Testing multiple hypotheses with skewed alternatives

In many practical cases of multiple hypothesis problems, it can be expected that the alternatives are not symmetrically distributed. If it is known a priori that the distributions of the alternatives are skewed, we show that this information yields high power procedures as compared to the procedures based on symmetric alternatives when testing multiple hypotheses. We propose a Bayesian decision theoretic rule for multiple directional hypothesis testing, when the alternatives are distributed as skewed, under a constraint on a mixed directional false discovery rate. We compare the proposed rule with a frequentist\u27s rule of Benjamini and Yekutieli (2005) using simulations. We apply our method to a well-studied HIV dataset

Function of monocytes and monocyte-derived macrophages in α1-antitrypsin deficiency.

α1-antitrypsin deficiency is the most widely recognised genetic disorder causing chronic obstructive pulmonary disease (COPD). Mutant Z α1-antitrypsin expression has previously been linked to intracellular accumulation and polymerisation of this proteinase inhibitor. Subsequently, this has been described to underlie an exaggerated endoplasmic reticulum stress response and enhanced nuclear factor-κB signalling. However, whether monocyte-derived macrophages display the same features remains unknown. Monocytes from homozygous PiZZ α1-antitrypsin deficiency patients and PiMM controls were cultured for 6 days in the presence of granulocyte-macrophage or macrophage colony-stimulating factor to obtain pro- and anti-inflammatory macrophages (mφ-1 and mφ-2, respectively). We first showed that, in contrast to monocytes, pre-stressed mφ-1 and mφ-2 from healthy blood donors display an enhanced endoplasmic reticulum stress response upon a lipopolysaccharide trigger (XBP1 splicing, CHOP, GADD34 and GRP78 mRNA). However, this endoplasmic reticulum stress response did not differ between monocyte-derived macrophages and monocytes from ZZ patients compared to MM controls. Furthermore, these ZZ cells do not secrete higher cytokine levels, and α1-antitrypsin polymers were not detectable by ELISA. These data suggest that monocyte-derived macrophages are not the local source of Z α1-antitrypsin polymers found in the lung and that endoplasmic reticulum stress and pro-inflammatory cytokine release is not altered.This study was supported by a grant from the Netherlands Asthma Foundation (grant no. 3.2.08.0032). E.F.A. van't Wout is an European Alpha-1-Antitrypsin Laurell’s Training Awardee (sponsored by Grifols, Barcelona, Spain). D.A. Lomas is supported by the Medical Research Council (London, UK) and the NIHR UCLH Biomedical Research Centre (London). S.J. Marciniak is a Medical Research Council Senior Clinical Research Fellow (grant no. G1002610)

Polymorphism in HIV-1 dependency factor PDE8A affects gene expression and HIV-1 replication in primary macrophages

The limited size of the human immunodeficiency virus 1 (HIV-1) genome and the small number of proteins it encodes make the virus highly dependent on host proteins for its replication. Four genome-wide RNAi screens have recently identified a large number of HIV-1 dependency factors (HDFs), with the majority of these proteins never before associated with HIV-1 replication. Recently, we reported more than 3 log variation in the ability of HIV-1 to replicate in monocyte derived macrophages (MDM) derived from \u3e4OO healthy seronegative blood donors. In our present study we determined whether single nucleotide polymorphisms (SNPs) in the genes encoding the newly identified HDFs were associated with this variation in HIV-1 replication

Outpatient parenteral antifungal therapy (OPAT) for invasive fungal infections with intermittent dosing of liposomal amphotericin B

