Search

Introduction: Asthma is characterized by preventable morbidity, cost, and inequity. We sought to build an Asthma Learning Health System (ALHS) to coordinate regional pediatric asthma improvement activities. Methods: We generated quantitative and qualitative insights pertinent to a better, more equitable care delivery system. We used electronic health record data to calculate asthma hospitalization rates for youth in our region. We completed an "environmental scan" to catalog the breadth of asthma-related efforts occurring in our children's hospital and across the region. We supplemented the scan with grouplevel assessments and focus groups with parents, clinicians, and community partners. We used insights from this descriptive epidemiology to inform the definition of shared aims, drivers, measures, and prototype interventions. Results: Greater Cincinnati's youth are hospitalized for asthma at a rate three times greater than the U.S. average. Black youth are hospitalized at a rate five times greater than non-Black youth. Certain neighborhoods bear the disproportionate burden of asthma morbidity. Across Cincinnati, there are many asthma-relevant activities that seek to confront this morbidity; however, efforts are largely disconnected. Qualitative insights highlighted the importance of cross-sector coordination, evidence-based acute and preventive care, healthy homes and neighborhoods, and accountability. These insights also led to a shared, regional aim: to equitably reduce asthma-related hospitalizations. Early interventions have included population-level pattern recognition, multidisciplinary asthma action huddles, and enhanced social needs screening and response. Conclusion: Learning health system methods are uniquely suited to asthma's complexity. Our nascent ALHS provides a scaffold atop which we can pursue better, more equitable regional asthma outcomes. [ABSTRACT FROM AUTHOR]

Introduction: A learning health network is a type of learning health system in which stakeholders use network organization to improve health and health care. Building on existing resources in the cystic fibrosis (CF) community, the Cystic Fibrosis Learning Network (CFLN) was designed to improve medical outcomes and quality of life through an intentional focus on achieving reliable evidence‐based chronic care delivery and creating a system for data‐driven collaborative learning. Methods: We describe the development and growth of the CFLN considering six domains of a Network Maturity Grid: system leadership; governance and policy management; quality improvement (QI); engagement and community building; data and analytics; and research. We illustrate the impact of the CFLN experience on chronic care processes and indicators of collaborative infrastructure. Results: The CFLN represents 36 accredited care centers in the CF Foundation Care Center Network caring for over 6300 patients. Of 6779 patient clinical care visits/quarter, 77% are entered into the CF Foundation Patient Registry within 30 days, providing timely means to track outcomes. Collaborative visit planning is occurring in 93% of clinical care visits to share agenda setting with patients and families. Almost all CFLN teams (94%, n = 34) have a patient/family partner (PFP), and 74% of PFPs indicate they are actively participating, taking ownership of, or leading QI initiatives with the interdisciplinary care team. In 2022, 97% of centers reported completing 1–13 improvement cycles per month, and 82% contributed to monthly QI progress reports to share learning. Conclusion: The CFLN is a maturing, collaborative infrastructure. CFLN centers practice at an advanced level of coproduction. The CFLN fosters interdisciplinary and PFP leadership and the performance of consistent data‐driven improvement cycles. CFLN centers are positioned to respond to rapid changes in evidence‐based care and advance the practice of QI and implementation science on a broader scale. [ABSTRACT FROM AUTHOR]

Summary: Background: The effects of H4R antagonists in preclinical asthma models support the study of antagonists of the H4R in the treatment of asthma in humans. JNJ‐39758979 is a potent and highly selective oral H4R antagonist. Objective: We sought to evaluate the safety and efficacy of the H4R‐antagonist JNJ‐39758979 in adult patients with uncontrolled asthma. Methods: One hundred and fifteen eligible patients were randomly assigned to JNJ‐39758979 300 mg or placebo once daily for 12 weeks in this phase 2a, double‐blind, multicenter, placebo‐controlled study. Primary efficacy was assessed via week‐12 change from baseline in pre‐bronchodilator forced expiratory volume in 1 second (FEV1). Secondary efficacy assessments included patient‐reported outcome (PRO) asthma assessments (Asthma Daily Diary data [AM and PM peak expiratory flow rate, number of puffs of albuterol/salbutamol, the presence of nocturnal awakenings and asthma symptom score]). Results: The study did not meet the primary end‐point. However, nominally significant improvements in pre‐bronchodilator FEV1 were observed with JNJ‐39758979 versus placebo at week 12 in pre‐specified subgroups with elevated exhaled nitric oxide, sputum eosinophils or blood eosinophils at baseline. Nominally significant improvements across PRO assessments were consistently observed in the overall population, as well as in eosinophilic subgroups. Safety, such as adverse event rates, was comparable between JNJ‐39758979 and placebo. No serious adverse events were reported. No clinically relevant changes in laboratory values were observed. Conclusions and Clinical Relevance: The findings suggest potential benefit of H4R antagonists on lung function and asthma control in eosinophilic asthma patients and warrant further evaluation of this mechanism in asthma with eosinophilic inflammation. NCT00946569. [ABSTRACT FROM AUTHOR]

