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Background: Asthma is a heterogeneous disease with variability among patients in characteristics such as lung function, symptoms and control, body weight, markers of inflammation, and responsiveness to glucocorticoids (GC). Cluster analysis of well-charact

Rationale: Patients with asthma exhibit variable response to inhaled corticosteroids (ICS). Vitamin D is hypothesized to exert effects on phenotype and glucocorticoid (GC) response in asthma.Objectives: To determine the effect of vitamin D levels on phenotype and GC response in asthma.Methods: Nonsmoking adults with asthma were enrolled in a study assessing the relationship between serum 25(OH)D (vitamin D) concentrations and lung function, airway hyperresponsiveness (AHR), and GC response, as measured by dexamethasone-induced expression of mitogen-activated protein kinase phosphatase (MKP)-1 by peripheral blood mononuclear cells.Measurements and Main Results: A total of 54 adults with asthma (FEV(1), 82.9 +/- 15.7% predicted [mean +/- SD], serum vitamin D levels of 28.1 +/- 10.2 ng/ml) were enrolled. Higher vitamin D levels were associated with greater lung function, with a 22.7 (+/-9.3) ml (mean +/- SE) increase in FEV(1) for each nanogram per milliliter increase in vitamin D (P = 0.02). Participants with vitamin D insufficiency (<30 ng/ml) demonstrated increased AHR, with a provocative concentration of methacholine inducing a 20% fall in FEV(1) of 1.03 (+/-0.2) mg/ml versus 1.92 (+/-0.2) mg/ml in those with vitamin D of 30 ng/ml or higher (P = 0.01). In ICS-untreated participants, dexamethasone-induced MKP-1 expression increased with higher vitamin D levels, with a 0.05 (+/-0.02)-fold increase (P = 0.02) in MKP-1 expression observed for each nanogram per milliliter increase in vitamin D, a finding that occurred in the absence of a significant increase in IL-10 expression.Conclusions: In asthma, reduced vitamin D levels are associated with impaired lung function, increased AHR, and reduced GC response, suggesting that supplementation of vitamin D levels in patients with asthma may improve multiple parameters of asthma severity and treatment response. Clinical trials registered with www.clinicaltrials.gov (NCT00495157, NCT00565266, and NCT00557180). [ABSTRACT FROM AUTHOR]

Abstract Background Reporting of health research is often inadequate and incomplete. Complete and transparent reporting is imperative to enable readers to assess the validity of research findings for use in healthcare and policy decision-making. To this end, many guidelines, aimed at improving the quality of health research reports, have been developed for reporting a variety of research types. Despite efforts, many reporting guidelines are underused. In order to increase their uptake, evidence of their effectiveness is important and will provide authors, peer reviewers and editors with an important resource for use and implementation of pertinent guidance. The objective of this study was to assess whether endorsement of reporting guidelines by journals influences the completeness of reporting of health studies. Methods Guidelines providing a minimum set of items to guide authors in reporting a specific type of research, developed with explicit methodology, and using a consensus process will be identified from an earlier systematic review and from the EQUATOR (Enhancing the QUAlity and Transparency Of health Research) Network’s reporting guidelines library. MEDLINE, EMBASE, the Cochrane Methodology Register and Scopus will be searched for evaluations of those reporting guidelines; relevant evaluations from the recently conducted CONSORT systematic review will also be included. Single data extraction with 10% verification of study characteristics, 20% of outcomes and complete verification of aspects of study validity will be carried out. We will include evaluations of reporting guidelines that assess the completeness of reporting: (1) before and after journal endorsement, and/or (2) between endorsing and non-endorsing journals. For a given guideline, analyses will be conducted for individual and the total sum of items. When possible, standard, pooled effects with 99% confidence intervals using random effects models will be calculated. Discussion Evidence on which guidelines have been evaluated and which are associated with improved completeness of reporting is important for various stakeholders, including editors who consider which guidelines to endorse in their journal editorial policies.

Abstract Background There is a significant public health burden associated with substance use in Canada. The early detection and/or treatment of risky substance use has the potential to dramatically improve outcomes for those who experience harms from the non-medical use of psychoactive substances, particularly adolescents whose brains are still undergoing development. The Screening, Brief Intervention, and Referral to Treatment model is a comprehensive, integrated approach for the delivery of early intervention and treatment services for individuals experiencing substance use-related harms, as well as those who are at risk of experiencing such harm. Methods This article describes the protocol for a systematic review of the effectiveness of brief interventions as part of the Screening, Brief Intervention, and Referral to Treatment model for reducing the non-medical use of psychoactive substances. Studies will be selected in which brief interventions target non-medical psychoactive substance use (excluding alcohol, nicotine, or caffeine) among those 12 years and older who are opportunistically screened and deemed at risk of harms related to psychoactive substance use. We will include one-on-one verbal interventions and exclude non-verbal brief interventions (for example, the provision of information such as a pamphlet or online interventions) and group interventions. Primary, secondary and adverse outcomes of interest are prespecified. Randomized controlled trials will be included; non-randomized controlled trials, controlled before-after studies and interrupted time series designs will be considered in the absence of randomized controlled trials. We will search several bibliographic databases (for example, MEDLINE, EMBASE, CINAHL, PsycINFO, CORK) and search sources for grey literature. We will meta-analyze studies where possible. We will conduct subgroup analyses, if possible, according to drug class and intervention setting. Discussion This review will provide evidence on the effectiveness of brief interventions as part of the Screening, Brief Intervention, and Referral to Treatment protocol aimed at the non-medical use of psychoactive substances and may provide guidance as to where future research might be most beneficial.