Triazole resistant A. fumigatus has been documented in many parts of the world. In the Netherlands, incidence is now above 10% and results in the need for long-term parenteral therapy with liposomal amphotericin B (LAmB). The long terminal half-life of LAmB suggests that intermittent dosing could be effective, making the application of outpatient antifungal therapy (OPAT) possible. Here, we report our experience with the use of OPAT for Invasive Fungal Infections (IFI). All adult patients treated with LAmB with a 2 or 3 times weekly administration via the outpatient departments in four academic tertiary care centers in the Netherlands and Belgium since January 2010 were included in our analysis. Patient characteristics were collected, as well as information about diagnostics, therapy dose and duration, toxicity, treatment history and outcome of the IFI. In total, 18 patients were included. The most frequently used regimen (67%) was 5 mg/kg 3 times weekly. A partial response to the daily treatment prior to discharge was confirmed by CT-scan in 17 (94%) of patients. A favorable outcome was achieved in 13 (72%) patients. Decrease in renal function occurred in 10 (56%) cases but was reversible in all and was treatment limiting in one patient only. The 100-day mortality and 1-year mortality after initiation of OPAT were 0% and 6%, respectively. In a selected population, and after confirmation of initial response to treatment, our data support the use of OPAT with LAmB for treatment of IFI in an intermittent dosing regimen

Few-Layer Graphene Kills Selectively Tumor Cells from Myelomonocytic Leukemia Patients

In the cure of cancer, a major cause of todayQs mortality, chemotherapy is the most common treatment, though serious frequent challenges are encountered by current anticancer drugs. We discovered that few-layer graphene (FLG) dispersions have a specific killer action on monocytes, showing neither toxic nor activation effects on other immune cells. We confirmed the therapeutic application of graphene on an aggressive type of cancer that is myelomonocytic leukemia, where the monocytes are in their malignant form. We demonstrated that graphene has the unique ability to target and boost specifically the necrosis of monocytic cancer cells. Moreover, the comparison between FLG and a common chemotherapeutic drug, etoposide, confirmed the higher specificity and toxicity of FLG. Since current chemotherapy treatments of leukemia still cause serious problems, these findings open the way to new and safer therapeutic approaches

Procalcitonin reflects bacteremia and bacterial load in urosepsis syndrome: a prospective observational study

Introduction: Guidelines recommend that two blood cultures be performed in patients with febrile urinary tract infection (UTI), to detect bacteremia and help diagnose urosepsis. The usefulness and cost-effectiveness of this practice have been criticized. This study aimed to evaluate clinical characteristics and the biomarker procalcitonin (PCT) as an aid in predicting bacteremia. Methods: A prospective observational multicenter cohort study included consecutive adults with febrile UTI in 35 primary care units and 8 emergency departments of 7 regional hospitals. Clinical and microbiological data were collected and PCT and time to positivity (TTP) of blood culture were measured. Results: Of 581 evaluable patients, 136 (23%) had bacteremia. The median age was 66 years (interquartile range 46 to 78 years) and 219 (38%) were male. We evaluated three different models: a clinical model including seven bedside characteristics, the clinical model plus PCT, and a PCT only model. The diagnostic abilities of these models as reflected by area under the curve of the receiver operating characteristic were 0.71 (95% confidence interval (CI): 0.66 to 0.76), 0.79 (95% CI: 0.75 to 0.83) and 0.73 (95% CI: 0.68 to 0.77) respectively. Calculating corresponding sensitivity and specificity for the presence of bacteremia after each step of adding a significant predictor in the model yielded that the PCT > 0.25 mu g/l only model had the best diagnostic performance (sensitivity 0.95; 95% CI: 0.89 to 0.98, specificity 0.50; 95% CI: 0.46 to 0.55). Using PCT as a single decision tool, this would result in 40% fewer blood cultures being taken, while still identifying 94 to 99% of patients with bacteremia. The TTP of E. coli positive blood cultures was linearly correlated with the PCT log value; the higher the PCT the shorter the TTP (R-2 = 0.278, P = 0.007). Conclusions: PCT accurately predicts the presence of bacteremia and bacterial load in patients with febrile UTI. This may be a helpful biomarker to limit use of blood culture resources.Immunogenetics and cellular immunology of bacterial infectious disease

