CD23 can negatively regulate B-cell receptor signaling.

CD23 has been implicated as a negative regulator of IgE and IgG antibody responses. However, whether CD23 has any role in B-cell activation remains unclear. We examined the expression of CD23 in different subsets of peripheral B cells and the impact of CD23 expression on the early events of B-cell receptor (BCR) activation using CD23 knockout (KO) mice.

Impaired immunological synapse in sperm associated antigen 6 (SPAG6) deficient mice.

Sperm associated antigen 6 (SPAG6), a component of the central apparatus of the "9 + 2" axoneme, plays a central role in ciliary and flagellar motility; but, its contribution to adaptive immunity and immune system development is completely unknown. While immune cells lack a cilium, the immunological synapse is a surrogate cilium as it utilizes the same machinery as ciliogenesis including the nucleation of microtubules at the centrosome. This prompted our hypothesis that SPAG6 critically regulates the formation and function of immunological synapses.

Macrophage migration inhibitory factor deficiency enhances immune response to Nippostrongylus brasiliensis.

Infections with helminth parasites are endemic in the developing world and are a target for intervention with new therapies. Macrophage migration inhibitory factor (MIF) is a cytokine with pleiotropic effects in inflammation and immune responses. We investigated the role of MIF in a naturally cleared model of helminth infection in rodents, Nippostrongylus brasiliensis.

A calcium-redox feedback loop controls human monocyte immune responses: The role of ORAI Ca2+ channels.

In phagocytes, pathogen recognition is followed by Ca(2+) mobilization and NADPH oxidase 2 (NOX2)-mediated "oxidative burst," which involves the rapid production of large amounts of reactive oxygen species (ROS). We showed that ORAI Ca(2+) channels control store-operated Ca(2+) entry, ROS production, and bacterial killing in primary human monocytes. ROS inactivate ORAI channels that lack an ORAI3 subunit.

Using Cystic Fibrosis Therapies for Non-Cystic Fibrosis Bronchiectasis.

Non-cystic fibrosis bronchiectasis (NCFB) is an increasingly prevalent disease that places a significant burden on patients and health systems globally. Although many of the therapies used to treat NCFB were originally developed as cystic fibrosis (CF) therapies, not all of them have been demonstrated to be efficacious in NCFB and some may even be harmful. This article explores the evidence for which therapeutic strategies used to treat CF have been translated into the care of NCFB.

A phase 3, multi-center, multinational, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of levofloxacin inhalation solution (APT-1026) in stable cystic fibrosis patients.

Rationale: For patients with cystic fibrosis (CF), the use of inhaled antibiotics has become standard of care to suppress chronic Pseudomonas airways infection. There are limited antibiotic options formulated and approved for inhaled use and antibiotic efficacies attenuate over time, making additional inhaled antibiotic classes desirable. APT-1026 (levofloxacin inhalation solution, LIS) is a fluoroquinolone in development for management of chronic P.

Why Hire a Doctor of Nursing Practice-Prepared Nurse? The Value Added Impact of the Practice Doctorate.

Nursing leaders are essential in promoting the doctor of nursing practice (DNP)-prepared nurse in various innovative roles (Nichols, O'Connor, & Dunn, 2014). However, according to the recently released RAND study, (Auerbach et al., 2014) employers and health care organizations need outreach and data to understand the added competencies and capabilities of DNP-educated nurses.

Use of the Novel Therapeutic Agent Miltefosine for the Treatment of Primary Amebic Meningoencephalitis: Report of 1 Fatal and 1 Surviving Case.

Primary amebic meningoencephalitis (PAM) is a fulminant central nervous system infection caused by the thermophilic free-living ameba Naegleria fowleri. Few survivals have been documented and adequate treatment is lacking. We report 2 PAM cases, 1 fatal and 1 surviving, treated with the novel antiparasitic agent miltefosine.

The Theory of Value-Based Payment Incentives and Their Application to Health Care.