Abstract Background Globally, suboptimal prescribing practices and medication errors are common. Guidance to health professionals and consumers alone is not sufficient to optimise behaviours, therefore strategies to promote evidence-based decision making and practice, such as decision support tools or reminders, are important. The literature in this area is growing, but is of variable quality and dispersed across sources, which makes it difficult to identify, access, and assess. To overcome these problems, by synthesizing and evaluating the data from systematic reviews, we have developed Rx for Change to provide a comprehensive, online database of the evidence for strategies to improve drug prescribing and use. Methods We use reliable and valid methods to search and screen the literature, and to appraise and analyse the evidence from relevant systematic reviews. We then present the findings in an online format which allows users to easily access pertinent information related to prescribing and medicines use. The database is a result of the collaboration between the Canadian Agency for Drugs and Technologies in Health (CADTH) and two Cochrane review groups. Results To capture the body of evidence on interventions to improve prescribing and medicines use, we conduct comprehensive and regular searches in multiple databases, and hand-searches of relevant journals. We screen articles to identify relevant systematic reviews, and include them if they are of moderate or high methodological quality. Two researchers screen, assess quality, and extract data on demographic details, intervention characteristics, and outcome data. We report the results of our analysis of each systematic review using a standardised quantitative and qualitative format. Rx for Change currently contains over 200 summarised reviews, structured in a multi-level format. The reviews included in the database are diverse, covering various settings, conditions, or diseases and targeting a range of professional and consumer behaviors. Conclusions Rx for Change is a novel database that synthesizes current research evidence about the effects of interventions to improve drug prescribing practices and medicines use.

Patients with metastatic brain melanomas (MBM) experience shorter-lasting survival than patients with extracranial metastases, and this is associated with a higher fraction of dysfunctional CD8 T cells. The goal of this study was to understand the underlying cause of T cell dysfunction in MBM. To accomplish this, we compared murine B16 melanomas implanted intracranially (IC) or subcutaneously (SC). CD8 T cell activation was not altered, but representation in IC tumors was lower. Transferred activated or naïve CD8 T cells accumulated in similar numbers in both tumors, suggesting that the vasculature does not differentially impair T cell presence. Surprisingly, we found no evidence for T cell activation in draining lymph nodes of SC or IC tumor-bearing mice, consistent with the fact that dendritic cells (DC) that had acquired tumor antigen showed an immature phenotype. Instead, T cell activation occurred within both tumors, where the majority of tumor antigen + myeloid cells were found. While, the numbers of intratumoral DC were comparable, those in IC tumors acquired less tumor antigen, and were alternatively matured based on upregulation of MHCII without upregulation of CD86. Additionally, in IC tumors, the largest population of tumor antigen + myeloid cells were microglia. However, their presence did not influence either antigen acquisition or the phenotype of other myeloid cell populations. Overall, our data suggest that diminished representation of CD8 T cells in IC tumors is a consequence of alternatively matured DC and/or microglia that induce distinctly activated T cells, which ultimately fail to continue to accumulate inside the tumor., (© 2024. The Author(s).)

Background: Laryngopharyngeal reflux (LPR) is associated with gastroesophageal reflux and is known to cause poor asthma control. Moreover, LPR and asthma frequently coexist in the same individual. Controlling LPR could be associated with improved asthma control. The Supraglottic Index (SGI) is a clinically applied visual scale, which correlates with the presence of LPR. The role of SGI in monitoring LPR therapy in individuals with asthma is not known., Objective: To determine whether the SGI can be used over time to assess the presence of LPR in patients with asthma, and whether the SGI improves with LPR treatment., Methods: This is a pilot study in 15 participants with asthma. Those without evidence of LPR by SGI measurement were assigned to the observation arm. Those with LPR were assigned to the treatment arm and were treated with either standard-of-care LPR treatment (antacids and behavioral management) or a novel therapy (upper esophageal assist device)., Results: The SGI remained stable in individuals with asthma who underwent observation over 8 weeks. The SGI improved in participants with asthma treated for LPR (P = .024)., Conclusion: The SGI is a readily available clinical tool to assess the presence of LPR and monitor its therapy in asthma., Competing Interests: Disclosures Dr Manka has received consultant fees from GlaxoSmithKline and CarelonRx, unrelated to this report. Dr Guntur has received consultant fees from AstraZeneca and Regeneron, unrelated to this report. The remaining authors have no conflicts of interest to report., (Copyright © 2024 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Whereas temporal variability of plant phenology in response to climate change has already been well studied, the spatial variability of phenology is not well understood. Given that phenological shifts may affect biotic interactions, there is a need to investigate how the variability in environmental factors relates to the spatial variability in herbaceous species' phenology by at the same time considering their functional traits to predict their general and species-specific responses to future climate change. In this project, we analysed phenology records of 148 herbaceous species, which were observed for a single year by the PhenObs network in 15 botanical gardens. For each species, we characterised the spatial variability in six different phenological stages across gardens. We used boosted regression trees to link these variabilities in phenology to the variability in environmental parameters (temperature, latitude and local habitat conditions) as well as species traits (seed mass, vegetative height, specific leaf area and temporal niche) hypothesised to be related to phenology variability. We found that spatial variability in the phenology of herbaceous species was mainly driven by the variability in temperature but also photoperiod was an important driving factor for some phenological stages. In addition, we found that early-flowering and less competitive species characterised by small specific leaf area and vegetative height were more variable in their phenology. Our findings contribute to the field of phenology by showing that besides temperature, photoperiod and functional traits are important to be included when spatial variability of herbaceous species is investigated., (© 2024. The Author(s).)

