: Multicenter Automatic Defibrillator Implantation Trial I (MADIT I), MADIT II, Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation (DEFINITE), and Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT). In total, 3359 patients were included in the analysis. The primary outcome of interest was all-cause death. Compared with patients without diabetes (n = 2363), patients with diabetes (n = 996) were older and had a higher burden of cardiovascular risk factors. During a median follow-up of 2.6 years, 437 patients without diabetes died (178 with ICD vs. 259 without) and 280 patients with diabetes died (128 with ICD vs. 152 without). ICDs were associated with a reduced risk of all-cause mortality among patients without diabetes [hazard ratio (HR) 0.56, 95% confidence interval (CI) 0.46-0.67] but not among patients with diabetes (HR 0.88, 95% CI 0.7-1.12; interaction P = 0.015).Conclusion: Among patients with HF and diabetes, primary prevention ICD in combination with medical therapy vs. medical therapy alone was not significantly associated with a reduced risk of all-cause death. Further studies are needed to evaluate the effectiveness of ICDs among patients with diabetes. [ABSTRACT FROM AUTHOR]

Patients with chronic myelogenous leukemia (CML) respond well to tyrosine kinase inhibitors (TKIs) of the Bcr-Abl oncoprotein. However, intolerance and resistance to these agents remains a challenge, and TKIs are unable to eradicate rare leukemia-initiating cells. Leukemia treatment would benefit from a better understanding of molecular signals that are necessary for the survival of leukemia-initiating cells but dispensable for normal hematopoietic stem cells. Leukemia-initiating cells in CML can arise from myeloid progenitor cells, a population that we have reported in normal hematopoiesis to depend on the RNA-editing enzyme adenosine deaminase acting on RNA-1 (ADAR1). We now report that Bcr-Abl transformed leukemic cells were ADAR1-dependent in a conditional ADAR1 knockout mouse model. ADAR1 deletion reversed leukocytosis and splenomegaly, and preferentially depleted primitive Lin-Sca+Kit+ (LSK) leukemic cells but not LSK cells lacking the leukemic oncoprotein. ADAR1 deletion ultimately normalized the peripheral white blood count, eliminating leukemic cells as assessed by PCR. These results uncover a novel requirement for ADAR1 in myeloid leukemic cells and indicate that ADAR1 may comprise a new molecular target for CML-directed therapeutics. [ABSTRACT FROM AUTHOR]

Prolonged quiescence of haematopoietic stem cells has been proposed to support durable haematopoiesis through clonal succession. Genetic experiments in mice have implicated the cyclin-dependent kinase inhibitor (cdki) p21Waf1 in sustaining stem cell quiescence, and the cdki p27Kip1 in inhibiting the expansion of more mature progenitor cells. The expression of these inhibitory proteins in human haematopoietic stem cell candidates has not hitherto been studied. We describe a rare subpopulation (3 × 10−7 umbilical cord mononuclear cells) of lineage-negative cells that exhibited sustained resistance over months to cytokine-induced cycling, and characterized the expression of p21Waf1 and p27Kip1 proteins in these cells. Whereas p27Kip1 was uniformly expressed in these cells, the expression of p21Waf1 in this population and in lineage-negative CD34+ cells was variable. For this rare subset of cells exhibiting prolonged quiescence, p21Waf1 may be dispensable and p27Kip1 necessary for growth arrest. [ABSTRACT FROM AUTHOR]

Objectives To heighten the understanding of host–disease interactions by adolescents and young adults, using a trading card game format. Design A trading card game was developed in which paired students attack one another with pathogens or parry those attacks with appropriate defences. Twenty-five infectious pathogens or cancers, 30 defence agents and 6 health status modifying conditions were included. Setting A middle school, upper school and medical school in the United States. Subjects 8th grade, 10th grade and first year medical students. Results The game was tested using pre-test/post-test evaluations in 8th graders, 10th graders and medical students. Factual information, pathogen-organ specificity, and general concepts were tested. There was a significant increase in test scores, from 39% to 58% correct in the 8th graders (P < 0·0001), from 47% to 59% among 10th graders (P = 0·0007), and from 80% to 88% (P = 0·049) among the medical students. Responses to control questions unrelated to the game did not improve. Conclusion An interactive trading card format is a useful method for conveying information about host defence. [ABSTRACT FROM AUTHOR]

Summary. We describe a B-cell line, BDCM, which arose spontaneously from culture of a pheresis product from a patient with M5a myeloid leukaemia. Cell growth was associated with autocrine activation of the s ignal t ransducer and a ctivator of t ranscription 1 (Stat-1) transcription factor. Although the cells expressed several B-cell surface markers and had a rearranged immunoglobin J region, they also exhibited several characteristics associated with dendritic cells. These included extensive surface projections, cross-priming ability and strong T cell-stimulating capability. In addition, the cytokine production profile of BDCM cells was nearly identical to that of mature monocyte-derived dendritic cells. [ABSTRACT FROM AUTHOR]

Ciprofloxacin is an investigational quinolone agent possessing an impressive antibacterial spectrum. Its pharmacokinetics were studied in six volunteers after 250-mg and 500-mg single oral doses, and its bactericidal activity compared to that of trimethoprim-sulfamethoxazole given to the same volunteers. Mean peak serum levels were 1.45 μg/mL and 2.46 μg/mL for 250-mg and 500-mg doses, and time to peak was 1 and 1.3 hours. The 12-hour levels were 0.12 μg and 0.22 μg. Half-life (T1/2)α were 0.32 and 0.43 with T1/2β were 3.97 and 4.15 and volume of distribution (area) were 80L and 90L, respectively. Area under the concentration curve (AUC) was 5.65 h · μg/mL and 10.37h · μg/mL. Serum clearance was 23L for both doses. Approximately 49% of the 250-mg dose and 43% of the 500-mg dose was recovered in the urine. Bactericidal levels were determined against clinical isolates. Sera at 1.5 hours after the 500-mg dose averaged bactericidal levels of 1:20 or better for an Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and beta-lactamase producing Haemophilus influenzae and Branhamella catarrhalis. Urinary bactericidal levels at eight to 12 hours were 1:157 for E coli, K pneumoniae, gentamicin-piperacillin resistant P aeruginosa, Staphylococcus aureus, and 1:20 for Streptococcus faecalis. Serum bactericidal levels were superior, and urine bactericidal levels were superior or equal to the bactericidal levels obtained with trimethoprim-sulfamethoxazole. Ciprofloxacin's in vitro activity and human pharmacology should permit a twice or once daily dosing schedule for system 1C infections due to most Enterobacteriaceae, Haemophilus, Branhamella and Pseudomonas, and S aureus, and once daily for urinary gastrointestinal infections. [ABSTRACT FROM AUTHOR]