Candida tropicalis arthritis of the elbow in a patient with Ewing's sarcoma that successfully responded to itraconazole

Fungal infections are rarely responsible for arthritis. Few cases of fungal arthritis have been reported, even in immunocompromised hosts susceptible to low-virulence organisms. Herein, the authors report the first case of Candida tropicalis arthritis in a child with a solid tumor. A 13-year-old boy with Ewing's sarcoma developed arthritis in his elbow during the neutropenic period after chemotherapy. Despite treatment with broad-spectrum antibiotics, his condition did not improve and serial blood cultures failed to reveal any causative organisms. After surgical drainage, culture of the joint fluid revealed the presence of C. tropicalis. Itraconazole treatment was started and after 3 months of therapy, the patient completely recovered full elbow function

Mathematically Gifted Adolescents Have Deficiencies in Social Valuation and Mentalization

Many mathematically gifted adolescents are characterized as being indolent, underachieving and unsuccessful despite their high cognitive ability. This is often due to difficulties with social and emotional development. However, research on social and emotional interactions in gifted adolescents has been limited. The purpose of this study was to observe differences in complex social strategic behaviors between gifted and average adolescents of the same age using the repeated Ultimatum Game. Twenty-two gifted adolescents and 24 average adolescents participated in the Ultimatum Game. Two adolescents participate in the game, one as a proposer and the other as a responder. Because of its simplicity, the Ultimatum Game is an apt tool for investigating complex human emotional and cognitive decision-making in an empirical setting. We observed strategic but socially impaired offers from gifted proposers and lower acceptance rates from gifted responders, resulting in lower total earnings in the Ultimatum Game. Thus, our results indicate that mathematically gifted adolescents have deficiencies in social valuation and mentalization

Regulation of YKL-40 expression by corticosteroids:effect on pro-inflammatory macrophages in vitro and its modulation in COPD in vivo

Macrophages constitute a heterogeneous cell population with pro- (MΦ1) and anti-inflammatory (MΦ2) cells. The soluble chitinase-like-protein YKL-40 is expressed in macrophages and various other cell types, and has been linked to a variety of inflammatory diseases, including COPD. Dexamethasone strongly reduces YKL-40 expression in peripheral blood mononuclear cells (PBMC) in vitro. We hypothesized that: a) YKL-40 is differentially expressed by MΦ1 and MΦ2, b) is decreased by corticosteroids and c) that long-term treatment with inhaled corticosteroids (ICS) affects YKL-40 levels in serum and sputum of COPD patients. Monocytes of healthy subjects were cultured in vitro for 7 days with either GM-CSF or M-CSF (for MΦ1 and MΦ2, respectively) and stimulated for 24 h with LPS, TNFα, or oncostatin M (OSM). MΦ1 and MΦ2 differentiation was assessed by measuring secretion of IL-12p40 and IL-10, respectively. YKL-40 expression in macrophages was measured by quantitative RT-PCR (qPCR) and ELISA; serum and sputum YKL-40 levels were analyzed by ELISA. Pro-inflammatory MΦ1 cells secreted significantly more YKL-40 than MΦ2, which was independent of stimulation with LPS, TNFα or OSM (p < 0.001) and confirmed by qPCR. Dexamethasone dose-dependently and significantly inhibited YKL-40 protein and mRNA levels in MΦ1. Serum YKL-40 levels of COPD patients were significantly higher than sputum YKL-40 levels but were not significantly changed by ICS treatment. YKL-40 secretion from MΦ1 cells is higher than from MΦ2 cells and is unaffected by further stimulation with pro-inflammatory agents. Furthermore, YKL-40 release from cultured monocyte-derived macrophages is inhibited by dexamethasone especially in MΦ1, but ICS treatment did not change YKL-40 serum and sputum levels in COPD. These results indicate that YKL-40 expression could be used as a marker for MΦ1 macrophages in vitro, but not for monitoring the effect of ICS in COPD. ClinicalTrials.gov, registration number: NCT0015884