Phenology has emerged as key indicator of the biological impacts of climate change, yet the role of functional traits constraining variation in herbaceous species' phenology has received little attention. Botanical gardens are ideal places in which to investigate large numbers of species growing under common climate conditions. We ask whether interspecific variation in plant phenology is influenced by differences in functional traits. We recorded onset, end, duration and intensity of initial growth, leafing out, leaf senescence, flowering and fruiting for 212 species across five botanical gardens in Germany. We measured functional traits, including plant height, absolute and specific leaf area, leaf dry matter content, leaf carbon and nitrogen content and seed mass and accounted for species' relatedness. Closely related species showed greater similarities in timing of phenological events than expected by chance, but species' traits had a high degree of explanatory power, pointing to paramount importance of species' life-history strategies. Taller plants showed later timing of initial growth, and flowered, fruited and underwent leaf senescence later. Large-leaved species had shorter flowering and fruiting durations. Taller, large-leaved species differ in their phenology and are more competitive than smaller, small-leaved species. We assume climate warming will change plant communities' competitive hierarchies with consequences for biodiversity., (© 2022 The Authors. New Phytologist © 2022 New Phytologist Foundation.)

Dendritic cells are potently activated by the synergistic action of CD40 stimulation in conjunction with signaling through toll like receptors, subsequently priming T cells. Cancer vaccines targeting the activation of dendritic cells in this manner show promise in murine models and are being developed for human patients. While the efficacy of vaccines based on CD40 and toll like receptor stimulation has been established, further investigation is needed to understand the mechanism of tumor control and how vaccination alters tumor infiltrating immune cells. In this study we vaccinated mice bearing established murine melanoma tumors with agonistic anti-CD40, polyI:C, and tumor antigen. Vaccination led to increased intratumoral T cell numbers and delayed tumor growth, yet did not require trafficking of T cells from the periphery. Pre-existing intratumoral T cells exhibited an acute burst in proliferation but became less functional in response to vaccination. However, the increased intratumoral T cell numbers yielded increased numbers of effector T cells per tumor. Together, our data indicate that the existing T cell response and intratumoral dendritic cells are critical for vaccination efficacy. It also suggests that circulating T cells responding to vaccination may not be an appropriate biomarker for vaccine efficacy., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

Background: Focused ultrasound (FUS) activation of microbubbles (MBs) for blood-brain (BBB) and blood-tumor barrier (BTB) opening permits targeted therapeutic delivery. While the effects of FUS+MBs mediated BBB opening have been investigated for normal brain tissue, no such studies exist for intracranial tumors. As this technology advances into clinical immunotherapy trials, it will be crucial to understand how FUS+MBs modulates the tumor immune microenvironment. Methods and Results: Bulk RNA sequencing revealed that FUS+MBs BTB/BBB opening (1 MHz, 0.5 MPa peak-negative pressure) of intracranial B16F1cOVA tumors increases the expression of genes related to proinflammatory cytokine and chemokine signaling, pattern recognition receptor signaling, and antigen processing and presentation. Flow cytometry revealed increased maturation (i.e. CD86) of dendritic cells (DCs) in the meninges and altered antigen loading of DCs in both the tumor and meninges. For DCs in tumor draining lymph nodes, FUS+MBs had no effect on maturation and elicited only a trend towards increased presentation of tumor-derived peptide by MHC. Neither tumor endothelial cell adhesion molecule expression nor homing of activated T cells was affected by FUS+MBs. Conclusion: FUS+MBs-mediated BTB/BBB opening elicits signatures of inflammation; however, the response is mild, transient, and unlikely to elicit a systemic response independent of administration of immune adjuvants., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Premise of the Study: To improve our understanding of the patterns and drivers of fleshy fruit phenology, we examined the sequence, patterns across years and locations, and drivers of fruiting times at five botanical gardens on three continents., Methods: We monitored four stages of fruit phenology for 406 temperate, fleshy-fruited, woody plant species in 2014 and 2015., Key Results: Across all gardens, ripe fruits were present from May to March of the following year, with peak fruiting durations ranging from under 1 week to over 150 days. Species-level first fruiting and onset of peak fruiting dates were strongly associated with one another within sites and were more consistent between years and sites than the end of peak fruiting and last fruiting date. The order of fruiting among species between years and gardens was moderately consistent, and both peak fruiting times and fruiting durations were found to be phylogenetically conserved., Conclusions: The consistent order of fruiting among species between years and locations indicates species-specific phenological responses to environmental conditions. Wide variation in fruiting times across species and in the duration of peak fruiting reinforces the importance of understanding how plant phenology impacts dispersers and monitoring the health and consistency of these interactions., (© 2018 Botanical Society of America.)

