Pyridodiazepine amines are selective therapeutic agents for helicobacter pylori by suppressing growth through inhibition of glutamate racemase but are predicted to require continuous elevated levels in plasma to achieve clinical efficacy.

A pyridodiazepine amine inhibitor of Helicobacter pylori glutamate racemase (MurI) was characterized. The compound was selectively active against H. pylori, and growth suppression was shown to be mediated through the inhibition of MurI by several methods.

Effects of position and operator on high-frequency ultrasound scan quality.

Objectives: High-frequency ultrasound may evaluate those at risk for pressure ulcers. Images may be obtained by clinicians with limited training. The prone position is recommended for obtaining sacral scans but may not be feasible in the critically ill.

Molecular and genetic properties of tumors associated with local immune cytolytic activity.

How the genomic landscape of a tumor shapes and is shaped by anti-tumor immunity has not been systematically explored. Using large-scale genomic data sets of solid tissue tumor biopsies, we quantified the cytolytic activity of the local immune infiltrate and identified associated properties across 18 tumor types. The number of predicted MHC Class I-associated neoantigens was correlated with cytolytic activity and was lower than expected in colorectal and other tumors, suggesting immune-mediated elimination.

Top Differential Diagnosis Should Be Microscopic Polyangiitis in ANCA-Positive Patient with Diffuse Pulmonary Hemorrhage and Hemosiderosis.

A rat model of antineutrophil cytoplasmic antibody (ANCA) associated vasculitides reveals crescentic glomerulonephritis as seen in human renal biopsies and diffuse lung hemorrhage that is not well documented in human lung biopsies. A 64-year-old male, with shortness of breath and mild elevation of serum creatinine, was found to have a positive serum test for ANCA, but negative antiglomerular basement membrane antibody. A renal biopsy showed pauci-immune type of crescentic glomerulonephritis and focal arteritis.

High-resolution sequencing and modeling identifies distinct dynamic RNA regulatory strategies.

Cells control dynamic transitions in transcript levels by regulating transcription, processing, and/or degradation through an integrated regulatory strategy. Here, we combine RNA metabolic labeling, rRNA-depleted RNA-seq, and DRiLL, a novel computational framework, to quantify the level; editing sites; and transcription, processing, and degradation rates of each transcript at a splice junction resolution during the LPS response of mouse dendritic cells. Four key regulatory strategies, dominated by RNA transcription changes, generate most temporal gene expression patterns.

Decreased tissue factor expression with increased CD11b upregulation on elastin-based biomaterial coatings.

Elastin-like polypeptide (ELP) coatings have been shown to have non-thrombogenic properties both in vitro and in vivo. In this work, we expand our understanding of this phenomenon by investigating the interaction of these coatings with leukocytes. Citrated whole blood was exposed to a shear rate of 300 s for 2 hours at 37 °C on ELP1- and ELP4-coated polyethylene terephthalate (Mylar™) surfaces in a cone and plate device.

Dnase2a deficiency uncovers lysosomal clearance of damaged nuclear DNA via autophagy.

Deficiencies in DNA-degrading nucleases lead to accumulation of self DNA and induction of autoimmunity in mice and in monogenic and polygenic human diseases. However, the sources of DNA and the mechanisms that trigger immunity remain unclear. We analyzed mice deficient for the lysosomal nuclease Dnase2a and observed elevated levels of undegraded DNA in both phagocytic and nonphagocytic cells.

A critical analysis of the implementation of service user involvement in primary care research and health service development using normalization process theory.

Background: There have been recent important advances in conceptualizing and operationalizing involvement in health research and health-care service development. However, problems persist in the field that impact on the scope for meaningful involvement to become a routine - normalized - way of working in primary care. In this review, we focus on current practice to critically interrogate factors known to be relevant for normalization - definition, enrolment, enactment and appraisal.

Optimization of pyrrolamide topoisomerase II inhibitors toward identification of an antibacterial clinical candidate (AZD5099).

AZD5099 (compound 63) is an antibacterial agent that entered phase 1 clinical trials targeting infections caused by Gram-positive and fastidious Gram-negative bacteria. It was derived from previously reported pyrrolamide antibacterials and a fragment-based approach targeting the ATP binding site of bacterial type II topoisomerases. The program described herein varied a 3-piperidine substituent and incorporated 4-thiazole substituents that form a seven-membered ring intramolecular hydrogen bond with a 5-position carboxylic acid.