A major obstacle in predicting and preventing the development of autoimmune type 1 diabetes (T1D) in at-risk individuals is the lack of well-established early biomarkers indicative of ongoing beta cell stress during the pre-clinical phase of disease. Recently, serum levels of the α cytoplasmic isoform of heat-shock protein 90 (hsp90) were shown to be elevated in individuals with new-onset T1D. We therefore hypothesized that hsp90 α could be released from beta cells in response to cellular stress and inflammation associated with the earliest stages of T1D. Here, human beta cell lines and cadaveric islets released hsp90 α in response to stress induced by treatment with a combination of pro-inflammatory cytokines including interleukin-1 β, tumour necrosis factor- α and interferon- γ. Mechanistically, hsp90 α release was found to be driven by cytokine-induced endoplasmic reticulum stress mediated by c-Jun N-terminal kinase (JNK), a pathway that can eventually lead to beta cell apoptosis. Cytokine-induced beta cell hsp90 α release and JNK activation were significantly reduced by pre-treating cells with the endoplasmic reticulum stress-mitigating chemical chaperone tauroursodeoxycholic acid. The hsp90 α release by cells may therefore be a sensitive indicator of stress during inflammation and a useful tool in assessing therapeutic mitigation of cytokine-induced cell damage linked to autoimmunity. [ABSTRACT FROM AUTHOR]

This trial was conducted to evaluate the safety and efficacy of the H4R-antagonist JNJ-39758979 in adult Japanese patients with moderate atopic dermatitis ( AD). Eligible patients were randomly assigned to JNJ-39758979 300 mg, 100 mg or placebo once daily for 6 weeks in this phase 2a, double-blind, multicenter, placebo-controlled study. Primary efficacy was assessed via week-6 Eczema Area and Severity Index ( EASI) scores. Secondary efficacy assessments included Investigator's Global Assessment ( IGA) and patient-reported outcome ( PRO) pruritus assessments (Pruritus Categorical Response Scale [ PCRS], Pruritus Numeric Rating Scales [ PNRS], Pruritus Interference Numeric Rating Scale [ PINRS] and Subject's Global Impressions of Change in Pruritus [ SGICP]). Eighty-eight of 105 planned patients were randomized before the study was stopped and unblinded for safety reasons. The study did not meet the primary end-point. However, numerical improvements (i.e. decreases) in median EASI were observed with JNJ-39758979 100 mg (−3.7) and 300 mg (−3.0) versus placebo (−1.3) at week 6. Nominally significant improvements across PRO PCRS, PNRS and SGICP assessments were consistently observed, particularly with JNJ-39758979 300 mg. Safety, including adverse events ( AE), was comparable between JNJ-39758979 and placebo with the exception of two patients (both receiving JNJ-39758979 300 mg) with serious AE of neutropenia, leading to premature study discontinuation. No deaths were reported. Except for neutropenia, no clinically relevant changes in laboratory values were observed. Although not conclusive, findings suggest H4R-antagonism may be beneficial for AD, particularly in controlling pruritus. JNJ-39758979 appears to be associated with drug-induced agranulocytosis, likely an off-target effect. [ABSTRACT FROM AUTHOR]

The NanoRelease Food Additive project developed a catalog to identify potential engineered nanomaterials (ENMs) used as ingredients, using various food-related databases. To avoid ongoing debate on defining the term nanomaterial, NanoRelease did not use any specific definition other than the ingredient is not naturally part of the food chain, and its dimensions are measured in the nanoscale. Potential nanomaterials were categorized based on physical similarity; analysis indicated that the range of ENMs declared as being in the food chain was limited. Much of the catalog's information was obtained from product labeling, likely resulting in both underreporting (inconsistent or absent requirements for labeling) and/or overreporting (inability to validate entries, or the term nano was used, although no ENM material was present). Three categories of ingredients were identified: emulsions, dispersions, and their water-soluble powdered preparations (including lipid-based structures); solid encapsulates (solid structures containing an active material); and metallic or other inorganic particles. Although much is known regarding the physical/chemical properties for these ingredient categories, it is critical to understand whether these properties undergo changes following their interaction with food matrices during preparation and storage. It is also important to determine whether free ENMs are likely to be present within the gastrointestinal tract and whether uptake of ENMs may occur in their nanoform physical state. A practical decision-making scheme was developed to help manage testing requirements. [ABSTRACT FROM AUTHOR]