Background: Chronic Refractory Cough (CRC) is a common condition that significantly impairs patients' quality of life. Unfortunately, in many situations patients continue to experience CRC in spite of following published guidelines for diagnosis and treatment., Methods: 99 patients were referred to National Jewish Health (NJH), a specialty respiratory center for evaluation of CRC (cough ≥ 8 weeks duration). Study duration occurred over 18 months. Intake evaluation for all patients included history, physical examination, spirometry and fiberoptic laryngoscopy. Testing to confirm causes of CRC were performed. Specific therapy for each potential cause was provided. A visual analog cough scale measured cough response., Results: Ten final diagnostic categories were found in the cohort of 99 patients with CRC: Obstructive sleep apnea (apnea/hypoxia index ≥ 5), rhinosinusitis, Tracheobronchomalacia (≥65% collapse of airway with dynamic expiratory imaging), esophageal dysmotility, gastroesophageal reflux, abnormal swallowing with laryngeal penetration, asthma, COPD, bronchiectasis and paradoxical vocal cord movement. In these patients there were 42 incorrect intake diagnoses and 101 new diagnoses established. Patients with CRC have had multiple diagnoses (3.8 ± 1.6) associated with chronic cough. With directed therapy 71/76 (93%) patients had resolution or improvement in cough symptoms., Conclusions: Among patients referred to a specialty respiratory center with CRC multiple concomitant diagnoses for cough were common. Certain diagnoses such as OSA and TBM have not been reported in cough guidelines but in this study are commonly associated diagnoses. Targeted therapy for each recognized diagnosis improves patient response., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Given the strong environmental influence on both epigenetic marks and allergic asthma in children, the epigenetic alterations in respiratory epithelia might provide insight into allergic asthma., Objective: We sought to identify DNA methylation and gene expression changes associated with childhood allergic persistent asthma., Methods: We compared genomic DNA methylation patterns and gene expression in African American children with persistent atopic asthma (n = 36) versus healthy control subjects (n = 36). Results were validated in an independent population of asthmatic children (n = 30) by using a shared healthy control population (n = 36) and in an independent population of white adult atopic asthmatic patients (n = 12) and control subjects (n = 12)., Results: We identified 186 genes with significant methylation changes, differentially methylated regions or differentially methylated probes, after adjustment for age, sex, race/ethnicity, batch effects, inflation, and multiple comparisons. Genes differentially methylated included those with established roles in asthma and atopy and genes related to extracellular matrix, immunity, cell adhesion, epigenetic regulation, and airflow obstruction. The methylation changes were substantial (median, 9.5%; range, 2.6% to 29.5%). Hypomethylated and hypermethylated genes were associated with increased and decreased gene expression, respectively (P < 2.8 × 10 -6 for differentially methylated regions and P < 7.8 × 10 -10 for differentially methylated probes). Quantitative analysis in 53 differentially expressed genes demonstrated that 32 (60%) have significant methylation-expression relationships within 5 kb of the gene. Ten loci selected based on the relevance to asthma, magnitude of methylation change, and methylation-expression relationships were validated in an independent cohort of children with atopic asthma. Sixty-seven of 186 genes also have significant asthma-associated methylation changes in nasal epithelia of adult white asthmatic patients., Conclusions: Epigenetic marks in respiratory epithelia are associated with allergic asthma and gene expression changes in inner-city children., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Background and Aims: Autumn leaf senescence marks the end of the growing season in temperate ecosystems. Its timing influences a number of ecosystem processes, including carbon, water and nutrient cycling. Climate change is altering leaf senescence phenology and, as those changes continue, it will affect individual woody plants, species and ecosystems. In contrast to spring leaf out times, however, leaf senescence times remain relatively understudied. Variation in the phenology of leaf senescence among species and locations is still poorly understood., Methods: Leaf senescence phenology of 1360 deciduous plant species at six temperate botanical gardens in Asia, North America and Europe was recorded in 2012 and 2013. This large data set was used to explore ecological and phylogenetic factors associated with variation in leaf senescence., Key Results: Leaf senescence dates among species varied by 3 months on average across the six locations. Plant species