Objectives: To present the implications of agency theory in microeconomics, augmented by behavioral economics, for different methods of value-based payment in health care; and to derive a set of future research questions and policy recommendations based on that conceptual analysis.

Data Sources: Original literature of agency theory, and secondarily behavioral economics, combined with applied research and empirical evidence on the application of those principles to value-based payment.

Study Design: Conceptual analysis and targeted review of theoretical research and empirical literature relevant to value-based payment in health care.

Implementing Value-Based Payment Reform: A Conceptual Framework and Case Examples.

This article develops a conceptual framework for implementation of value-based payment (VBP) reform and then draws on that framework to systematically examine six distinct multi-stakeholder coalition VBP initiatives in three different regions of the United States. The VBP initiatives deploy the following payment models: reference pricing, "shadow" primary care capitation, bundled payment, pay for performance, shared savings within accountable care organizations, and global payment. The conceptual framework synthesizes prior models of VBP implementation.

Retrospective case-series of Paecilomyces lilacinus ocular mycoses in Queensland, Australia.

Background: The purpose of this study was to report: (1) the varying presentation of Paecilomyces ocular infections arising in Queensland; (2) the significance of immunosuppression as a primary determinant of disease; (3) the outcomes of voriconazole use; and (4) the ongoing need for both surgical and medical management of this devastating fungal infection.

Methods: A retrospective case series of 21 culture proven individuals participated in this series and were identified via a review of the pathology reporting system utilized in the Queensland public health system. All culture proven individuals were subjected to a systematic chart review.

Improved detection of disease-associated variation by sex-specific characterization and prediction of genes required for fertility.

Despite its great potential, high-throughput functional genomic data are rarely integrated and applied to characterizing the genomic basis of fertility. We obtained and reprocessed over 30 functional genomics datasets from human and mouse germ cells to perform genome-wide prediction of genes underlying various reproductive phenotypes in both species. Genes involved in male fertility are easier to predict than their female analogs.

Combinatorial cancer immunotherapy strategies with proapoptotic small-molecule IAP antagonists.

Members of the inhibitor of apoptosis (IAP) family control several critical aspects of innate immunity, cell death, and tumorigenesis. Small molecule antagonists that target specific IAP oncoproteins, primarily cIAP1 and cIAP2, but potentially also XIAP and Livin, modulate distinct immune signal transduction pathways that can lead to an increased sensitivity of tumors cells to cytokine-mediated apoptosis. These antagonists are based on the structure of an endogenous cellular IAP inhibitor called Smac.

VEGF-Mediated Induction of PRD1-BF1/Blimp1 Expression Sensitizes Tumor Vasculature to Oncolytic Virus Infection.

Oncolytic viruses designed to attack malignant cells can in addition infect and destroy tumor vascular endothelial cells. We show here that this expanded tropism of oncolytic vaccinia virus to the endothelial compartment is a consequence of VEGF-mediated suppression of the intrinsic antiviral response. VEGF/VEGFR2 signaling through Erk1/2 and Stat3 leads to upregulation, nuclear localization, and activation of the transcription repressor PRD1-BF1/Blimp1.

A Screen for Genomic Disorders of Infertility Identifies MAST2 Duplications Associated with Nonobstructive Azoospermia in Humans.

Since the cytogenetic identification of azoospermia factor regions 40 years ago, the Y chromosome has dominated research on the genetics of male infertility. We hypothesized that hotspots of structural rearrangement, which are dispersed across the genome, may mediate rare, recurrent copy number variations (CNVs), leading to severe infertility. We tested this hypothesis by contrasting patterns of rare CNVs in 970 Han Chinese men with idiopathic nonobstructive azoospermia and 1661 ethnicity-matched controls.

Rare double sex and mab-3-related transcription factor 1 regulatory variants in severe spermatogenic failure.