Mast cells are the major sources of histamine, which is released in response to immunological stimulations. The synthesis of histamine is catalyzed by histidine decarboxylase ( HDC). Previous studies have shown that Hdc−/− mast cells exhibit aberrant granule morphology with severely decreased granule content. Here, we investigated whether the histamine synthesized in mast cells regulates the granule maturation of murine mast cells. Several genes, including those encoding granule proteases and enzymes involved in heparin biosynthesis, were downregulated in Hdc−/− peritoneal mast cells. Impaired granule maturation was also found in Hdc−/− BM-derived cultured mast cells when they were cocultured with fibroblasts in the presence of c-kit ligand. Exogenous application of histamine and several H4 receptor agonists restored the granule maturation of Hdc−/− cultured mast cells. However, the maturation of granules was largely normal in Hrh4−/− peritoneal mast cells. Depletion of cellular histamine with tetrabenazine, an inhibitor of vesicular monoamine transporter-2, did not affect granule maturation. In vivo experiments with mast cell deficient KitW/ KitW-v mice indicated that the expression of the Hdc gene in mast cells is required for granule maturation. These results suggest that histamine promotes granule maturation in mast cells and acts as an proinflammatory mediator. [ABSTRACT FROM AUTHOR]

Background and Purpose: Among the pathogenic mechanisms of asthma, a role for oxidative/nitrosative stress has been well documented. Recent evidence suggests that histamine H₄ receptors play a modulatory role in allergic inflammation. Here we report the effects of compound JNJ 7777120 (JNJ), a selective H4 receptor antagonist, on antigen-induced airway inflammation, paying special attention to its effects on lipocortin-1 (LC-1/annexin-A1), a 37 kDA anti-inflammatory protein that plays a key role in the production of inflammatory mediators.Experimental Approach: Ovalbumin (OA)-sensitized guinea pigs placed in a respiratory chamber were challenged with antigen. JNJ (5, 7.5 and 10 mg.kg⁻¹) was given i.p. for 4 days before antigen challenge. Respiratory parameters were recorded. Bronchoalveolar lavage (BAL) fluid was collected and lung specimens taken for further analyses 1 h after antigen challenge. In BAL fluid, levels of LC-1, PGD2 , LTB4 and TNF-α were measured. In lung tissue samples, myeloperoxidase, caspase-3 and Mn-superoxide dismutase activities and 8-hydroxy-2-deoxyguanosine levels were measured.Key Results: OA challenge decreased LC-1 levels in BAL fluid, induced cough, dyspnoea and bronchoconstriction and increased PGD2 , LTB4 and TNF-α levels in lung tissue. Treatment with JNJ dose-dependently increased levels of LC-1, reduced respiratory abnormalities and lowered levels of PGD2 , LTB4 and TNF-α in BAL fluid.Conclusions and Implications: Antigen-induced asthma-like reactions in guinea pigs decreased levels of LC-1 and increased TNF-α and eicosanoid production. JNJ pretreatment reduced allergic asthmatic responses and airway inflammation, an effect associated with LC-1 up-regulation. [ABSTRACT FROM AUTHOR]

Background and Purpose Among the pathogenic mechanisms of asthma, a role for oxidative/nitrosative stress has been well documented. Recent evidence suggests that histamine H4 receptors play a modulatory role in allergic inflammation. Here we report the effects of compound JNJ 7777120 ( JNJ), a selective H4 receptor antagonist, on antigen-induced airway inflammation, paying special attention to its effects on lipocortin-1 ( LC-1/annexin- A1), a 37 kDA anti-inflammatory protein that plays a key role in the production of inflammatory mediators. Experimental Approach Ovalbumin ( OA)-sensitized guinea pigs placed in a respiratory chamber were challenged with antigen. JNJ (5, 7.5 and 10 mg·kg−1) was given i.p. for 4 days before antigen challenge. Respiratory parameters were recorded. Bronchoalveolar lavage ( BAL) fluid was collected and lung specimens taken for further analyses 1 h after antigen challenge. In BAL fluid, levels of LC-1, PGD2, LTB4 and TNF-α were measured. In lung tissue samples, myeloperoxidase, caspase-3 and Mn-superoxide dismutase activities and 8-hydroxy-2-deoxyguanosine levels were measured. Key Results OA challenge decreased LC-1 levels in BAL fluid, induced cough, dyspnoea and bronchoconstriction and increased PGD2, LTB4 and TNF-α levels in lung tissue. Treatment with JNJ dose-dependently increased levels of LC-1, reduced respiratory abnormalities and lowered levels of PGD2, LTB4 and TNF-α in BAL fluid. Conclusions and Implications Antigen-induced asthma-like reactions in guinea pigs decreased levels of LC-1 and increased TNF-α and eicosanoid production. JNJ pretreatment reduced allergic asthmatic responses and airway inflammation, an effect associated with LC-1 up-regulation. Linked Articles This article is part of a themed issue on Histamine Pharmacology Update. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2013.170.issue-1 [ABSTRACT FROM AUTHOR]