tended to undergo leaf senescence in the same order in the autumns of both years at each location, but the order of senescence was only weakly correlated across sites. Leaf senescence times were not related to spring leaf out times, were not evolutionarily conserved and were only minimally influenced by growth habit, wood anatomy and percentage colour change or leaf drop. These weak patterns of leaf senescence timing contrast with much stronger leaf out patterns from a previous study., Conclusions: The results suggest that, in contrast to the broader temperature effects that determine leaf out times, leaf senescence times are probably determined by a larger or different suite of local environmental effects, including temperature, soil moisture, frost and wind. Determining the importance of these factors for a wide range of species represents the next challenge for understanding how climate change is affecting the end of the growing season and associated ecosystem processes., (© The Author 2015. Published by Oxford University Press on behalf of the Annals of Botany Company. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Medication dosing errors remain commonplace and may result in potentially life-threatening outcomes, particularly for pediatric patients where dosing often requires weight-based calculations. Novel medication delivery systems that may reduce dosing errors resonate with national healthcare priorities. Our goal was to evaluate novel, prefilled medication syringes labeled with color-coded volumes corresponding to the weight-based dosing of the Broselow Tape, compared to conventional medication administration, in simulated prehospital pediatric resuscitation scenarios., Methods: We performed a prospective, block-randomized, cross-over study, where 10 full-time paramedics each managed two simulated pediatric arrests in situ using either prefilled, color-coded syringes (intervention) or their own medication kits stocked with conventional ampoules (control). Each paramedic was paired with two emergency medical technicians to provide ventilations and compressions as directed. The ambulance patient compartment and the intravenous medication port were video recorded. Data were extracted from video review by blinded, independent reviewers., Results: Median time to delivery of all doses for the intervention and control groups was 34 (95% CI: 28-39) seconds and 42 (95% CI: 36-51) seconds, respectively (difference=9 [95% CI: 4-14] seconds). Using the conventional method, 62 doses were administered with 24 (39%) critical dosing errors; using the prefilled, color-coded syringe method, 59 doses were administered with 0 (0%) critical dosing errors (difference=39%, 95% CI: 13-61%)., Conclusions: A novel color-coded, prefilled syringe decreased time to medication administration and significantly reduced critical dosing errors by paramedics during simulated prehospital pediatric resuscitations., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Study Objective: The Institute of Medicine has called on the US health care system to identify and reduce medical errors. Unfortunately, medication dosing errors remain commonplace and may result in potentially life-threatening outcomes, particularly for pediatric patients when dosing requires weight-based calculations. Novel medication delivery systems that may reduce dosing errors resonate with national health care priorities. Our goal was to evaluate novel, prefilled medication syringes labeled with color-coded volumes corresponding to the weight-based dosing of the Broselow Tape, compared with conventional medication administration, in simulated pediatric emergency department (ED) resuscitation scenarios., Methods: We performed a prospective, block-randomized, crossover study in which 10 emergency physician and nurse teams managed 2 simulated pediatric arrest scenarios in situ, using either prefilled, color-coded syringes (intervention) or conventional drug administration methods (control). The ED resuscitation room and the intravenous medication port were video recorded during the simulations. Data were extracted from video review by blinded, independent reviewers., Results: Median time to delivery of all doses for the conventional and color-coded delivery groups was 47 seconds (95% confidence interval [CI] 40 to 53 seconds) and 19 seconds (95% CI 18 to 20 seconds), respectively (difference=27 seconds; 95% CI 21 to 33 seconds). With the conventional method, 118 doses were administered, with 20 critical dosing errors (17%); with the color-coded method, 123 doses were administered, with 0 critical dosing errors (difference=17%; 95% CI 4% to 30%)., Conclusion: A novel color-coded, prefilled syringe decreased time to medication administration and significantly reduced critical dosing errors by emergency physician and nurse teams during simulated pediatric ED resuscitations., (Copyright © 2015 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