A study of erosive phenotypes in lupus arthritis using magnetic resonance imaging and anti-citrullinated protein antibody, anti-RA33 and RF autoantibody status.

Objectives: The aims of this study were to investigate the extent of MRI-determined joint disease (erosion and synovitis) in SLE and to link this to autoantibody profiles known to be relevant to SLE, including ACPA, RF and anti-RA33 antibodies.

Methods: Contrast-enhanced MRI of the hand and wrist was performed in 34 symptomatic SLE patients and in 15 RA patients with similar disease duration. Images were scored by two observers using the OMERACT rheumatoid arthritis MRI scoring (RAMRIS) system.

A preseason cardiorespiratory profile of dancers in nine professional ballet and modern companies.

While studies have investigated the physical demands of dance in terms of cardiorespiratory fitness, there are no recent comparisons of cardiorespiratory response to exercise among professional dancers of different genres. Our purpose was to: 1. develop a cardiorespiratory profile of professional dancers; 2.

The use of an adeno-associated viral vector for efficient bicistronic expression of two genes in the central nervous system.

Recombinant adeno-associated viral (AAV) vectors are one of the most promising therapeutic delivery systems for gene therapy to the central nervous system (CNS). Preclinical testing of novel gene therapies requires the careful design and production of AAV vectors and their successful application in a model of CNS injury. One major limitation of AAV vectors is their limited packaging capacity (<5 kb) making the co-expression of two genes (e.

Preliminary Efficacy of a Behavioral Parent Training Program for Children With ADHD in Pakistan.

Objective: In an effort to address the lack of evidence-based interventions for ADHD in developing South Asian countries, we examined the preliminary efficacy of a behavioral parent training program in Pakistan.

Method: A quasi-experimental design was utilized. Eighty-five 4- to 12-year-old children with clinically significant ADHD symptoms participated: 55 were recruited from hospital clinics (active treatment group) and 30 were recruited from schools (waitlist control group).

A novel dried blood spot-LCMS method for the quantification of methotrexate polyglutamates as a potential marker for methotrexate use in children.

Objective: Development and validation of a selective and sensitive LCMS method for the determination of methotrexate polyglutamates in dried blood spots (DBS).

Methods: DBS samples [spiked or patient samples] were prepared by applying blood to Guthrie cards which was then dried at room temperature. The method utilised 6-mm disks punched from the DBS samples (equivalent to approximately 12 µl of whole blood).

Synovial membrane protein expression differs between juvenile idiopathic arthritis subtypes in early disease.

Introduction: Juvenile idiopathic arthritis (JIA) is the most common rheumatological disease of childhood with a prevalence of around 1 in 1,000. Without appropriate treatment it can have devastating consequences including permanent disability from joint destruction and growth deformities. Disease aetiology remains unknown.

A phase I study of temsirolimus and thoracic radiation in non--small-cell lung cancer.

Background: The addition of targeted agents to thoracic radiation has not improved outcomes in patients with locally advanced non-small-cell lung cancer (NSCLC). To improve cure rates in locally advanced NSCLC, effective targeted therapies need to be identified that can be given safely with radiation therapy. Temsirolimus is an inhibitor of the mammalian target of rapamycin (mTOR) pathway and has single-agent activity in lung cancer.

Reversal of in situ T-cell exhaustion during effective human antileukemia responses to donor lymphocyte infusion.

Increasing evidence across malignancies suggests that infiltrating T cells at the site of disease are crucial to tumor control. We hypothesized that marrow-infiltrating immune populations play a critical role in response to donor lymphocyte infusion (DLI), an established and potentially curative immune therapy whose precise mechanism remains unknown. We therefore analyzed marrow-infiltrating immune populations in 29 patients (22 responders, 7 nonresponders) with relapsed chronic myelogenous leukemia who received CD4(+) DLI in the pre-tyrosine kinase inhibitor era.

Discovery of a novel class of dimeric Smac mimetics as potent IAP antagonists resulting in a clinical candidate for the treatment of cancer (AZD5582).

A series of dimeric compounds based on the AVPI motif of Smac were designed and prepared as antagonists of the inhibitor of apoptosis proteins (IAPs). Optimization of cellular potency, physical properties, and pharmacokinetic parameters led to the identification of compound 14 (AZD5582), which binds potently to the BIR3 domains of cIAP1, cIAP2, and XIAP (IC50 = 15, 21, and 15 nM, respectively). This compound causes cIAP1 degradation and induces apoptosis in the MDA-MB-231 breast cancer cell line at subnanomolar concentrations in vitro.