Abstract: Human type 2 diabetes is associated with β-cell apoptosis, and human islets from diabetic donors are ∼80% deficient in PAK1 protein. Toward addressing linkage of PAK1 to β-cell survival, PAK1–siRNA targeted MIN6 pancreatic β-cells were found to exhibit increased caspase-3 cleavage, cytosolic cytochrome-C and the pro-apoptotic protein Bad. PAK1+/− heterozygous mouse islets recapitulated the upregulation of Bad protein expression, as did hyperglycemic treatment of human or mouse islets; Bad levels were exacerbated most in PAK1+/− islets subjected to hyperglycemic stress. These data implicate PAK1 in β-cell survival via quenching of Bad protein expression, and suggest PAK1 as potential molecular target to preserve β-cell mass. [Copyright &y& Elsevier]

Abstract: Insulin-, and contraction-induced GLUT4 and fatty acid (FA) transporter translocation may share common trafficking mechanisms. Our objective was to examine the effects of partial Munc18c ablation on muscle glucose and FA transport, FA oxidation, GLUT4 and FA transporter (FAT/CD36, FABPpm, FATP1, FATP4) trafficking to the sarcolemma, and FAT/CD36 to mitochondria. In Munc18c−/+ mice, insulin-stimulated glucose transport and GLUT4 sarcolemmal appearance were impaired, but were unaffected by contraction. Insulin- and contraction-stimulated FA transport, sarcolemmal FA transporter appearance, and contraction-mediated mitochondrial FAT/CD36 were increased normally in Munc18c−/+ mice. Hence, Munc18c provides stimulus-specific regulation of GLUT4 trafficking, but not FA transporter trafficking. [Copyright &y& Elsevier]

Ground-based hyperspectral imaging combined with terrestrial lidar scanning is a novel technique for outcrop analysis, which has been applied to Early and Late Albian carbonates of the Pozalagua Quarry (Cantabrian Mountains, Spain). An image processing workflow has been developed for differentiating limestone from dolomite, providing additional sedimentary and diagenetic information, and the possibility to quantitatively delineate diagenetic phases in an accurate way. Spectral absorption signatures can be linked to specific sedimentary or diagenetic products, such as recent and palaeokarst, hydrothermal karst, (solution enlarged) fractures and different dolomite types. Some of the spectral signatures are related to iron, manganese, organic matter, clay and/or water content. Ground-truthing accessible parts of the quarry showed that the classification based on hyperspectral image interpretation was very accurate. This technique opens the possibility for quantitative data evaluation on sedimentary and diagenetic features in inaccessible outcrops. This study demonstrates the potential of ground-based imaging spectroscopy to provide information about the chemical-mineralogical distribution in outcrops, which could otherwise not be established using conventional field methods. [ABSTRACT FROM AUTHOR]

The histamine H receptor (HR) has been implicated in numerous inflammatory functions. Here it is shown that the receptor can mediate cytokine production from mast cells. Histamine and an HR agonist, JNJ 28610244, induced the production of IL-6 in mouse bone marrow (BM)-derived mast cells. This effect was blocked by two different HR antagonists and was not present in HR-deficient cells. In addition, histamine acting via the HR potentiated LPS-induced IL-6 production. Histamine-induced IL-6 production could be blocked by inhibitors of ERK and phosphoinositide 3-kinase γ (PI3Kγ) pathways. Furthermore, it was shown that HR activation can induce phosphorylation of ERK, MEK and AKT. HR activation led to a rapid and transient phosphorylation of these kinases, whereas with LPS the activation occurred at later time points. When both histamine and LPS were added, the phosphorylation was evident at 5 min and persisted for at least 60 min suggesting that changes in the kinetics of kinase activation may be one mechanism driving the signaling interaction between the HR and toll-like receptors. These observations suggest that the HR can synergize with other inflammatory signals to potentiate cytokine production and provides mechanistic information on the role of the HR in inflammation. [ABSTRACT FROM AUTHOR]

Aims We aimed to compare MRI measurements of the female levator hiatus and the most caudal 'levator ani' muscles between image slices in a plane axial to the body (AxB) and an axial plane parallel to the direction of the puborectalis muscle (AxPRM). Methods We performed high-resolution, T2-weighted axial magnetic resonance imaging (in two different planes) on 20 sequentially recruited asymptomatic nulliparous women. Levator hiatus measurements were compared between the two planes. Results The mean tilt angle of the AxPRM slices relative to the AxB slices was 18.9° (SD 8.5) and the area of the levator hiatus was 10% greater ( P = 0.04) in the AxPRM plane. Conclusions By rotating the acquisition plane to be parallel to the puborectalis muscle (sometimes called the plane of minimal hiatal dimensions), some of the measurements of the distal and medial pelvic floor muscles (and the hiatus defined by them) are altered. This issue is important because both MRI and 3D ultrasound are increasingly being used to evaluate the pelvic floor hiatus, and its relationship to childbirth injury and pelvic floor disorders. To make meaningful comparisons, it is important that both modalities are measuring the same thing. Neurourol. Urodynam. 30:113-116, 2011. © 2010 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