The double sex and mab-3-related transcription factor 1 (DMRT1) gene has long been linked to sex-determining pathways across vertebrates and is known to play an essential role in gonadal development and maintenance of spermatogenesis in mice. In humans, the genomic region harboring the DMRT gene cluster has been implicated in disorders of sex development and recently DMRT1 deletions were shown to be associated with non-obstructive azoospermia (NOA). In this work, we have employed different methods to screen a cohort of Portuguese NOA patients for DMRT1 exonic insertions and deletions [by multiplex ligation probe assay (MLPA); n = 68] and point mutations (by Sanger sequencing; n = 155).

Population-centered Risk- and Evidence-based Dental Interprofessional Care Team (PREDICT): study protocol for a randomized controlled trial.

Background: To improve the oral health of low-income children, innovations in dental delivery systems are needed, including community-based care, the use of expanded duty auxiliary dental personnel, capitation payments, and global budgets. This paper describes the protocol for PREDICT (Population-centered Risk- and Evidence-based Dental Interprofessional Care Team), an evaluation project to test the effectiveness of new delivery and payment systems for improving dental care and oral health.

Methods/design: This is a parallel-group cluster randomized controlled trial.

Using whole-genome sequences of the LG/J and SM/J inbred mouse strains to prioritize quantitative trait genes and nucleotides.

Background: The laboratory mouse is the most commonly used model for studying variation in complex traits relevant to human disease. Here we present the whole-genome sequences of two inbred strains, LG/J and SM/J, which are frequently used to study variation in complex traits as diverse as aging, bone-growth, adiposity, maternal behavior, and methamphetamine sensitivity.

Results: We identified small nucleotide variants (SNVs) and structural variants (SVs) in the LG/J and SM/J strains relative to the reference genome and discovered novel variants in these two strains by comparing their sequences to other mouse genomes.

Human genomics. Effect of predicted protein-truncating genetic variants on the human transcriptome.

Accurate prediction of the functional effect of genetic variation is critical for clinical genome interpretation. We systematically characterized the transcriptome effects of protein-truncating variants, a class of variants expected to have profound effects on gene function, using data from the Genotype-Tissue Expression (GTEx) and Geuvadis projects. We quantitated tissue-specific and positional effects on nonsense-mediated transcript decay and present an improved predictive model for this decay.

Increased B Cell ADAM10 in Allergic Patients and Th2 Prone Mice.

ADAM10, as the sheddase of the low affinity IgE receptor (CD23), promotes IgE production and thus is a unique target for attenuating allergic disease. Herein, we describe that B cell levels of ADAM10, specifically, are increased in allergic patients and Th2 prone WT mouse strains (Balb/c and A/J). While T cell help augments ADAM10 expression, Balb WT B cells exhibit increased ADAM10 in the naïve state and even more dramatically increased ADAM10 after anti-CD40/IL4 stimulation compared C57 (Th1 prone) WT B cells.

Trephine Use During Revision Total Hip Arthroplasty Resulting in Diaphyseal Osteonecrosis and Stress Fracture: A Case Report.

Case: A fifty-three-year-old woman presented with a fracture of an extensively porous-coated femoral component. Revision was performed with use of trephine reamers to remove the distal portion of the stem. Despite radiographs that showed an acceptable position of the revision stem, she experienced substantial thigh pain at four months postoperatively, which persisted at twelve months.

Aberrant ORM (yeast)-like protein isoform 3 (ORMDL3) expression dysregulates ceramide homeostasis in cells and ceramide exacerbates allergic asthma in mice.

Background: Asthma, a chronic inflammatory condition defined by episodic shortness of breath with expiratory wheezing and cough, is a serious health concern affecting more than 250 million persons. Genome-wide association studies have identified ORM (yeast)-like protein isoform 3 (ORMDL3) as a gene associated with susceptibility to asthma. Although its yeast ortholog is a negative regulator of de novo ceramide biosynthesis, how ORMDL3 contributes to asthma pathogenesis is not known.