Leaf out phenology affects a wide variety of ecosystem processes and ecological interactions and will take on added significance as leaf out times increasingly shift in response to warming temperatures associated with climate change. There is, however, relatively little information available on the factors affecting species differences in leaf out phenology. An international team of researchers from eight Northern Hemisphere temperate botanical gardens recorded leaf out dates of c. 1600 woody species in 2011 and 2012. Leaf out dates in woody species differed by as much as 3 months at a single site and exhibited strong phylogenetic and anatomical relationships. On average, angiosperms leafed out earlier than gymnosperms, deciduous species earlier than evergreen species, shrubs earlier than trees, diffuse and semi-ring porous species earlier than ring porous species, and species with smaller diameter xylem vessels earlier than species with larger diameter vessels. The order of species leaf out was generally consistent between years and among sites. As species distribution and abundance shift due to climate change, interspecific differences in leaf out phenology may affect ecosystem processes such as carbon, water, and nutrient cycling. Our open access leaf out data provide a critical framework for monitoring and modelling such changes going forward., (© 2014 The Authors. New Phytologist © 2014 New Phytologist Trust.)

Objective: We sought to characterize a novel cohort of patients with lung disease, anti-cyclic citrullinated peptide (CCP) antibody positivity, without rheumatoid arthritis (RA) or other connective tissue disease (CTD)., Methods: The study sample included 74 subjects with respiratory symptoms, evaluated January 2008-January 2010 and found to have a positive anti-CCP antibody but no evidence for RA or other CTD. Each underwent serologic testing, pulmonary physiology testing, and thoracic high-resolution computed tomography (HRCT) scan as part of routine clinical evaluation., Results: The majority of subjects were women, and most were former cigarette smokers. Four distinct radiographic phenotypes were identified: isolated airways disease (54%), isolated interstitial lung disease (ILD) (14%), mixed airways disease and ILD (26%), and combined pulmonary fibrosis with emphysema (7%). This cohort had a predominance of airways disease, either in isolation or along with a usual interstitial pneumonia-pattern of ILD. Among subjects with high-titer anti-CCP positivity (n=33), three developed the articular manifestations of RA during a median follow-up of 449 days., Conclusion: We have described a unique cohort of patients with anti-CCP antibody positivity and lung disease in the absence of existing RA or other CTD. The lung phenotypic characteristics of this cohort resemble those of established RA and a few of these patients have developed articular RA within a short period of follow-up. The implications of a positive anti-CCP antibody among patients with lung disease but not RA are not yet known, but we believe requires further investigation., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Asthma is a heterogeneous disease with variability among patients in characteristics such as lung function, symptoms and control, body weight, markers of inflammation, and responsiveness to glucocorticoids (GC). Cluster analysis of well-characterized cohorts can advance understanding of disease subgroups in asthma and point to unsuspected disease mechanisms. We utilized an hypothesis-free cluster analytical approach to define the contribution of obesity and related variables to asthma phenotype., Methodology and Principal Findings: In a cohort of clinical trial participants (n = 250), minimum-variance hierarchical clustering was used to identify clinical and inflammatory biomarkers important in determining disease cluster membership in mild and moderate persistent asthmatics. In a subset of participants, GC sensitivity was assessed via expression of GC receptor alpha (GCRα) and induction of MAP kinase phosphatase-1 (MKP-1) expression by dexamethasone. Four asthma clusters were identified, with body mass index (BMI, kg/m(2)) and severity of asthma symptoms (AEQ score) the most significant determinants of cluster membership (F = 57.1, p<0.0001 and F = 44.8, p<0.0001, respectively). Two clusters were composed of predominantly obese individuals; these two obese asthma clusters differed from one another with regard to age of asthma onset, measures of asthma symptoms (AEQ) and control (ACQ), exhaled nitric oxide concentration (F(E)NO) and airway hyperresponsiveness (methacholine PC(20)) but were similar with regard to measures of lung function (FEV(1) (%) and FEV(1)/FVC), airway eosinophilia, IgE, leptin, adiponectin and C-reactive protein (hsCRP). Members of obese clusters demonstrated evidence of reduced expression of GCRα, a finding which was correlated with a reduced induction of MKP-1 expression by dexamethasone, Conclusions and Significance: Obesity is an important determinant of asthma phenotype in adults. There is heterogeneity in expression of clinical and inflammatory biomarkers of asthma across obese individuals. Reduced expression of the dominant functional isoform of the GCR may mediate GC insensitivity in obese asthmatics.

In this study the authors investigated associations among children's observed responses to failure in an analogue entry situation, their attention deployment patterns, and skills and processes associated with self-regulation. Participants were 54 kindergarten and first-grade students who were either aggressive-rejected or low aggressive-popular based on peer nominations. Inhibitory control predicted the tendency to respond to entry failure by stopping and watching the group's activity. Baseline vagal tone and other-directed attention predicted children's tendency to change entry strategies after failure. Parent-rated attention skills moderated the relation between children's attention deployment patterns during the entry task and their responses to entry failure. Children who engaged in more other-directed attention were less likely to turn to solitary play after entry failure but only if they had high or moderate levels of attentional control. Other-directed attention was related to repeating previous entry bids without modification after entry failure but only when children had high levels of attention problems.

The explosive pentaerythritol tetranitrate (PETN) C(CH(2)-O-NO(2))(4) has been studied by (1)H NMR and (14)N NQR. The (14)N NQR frequency and spin-lattice relaxation time T(1Q) for the nu(+) line have been measured at temperatures from 255 to 325K. The (1)H NMR spin-lattice relaxation time T(1) has been measured at frequencies from 1.8kHz to 40MHz and at temperatures from 250 to 390K. The observed variations are interpreted as due to hindered rotation of the NO(2) group about the bond to the oxygen atom of the CH(2)-O group, which produces a transient change in the dipolar coupling of the CH(2) protons, generating a step in the (1)H T(1) at frequencies between 2 and 100kHz. The same mechanism could also explain the two minima observed in the temperature variation of the (14)N NQR T(1Q) near 284 and 316K, due in this case to the transient change in the (14)N...(1)H dipolar interaction, the first attributed to hindered rotation of the NO(2) group and the second to an increase in torsional amplitude of the NO(2) group due to molecular distortion of the flexible CH(2)-O-NO(2) chain which produces a 15% increase in the oscillational amplitude of the CH(2) group. The correlation times governing the (1)H T(1) values are approximately 25 times longer than those governing the (14)N NQR T(1Q), explained by the slow spin-lattice cross-coupling between the two spin systems. At higher frequencies, the (1)H T(1) dispersion results show well-resolved dips between 200 and 904kHz assigned to level crossing with (14)N and weaker features between 3 and 5MHz tentatively assigned to level crossing with (17)O., (Copyright 2010 Elsevier Inc. All rights reserved.)