The study of source-to-sink systems relates long-term variations in sediment flux to morphogenic evolution of erosional–depositional systems. These variations are caused by an intricate combination of autogenic and allogenic forcing mechanisms that operate on multiple time scales – from individual transport events to large-scale filling of basins. In order to achieve a better understanding of how these mechanisms influence morphological characteristics on different scales, 29 submodern source-to-sink systems have been investigated. The study is based on measurements of morphological parameters from catchments, shelves and slopes derived from a ∼1 km global digital elevation model dataset, in combination with data on basin floor fans, sediment supply, water discharge and deposition rates derived from published literature. By comparing various morphological and sedimentological parameters within and between individual systems, a number of relationships governing system evolution and behaviour are identified. The results suggest that the amount of low-gradient floodplain area and river channel gradient are good indicators for catchment storage potential. Catchment area and river channel length is also related to shelf area and shelf width, respectively. Similarly to the floodplain area, these parameters are important for long-term storage of sediment on the shelf platform. Additionally, the basin floor fan area is correlative to the long-term deposition rate and the slope length. The slope length thus proves to be a useful parameter linking proximal and distal segments in source-to-sink systems. The relationships observed in this study provide insight into segment scale development of source-to-sink systems, and an understanding of these relationships in modern systems may result in improved knowledge on internal and external development of source-to-sink systems over geological time scales. They also allow for the development of a set of semi-quantitative guidelines that can be used to predict similar relationships in other systems where data from individual system segments are missing or lacking. [ABSTRACT FROM AUTHOR]

Technology can be used to maximize the effectiveness of academic advising for students in virtual institutions. [ABSTRACT FROM AUTHOR]

Abstract: Altered histamine metabolism is thought to be involved in the pathomechanism of nasal polyposis characterized by local eosinophil infiltration. The present study was performed to determine whether histamine receptors play a role in the effect of histamine in nasal polyp tissue. The findings suggest that the expression of H1 and H4 receptors is elevated in polyp tissue (p =0.045; p <0.001), while the level of H2 and H3 receptors is not increased significantly. The elevation of H1 and H4 receptors'' expression may indicate that the histamine related mechanisms are preferentially mediated through H1 and H4 histamine receptors in the polyp tissue. Simultaneously with increased H4 receptor expression, the concentration of eosinophil cationic protein (ECP) was increased significantly in polyp tissue (p =0.002). One may speculate that the H4 receptor mediated histamine effects have a role in eosinophil accumulation and activation in inflammatory diseases of the nasal and paranasal sinus mucosa, such as nasal polyposis. [Copyright &y& Elsevier]

There is considerable interest in understanding how factors such as time and geographic distance between isolates might influence the evolutionary direction of foot-and-mouth disease. Genetic differences between viruses can be measured as the proportion of nucleotides that differ for a given sequence or gene. We present a Bayesian hierarchical regression model for the statistical analysis of continuous data with sample space restricted to the interval (0, 1). The data are modelled using beta distributions with means that depend on covariates through a link function. We discuss methodology for: (i) the incorporation of informative prior information into an analysis; (ii) fitting the model using Markov chain Monte Carlo sampling; (iii) model selection using Bayes factors; and (iv) semiparametric beta regression using penalized splines. The model was applied to two different datasets. [ABSTRACT FROM AUTHOR]

Standard diagnostic test procedures involve dichotomization of serologic test results. The critical value or cut-off is determined to optimize a trade off between sensitivity and specificity of the resulting test. When sampled units from a population are tested, they are allocated as either infected or not according to the test outcome. Units with values high above the cut-off are treated the same as units with values just barely above the cut-off, and similarly for values below the cut-off. There is an inherent information loss in dichotomization. We thus develop a diagnostic screening method based on data that are not dichotomized within the Bayesian paradigm. Our method determines the predictive probability of infection for each individual in a sample based on having observed a specific serologic test result and provides inferences about the prevalence of infection in the population sampled. Our fully Bayesian method is briefly compared with a previously developed frequentist method. We illustrate the methodology with serologic data that have been previously analysed in the veterinary literature, and also discuss applications to screening for disease in humans. The method applies more generally to a variation of the classic parametric 2-population discriminant analysis problem. Here, in addition to training data, additional units are sampled and the goal is to determine their population status, and the prevalence(s) of the subpopulation(s) from which they were sampled. Copyright © 2005 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Molecular redundancy refers to the ability of genes to back up damaged genes or gene loss. Although this term is widely discussed in many scientific circles, the process is still ill-defined, as shown by reviewing examples from the literature. Exploring the collagen-induced arthritis model in the context of CD44 knockout mice, we suggest a mechanistic explanation for molecular redundancy that depends neither on upregulation of the compensating molecule nor on structural similarity between the original molecule and the replacement molecule. The backup process is dependent, however, on two key properties shared by the two molecules: ligand binding and support of cell trafficking. [ABSTRACT FROM AUTHOR]