Contribution of polyclonal free light chain deposition to tubular injury.

Introduction: Excretion of monoclonal free light chains (MFLC) beyond the renal threshold can cause kidney injury, but evidence for polyclonal free light chains (PFLC)-mediated injury is limited. We aimed to study the degree of PFLC deposition in the proximal tubules of chronic kidney disease (CKD) and hypothesized that excess deposition may contribute to tubular injury.

Methods: In this retrospective study, immunohistochemical staining to assess the degree of FLC deposition, periodic acid-Schiff staining for the degree of tubular brush border injury and trichrome staining for interstitial fibrosis were evaluated.

Plasma IL-6 levels correlate with clinical and ultrasound measures of arthritis in patients with systemic lupus erythematosus.

Objective: The objective of this paper is to elucidate the role of specific cytokines in lupus (SLE) arthritis.

Methods: Fifty SLE and 40 RA patients had an ultrasound (US) scan of their hand as per standardized protocols. US scores were expressed per joint and as a total 'US activity' score, (sum of power Doppler (PD) and grey-scale synovial hypertrophy scores in all joints) and a total erosion score.

Corelease of bioactive VEGF and HGF from viscous liquid poly(5-ethylene ketal ε-caprolactone-co-D,L-lactide).

The potential of a viscous liquid injectable delivery system composed of poly(5-ethylene ketal ε-caprolactone-co-D,L-lactide) (PEKCDLLA) to release bioactive vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) using an osmotic pressure release mechanism for the purpose of treating critical limb ischemia was investigated. VEGF and HGF were lyophilized separately with trehalose and bovine serum albumin (BSA) and incorporated into the polymer by simple mixing. VEGF and HGF were released by convective flow through superhydrated regions formed within the polymer as a result of the osmotic activity generated upon dissolution of the particles, along with the contributions of polymer degradation at later time points.

Acute tubular injury is an important component in type I acute antibody-mediated rejection.

Background: "Acute tubular necrosis (ATN)-like" changes in type I acute antibody- mediated rejection (AAMR) have been proposed since 2005, but the presence of "ATN-like" injury in AAMR has not well been established. The aim of this study was to confirm the presence of acute tubular injury in type I AAMR, using the specific proximal tubular injury marker, kidney injury molecule-1 (KIM-1).

Design: The study included 3 groups of cases, namely, a negative control group (normal nontransplantation renal parenchyma as group 1, n = 11), a positive control group (transplant ATN with negative C4d staining as group 2, n = 12), and study cases (type 1 AAMR as group 3, n = 19).

Food marketing targeting youth and families: what do we know about stores where moms actually shop?

Although efforts are underway to examine marketing that targets the youth and families in the retail food store environment, few studies have specifically focused on stores that families identify as their primary sites for food shopping. Between November 2011 and April 2012, we examined the frequency and types of marketing techniques of 114 packaged and nonpackaged items in 24 food stores that mothers of young children in Champaign County, IL, said they commonly frequented. Chi-square tests were used to determine whether significant differences existed between items with regard to marketing by store type, store food-assistance-program acceptance (i.

Effect of colesevelam and niacin on low-density lipoprotein cholesterol and glycemic control in subjects with dyslipidemia and impaired fasting glucose.

Background: Niacin monotherapy in patients with dyslipidemia and impaired fasting glucose (IFG) may result in hyperglycemia. Colesevelam has the unique dual approvals to lower low-density lipoprotein cholesterol (LDL-C) and to improve glycemic control in type 2 diabetes mellitus.

Objectives: The aim of our study was to evaluate the effect of combined colesevelam and niacin treatment on LDL-C-lowering and glycemic control in subjects with IFG and dyslipidemia.

Additive effects of parent adherence on social and behavioral outcomes of a collaborative school-home behavioral intervention for ADHD.

The present study evaluated the impact of the Collaborative Life Skills Program (CLS), a novel school-home psychosocial intervention, on social and behavioral impairments among children with attention and behavior problems. Fifty-seven ethnically/racially diverse children (70 % boys) with attention and/or behavior problems in the second through fifth grades participated in a pilot study. Ten school-based mental health professionals were trained and then implemented the intervention at their respective schools.