1. Experiments were carried out in 30 chronically catheterized foetal sheep (128-144 days; term 150 days) and in seven of these foetuses before, during and after acute hypoxaemia. The extent to which changes in sympathoadrenal activity and cardiac vagal activity affected the foetal cardiac response to hypoxaemia was measured. Three measurements were used: foetal heart rate (FHR), heart rate variability (HRV; measured as the coefficient of variation in pulse interval) and power spectral density (PSD; measured over the frequency ranges of 0.04-1.3 Hz). Cardiac vagal activity was blocked by atropine, beta-adrenoceptor activity was blocked by propranolol. 2. Under normoxaemic conditions, cardiac vagal blockade caused a rise in mean arterial pressure (MAP; P < 0.001), an increase in FHR (P < 0.001), a decrease in HRV (P < 0.001) and a decrease in PSD (P < 0.001). beta-adrenoceptor blockade caused a rise in MAP (P < 0.001), a fall in FHR (P < 0.01), a decrease in HRV (P < 0.001) but no change in PSD. 3. During mild hypoxaemia (PO2 = 12-14.5 mmHg) and moderate hypoxaemia (PO2 = 10-11.9 mmHg), foetal MAP (P < 0.001, P< 0.001), HRV (P < 0.01, P < 0.001) and PSD in the frequency range 0.04-0.45 Hz increased (P < 0.05-P < 0.001). Foetal heart rate decreased when foetuses became moderately hypoxaemic (P < 0.001). 4. After cardiac vagal blockade, hypoxaemia was associated with an increase in FHR compared with non-blocked hypoxaemic foetuses (P < 0.01, P < 0.001). The increase in HRV was abolished (P < 0.001, P < 0.001) as was the increase in PSD (P < 0.01-P < 0.001). 5. After beta-adrenoceptor blockade, the bradycardia that occurred during hypoxaemia was enhanced (P < 0.01, P < 0.05), the increase in HRV was not affected and neither was the increase in PSD. 6. As FHR and HRV of normoxaemic foetal sheep were affected both by atropine and propranolol, it would seem that both cardiac vagal and sympathoadrenal activity modulate the foetal heart under resting conditions. The lack of any effect of beta-adrenoceptor blockade on PSD under these conditions suggests that power spectral analysis (PSA) is not as sensitive as the other two methods in detecting sympathetically mediated modulation of the heart. 7. Because the hypoxaemia induced bradycardia and increase in HRV and in PSD were abolished by atropine (P < 0.01-P < 0.001), it is concluded that during hypoxaemia foetal HRV is mainly modulated by changes in cardiac vagal tone. Propranolol had no effect on foetal HRV, although it reduced it under normoxaemic conditions; therefore, it is concluded that cardiac sympathetic neural activity was not increased in acute hypoxaemia uncomplicated by acidosis. However, there was strong evidence of increased sympathoadrenal tone on the foetal heart in hypoxaemia, that is, there was a rise in FHR in hypoxaemic atropinized foetuses and a greater fall in FHR in beta-adrenoceptor blocked hypoxaemic foetuses. Therefore, this increased sympathetic influence on the foetal heart during hypoxaemia must be predominantly the result of increased adrenomedullary secretion of catecholamines. 8. Maintenance of foetal cardiac output depends on the chronotropic and ionotropic effects of catecholamines. Therefore, this adrenomedullary influence on the foetal heart during hypoxaemia is important to offset the opposing effects of increased cardiac vagal tone.

In 16 chronically catheterized fetal sheep the effects of reducing and restoring maternal renal blood flow (RBF) and thus inducing and reversing hypertension were studied in uninephrectomized pregnant ewes; controls were 3 fetuses that were carried by uninephrectomized ewes in which RBF was not reduced and that did not become hypertensive. Within 24-72 h of maternal RBF reduction, fetal arterial PO2 had fallen (P < 0.001) and PCO2 had increased (P < 0.025); fetal arterial pressure also increased (P < 0.005). These effects persisted, despite restoration of maternal RBF and reversal of maternal hypertension. Within 24-72 h of reduction of maternal RBF, fetal urine flow had increased (P < 0.005), and it remained elevated over the first 3 h after RBF was restored; 24-72 h later it was lower (P < 0.025) and returned to control levels. The excretion of sodium, potassium, and chloride showed a similar increase when maternal RBF was reduced (P < 0.001), with return to control values 24-72 h after RBF had been restored. Fetal glomerular filtration rate did not change; thus the natriuresis and diuresis that occurred were due to reduced tubular solute and water reabsorption (P < 0.025). These changes in fetal renal function may be related, in part, to changes in fetal PO2 and PCO2, but they are most likely due to reduced maternal renal function due to the restriction in maternal RBF, inasmuch as they were reversed when RBF was restored.

This paper discusses methods for obtaining image reconstructions from electron paramagnetic resonance (EPR) spectra which constitute object projections. An automatic baselining technique is described which treats each spectrum consistently; rotating the non-horizontal baselines which are caused by stray magnetic effects onto the horizontal axis. The convolved backprojection method is described for both two- and three-dimensional reconstruction and the effect of cut-off frequency on the reconstruction is illustrated. A slower, indirect, iterative method, which does a non-linear fit to the projection data, is shown to give a far smoother reconstructed image when the method of maximum entropy is used to determine the value of the final residual sum of squares. Although this requires more computing time than the convolved backprojection method, it is more flexible and overcomes the problem of numerical instability encountered in deconvolution. Images from phantom samples in vitro are discussed. The spectral data for these have been accumulated quickly and have a low signal-to-noise ratio. The results show that as few as 16 spectra can still be processed to give an image. Artifacts in the image due to a small number of projections using the convolved backprojection reconstruction method can be removed by applying a threshold, i.e. only plotting contours higher than a given value. These artifacts are not present in an image which has been reconstructed by the maximum entropy technique. At present these techniques are being applied directly to in vivo studies.