1: During mast cell degranulation, histamine is released in large quantities. Human eosinophils were found to express histamine H4 but not H3 receptors. The possible effects of histamine on eosinophils and the receptor mediating these effects were investigated in our studies. 2: Histamine (0.01-30?µM) induced a rapid and transient cell shape change in human eosinophils, but had no effects on neutrophils. The maximal shape change was at 0.3?µM histamine with EC50 at 19?nM. After 60?min incubation with 1?µM histamine, eosinophils were desensitized and were refractory to shape change response upon histamine restimulation. Histamine (0.01-1?µM) also enhanced the eosinophil shape change induced by other chemokines. 3: Histamine-induced eosinophil shape change was mediated by the H4 receptor. This effect was completely inhibited by H4 receptor-specific antagonist JNJ 7777120 (IC50 0.3?µM) and H3/H4 receptor antagonist thioperamide (IC50 1.4?µM), but not by selective H1, H2 or H3 receptor antagonists. H4 receptor agonists imetit (EC50 25?nM) and clobenpropit (EC50 72?nM) could mimic histamine effect in inducing eosinophil shape change. 4: Histamine (0.01-100?µM) induced upregulation of adhesion molecules CD11b/CD18 (Mac-1) and CD54 (ICAM-1) on eosinophils. This effect was mediated by the H4 receptor and could be blocked by H4 receptor antagonists JNJ 7777120 and thioperamide. 5: Histamine (0.01-10?µM) induced eosinophil chemotaxis with an EC50 of 83?nM. This effect was mediated by the H4 receptor and could be blocked by H4 receptor antagonists JNJ 7777120 (IC50 86?nM) and thioperamide (IC50 519?nM). Histamine (0.5?µM) also enhanced the eosinophil shape change induced by other chemokines. 6: In conclusion, we have demonstrated a new mechanism of eosinophil recruitment driven by mast cells via the release of histamine. Using specific histamine receptor ligands, we have provided a definitive proof that the H4 receptor mediates eosinophil chemotaxis, cell shape change and upregulation of adhesion molecules. The effect of H4 receptor antagonists in blocking eosinophil infiltration could be valuable for the treatment of allergic diseases. The histamine-induced shape change and upregulation of adhesion molecules on eosinophils can serve as biomarkers for clinical studies of H4 receptor antagonists.British Journal of Pharmacology (2004) 142, 161-171. doi:10.1038/sj.bjp.0705729 [ABSTRACT FROM AUTHOR]

The effect of spontaneous abortion on the dairy industry is substantial, costing the industry on the order of $200 million per year in California alone. We analyse data from a cohort study of nine dairy herds in Central California. A key feature of the analysis is the observation that only a relatively small proportion of cows will abort (around 10¯15 per cent), so that it is inappropriate to analyse the time-to-abortion (TTA) data as if it were standard censored survival data, with cows that fail to abort by the end of the study treated as censored observations. We thus broaden the scope to consider the analysis of foetal lifetime distribution (FLD) data for the cows, with the dual goals of characterizing the effects of various risk factors on (i) the likelihood of abortion and, conditional on abortion status, on (ii) the risk of early versus late abortion. A single model is developed to accomplish both goals with two sets of specific herd effects modelled as random effects. Because multimodal foetal hazard functions are expected for the TTA data, both a parametric mixture model and a non-parametric model are developed. Furthermore, the two sets of analyses are linked because of anticipated dependence between the random herd effects. All modelling and inferences are accomplished using modern Bayesian methods. Copyright © 2003 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Evidence suggests that glucosamine inhibits distal components regulating insulin-stimulated GLUT4 translocation to the plasma membrane. Here we assessed whether key membrane docking and fusion events were targeted. Consistent with a plasma membrane-localized effect, 3T3-L1 adipocytes exposed to glucosamine displayed an increase in cell-surface O-linked glycosylation and a simultaneously impaired mobilization of GLUT4 by insulin. Analysis of syntaxin 4 and SNAP23, plasma membrane-localized target receptor proteins (t-SNAREs) for the GLUT4 vesicle, showed that they were not cell-surface targets of O-linked glycosylation. However, the syntaxin 4 binding protein, Munc18c, was targeted by O-linked glycosylation. This occurred concomitantly with a block in insulin-stimulated association of syntaxin 4 with its cognate GLUT4 vesicle receptor protein (v-SNARE), VAMP2. In conclusion, our data suggest that the mechanism by which glucosamine inhibits insulin-stimulated GLUT4 translocation involves modification of Munc18c. [Copyright &y& Elsevier]

p38 mitogen-activated protein kinase (MAPK) (p38/p38-α/CSBP2/RK) has been implicated in the regulation of many proinflammatory pathways. Because of this, it has received much attention as a potential drug target for controlling diseases such as rheumatoid arthritis, endotoxic shock, inflammatory bowel disease, osteoporosis, and many others. A number of small molecule inhibitors of this kinase have been described, and in this paper we have used surface plasmon resonance to directly measure and quantitate their binding to p38. Despite the relatively low molecular mass (≈ 400 Da) of these inhibitors, specific binding can be observed. For the two most potent inhibitors studied, SB 203580 and RWJ 67657, dissociation constants, Kd's, of 22 and 10 nm, respectively, were obtained. These values closely match the IC50 values observed in a cell-based TNFα release assay implying that p38 plays a major role in TNFα release. The association and dissociation rates for the binding of these inhibitors to p38 have also been quantitated. SB 203580 and RWJ 67657 have very similar association rates of around 8 × 105 m-1·s-1, and the differences in affinity are determined by different dissociation rates. The weaker binding compounds have dissociation rates similar to SB 203580, but the association rates vary by an order of magnitude or more. The direct measurement of compounds binding to p38 may help in understanding the difference between potency and efficacy for these inhibitors. This in turn may yield clues on how to develop better inhibitors. [ABSTRACT FROM AUTHOR]

Addresses some f the key issues to consider when hosting a nursing symposium. Target audience; Presenters; Time and location; Advertising; Fees; Audiovisual support; Implementation.

Conjugated linoleic acid (CLA; 18∶2), a group of positional and geometric isomers of linoleic acid (LA; 18∶2n−6), has been shown to modulate immune function through its effect on eicosanoid synthesis. This effect has been attributed to a reduced production of n−6 polyunsaturated fatty acid (PUFA), the precursor of eicosanoids. Since Δ6-desaturase is the rate-limiting enzyme of the n−6 PUFA production, it is our hypothesis that CLA, which has similar chemical structure to LA, interacts directly with Δ6-desaturase. A unique and simple model, i.e., baker's yeast ( Saccharomyces cerevisiae) transformed with fungal Δ6-desaturase gene, previously established, was used to investigate the direct effect of CLA on Δ6-desaturase. This model allows LA to be converted to γ-linolenic acid (GLA; 18∶3n−6) but not GLA to its metabolite(s). No metabolites of CLA were found in the lipids of the yeast transformed with Δ6-desaturase. The inability to convert CLA to conjugated GLA was not due to the failure of yeast cells to take up the CLA isomers. CLA mixture and individual isomers significantly inhibited the activity of Δ6-desaturase of the transformed yeast in vivo. Even though its uptake by the yeast was low, CLA c9, t11 isomer was found to be the most potent inhibitor of the four isomers tested, owing to its high inhibitory effect on Δ6-desaturase. Since CLA did not cause significant changes in the level of Δ6-desaturase mRNA, the inhibition of GLA production could not be attributed to suppression of Δ6-desaturate gene expression at the transcriptional level. [ABSTRACT FROM AUTHOR]

To examine the temporal relationship between pre- and post-docking events, we generated a Munc18c temperature-sensitive mutant (Munc18c/TS) by substitution of arginine 240 with a lysine residue. At the permissive temperature (23°C), overexpression of both the wild type (Munc18c/WT) and the R240K mutant inhibited insulin-stimulated GLUT4/IRAP vesicle translocation. However, at tile non-permissive temperature (37°C) only Munc18c/WT inhibited GLUT4/IRAP translocation whereas Munc18c/TS was without effect. Moreover, Munc18c/WT bound to syntaxin 4 at both 23 and 37°C whereas Munc18c/TS bound syntaxin 4 only at 23°C. This was due to a temperature-dependent conformational change in Munc18c/TS, as its ability to bind syntaxin 4 and effects on GLUT4 translocation were rapidly reversible while protein expression levels remained unchanged. Furthermore, insulin stimulation of Munc18c/TS-expressing cells at 23°C followed by temperature shift to 37°C resulted in an increased rate of GLUT4 translocation compared with cells stimulated at 37°C. To date, this is the first demonstration that the rate-limiting step for insulin-stimulated GLUT4 translocation is the trafficking of GLUT4 vesicles and not their fusion with the plasma membrane. [ABSTRACT FROM AUTHOR]