A resonator for the radiofrequency (250 MHz) electron paramagnetic resonance spectroscopy (EPRS) and imaging (EPRI) of biological samples is described. It has been designed for use with a 0.5 m bore EPR spectrometer. It is of the double split-ring type, 65 mm in diameter and 100 mm in length, and is equipped with a tuning-lock mechanism for fixed frequency operation. It can be used in the whole-body mode for small animals and as a surface coil for larger samples. The extent of sensitivity in the latter mode is ca. 20 mm. Larger resonators are being developed for whole-body human studies. A phase-locked crystal oscillator frequency source with high spectral purity is used to minimize noise demodulation and automatic tuning; coupling and phase controls have been included to compensate for motional artefacts. For purely aqueous nitroxides, the minimum detectable concentration is ca. 4 x 10(-7) M using an internal sample 100 ml in volume. Sensitivity in the surface coil mode is discussed and spectra from phantoms using both physiological saline and a human volunteer to induce realistic conduction losses are shown.

The effect on the fetal heart by inflating the fetal lungs with liquid or air while the animal was being maintained in utero by its normal placental circulation was investigated in 10 healthy, chronically catheterized fetal sheep of gestational age 126-137 days. It was found that initial attempts to inflate the lungs with volumes of air as small as 10 ml (i.e., with less than a predicted normal tidal volume) caused abrupt, powerful slowing of the fetal heart with, usually, an associated hypotension. Inflations with similarly small volumes of saline were ineffective. Atropine pretreatment abolished the cardiac slowing caused by the air inflations, indicating the operation of a neural reflex. An analysis of the pressure changes induced by the air and liquid inflations in airway, intrathoracic and intra-amniotic pressures showed that the cardiac slowing was primarily related to the level of mechanical stress applied across the fetal airway.

1. Renal function was studied in chronically catheterized fetal sheep (119-128 days gestation), before and during treatment of the ewe with the angiotensin converting enzyme (ACE) inhibitor, captopril, which crosses the placenta and blocks the fetal renin angiotensin system. 2. An i.v. dose of 15 mg (about 319 micrograms kg-1) of captopril to salt-replete ewes followed by an infusion to the ewe of 6 mg h-1 (about 128 micrograms kg-1 h-1) caused a fall in fetal arterial pressure (P < 0.01), and a rise in fetal renal blood flow (RBF) from 67.9 +/- 5.6 to 84.9 +/- 8.3 ml min-1 (mean +/- s.e. mean) (P < 0.05). Renal vascular resistance and glomerular filtration rate (GFR) fell (P < 0.01); fetal urine flow (P < 0.01); fetal urine flow (P < 0.01) and sodium excretion declined (P < 0.05). 3. Ewes were treated for the next 2 days with 15 mg captopril twice daily. On the 4th day, 15 mg was given to the ewe and fetal renal function studied for 2 h during the infusion of captopril (6 mg h-1) to the ewe. Of the 9 surviving fetuses, 3 were anuric and 3 had low urine flow rates. When 6 micrograms kg-1 h-1 of angiotensin II was infused directly into the fetus RBF fell from 69 +/- 10.1 ml min-1 to 31 +/- 13.9 ml min-1, GFR rose (P < 0.05) and urine flow (P < 0.01) and sodium excretion increased in all fetuses. 4. It is concluded that the small fall in fetal arterial pressure partly contributed to the fall in fetal GFR but in addition, efferent arteriolar tone fell so that the filtration pressure fell further. Thus maintenance of fetal renal function depends on the integrity of the fetal renin angiotensin system. These findings explain why use of ACE inhibitors in human pregnancy is associated with neonatal anuria.

After control measurements had been made, 15 chronically catheterized pregnant ewes (gestational age 123-141 days) were given 15 mg of captopril intravenously followed by an infusion of 6 mg/h. These doses blocked the pressor responses of both ewes and fetuses to 5 micrograms of angiotensin I. After captopril, maternal mean arterial pressure fell from 94 +/- 3.5 to 88 +/- 3.6 (SE) mmHg (P less than 0.0001) and pulse interval fell (P = 0.008). Maternal flow to the cotyledons fell from 766 +/- 118 to 525 +/- 77 ml/min (P = 0.002), as did flow to the remainder of the maternal placenta, i.e., the caruncles and their underlying myoendometrium (control flow 188 +/- 35 ml/min, flow 10-15 min after captopril 166 +/- 36.1 ml/min; P = 0.021). Flow to the rest of the myometrium did not change. Fetal arterial pressure fell from 46.9 +/- 1.6 to 44.1 +/- 1.6 mmHg (P less than 0.009), and fetal placental blood flow fell from 639.9 +/- 93.2 to 413.1 +/- 53.9 ml/min (P = 0.025). Flow to the fetal membranes declined also, from 53.2 +/- 6.5 to 35.6 +/- 3.3 ml/min (P less than 0.005). Maternal and fetal renal blood flows and fetal adrenal blood flows were unchanged. Fetal arterial PO2 was initially 19.5 +/- 0.8 mmHg; after captopril, it was 17.7 +/- 0.9 mmHg (P = 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)

In pregnant ewes, plasma protein levels over the gestation age range of 58-141 days fell progressively (r = -0.332, P less than 0.05, n = 36) but colloid osmotic pressure (COP, mmHg) did not change significantly. In fetal sheep carried by these ewes, plasma protein levels increased with age (r = 0.85, P less than 0.00001, n = 32). COP also rose (r = 0.8, P less than 0.00001, n = 23). Since maternal COP did not change and fetal COP increased, the net transplacental COP gradient between mother and fetus decreased with increasing age (r = -0.589, P less than 0.004, n = 22). Fetal plasma protein levels can be used to calculate fetal COP while maternal plasma protein levels cannot be used to calculate maternal COP.