The seroprevalence of infection was estimated from a sample of 889 cattle from 43 dairy herds in three counties in the Asturias region of Spain. The true prevalence of infection was estimated to be 30-6 per cent (95 per cent confidence interval (ca) 27.6 to 33.6). Seropositivity was associated with abortion during the previous year (odds ratio (OR)=3.31, P<0.001) and was slightly higher among purchased cattle (37.6 per cent), than among cattle raised on the farm (29.1 per cent) (P=0.078). Seropositive cows were more likely than seronegative cows to have had a seropositive dam (OR=2.3, P=0.011), suggesting that congenital transmission contributed to about 56 per cent of the infections. Herds with a true seroprevalence above 10 per cent had more dogs on the farm, than herds with a lower prevalence (P=0.032). The ORs relating abortion to seropositivity in individual herds ranged from 0.7 to 19, indicating that some herds experienced few abortions caused by , while others experienced more abortions due to the organism. Overall, 38.7 per cent of the abortions were estimated to have been attributable to . [ABSTRACT FROM PUBLISHER]

Two cDNA clones with homology to known desaturase genes were isolated from the fungus Mortierella alpina. The open reading frame in one clone encoded 399 amino acids and exhibited Δ12-desaturase activity when expressed in Saccharomyces cerevisiae in the presence of endogenous fatty acid substrate oleic acid. The insert in another clone contained an open reading frame encoding 457 amino acids and exhibited Δ6-desaturase activity in S. cerevisiae in the presence of exogenous fatty acid substrate linoleic acid. Expression of the Δ12-desaturase gene under appropriate media and temperature conditions led to the production of linoleic acid at levels up to 25% of the total fatty acids in yeast. When linoleic acid was provided as an exogenous substrate to the yeast cultures expressing the Δ6-desaturase activity, the level of γ-linolenic acid reached 10% of the total yeast fatty acids. Co-expression of both the Δ6- and Δ12-desaturase cDNA resulted in the endogenous production of γ-linolenic acid. The yields of γ-linolenic acid reached as high as 8% of total fatty acids in yeast. [ABSTRACT FROM AUTHOR]

We report the first implementation of fiber optics at 11 GHz in an experimental satellite communication EHF/ SHF research terminal [or airborne applications. Signal-to-noise and bit-error rate were measured to characterize the system after a 100-m-long fiber optic link replaced a 4-ft-long coaxial cable to enable X-band signal remoting. [ABSTRACT FROM AUTHOR]

Male mice of the CF-1 strain (Mus musculus) were allowed to take up lone residence in a small territory consisting of a 60-cm enclosure attached by a tubular runway to a standard mouse cage with food, water, and bedding. A group of ten mice, each of which resided in its own separate enclosure for 24 hours, were more aggressive toward intruders than other groups of ten mice following six-hour residence periods, or no such residence. Aggression toward intruders increased in repeated weekly tests of the six-hour residents, but after four weeks of testing did not reach the maximum stable level displayed by the 24-hour residents over four weeks of testing. In another experiment, the 24-hour residence period of groups of 20 CF-1 male mice was disturbed by briefly removing the mouse from the enclosure, before introducing the intruder, at various intervals prior to testing. Removal of the resident five minutes before testing resulted in a marked decrease in aggression toward intruders. Although Lesser decreases in aggression followed intervals of 30, 45, and 60 minutes, a 180 minute interval resulted in no appreciable effects compared to undisturbed controls. It is concluded that exposure to the stimuli provided by the enclosure results in an aggressive readiness in the resident mouse which reaches a high level within a 24-hour period. [ABSTRACT FROM AUTHOR]

Natural transformation is the mechanism of procaryotic gene transfer that involves the uptake and expression of genetic information encoded in extracellular DNA. This process has been regarded as a mechanism to transfer genes (primarily chromosomal markers) between closely related strains or species. Here we demonstrate the cell-contact-dependent transfer of a non-conjugative plasmid from a laboratory E. coli strain to a marine Vibrio species, the first report of intergeneric natural plasmid transformation involving a marine bacterium. The nucleic acid synthesis inhibitors nalidixic acid and rifampicin inhibited the ability of the E. coli to function as a donor. However, dead cells also served as efficient donors. There was an obligate requirement for cell contact. No transfer occurred in the presence of DNase I, when donors and recipients were separated by a 0.2-µm filter, or when spent medium alone was used as a source of transforming DNA. These results indicate that contact-mediated intergeneric plasmid exchange can occur in the absence of detectable viable donor cells and that small non-conjugative plasmids can be spread through heterogeneous microbial communities by a process previously not recognized, natural plasmid transformation. These findings are important in the assessment of genetic risk to the environment, particularly from wastewater treatment systems and the use of genetically engineered organisms in the environment. [ABSTRACT FROM AUTHOR]

An immune deficiency state is proposed as the cause of a disorder affecting a father and son with chronic dermatitis, purulent blepharitis with corneal ulceration, and scarring pyodermatous alopecia of the scalp. The results of immunologic investigation revealed abnormal neutrophil function with a variable decrease in intracellular killing, decreased lymphocyte transformation, increased serum IgG and IgE, and elevated serum copper levels. These findings will be compared with previously described immune deficiency disorders. [ABSTRACT FROM AUTHOR]