Long-term effects of allergen sensitization and exposure in adult asthma: a prospective study.

BACKGROUND: : We investigated the effects of sensitization and exposure to common domestic allergens on longitudinal changes in lung function and bronchial hyperresponsiveness. METHODS: : Subjects attended 2 visits that were 4 years apart. Skin prick testing was performed and household dust samples were collected for quantification of mite, dog, and cat allergens at baseline. Measurements of lung function, exhaled nitric oxide, and bronchial hyperresponsiveness were completed at both visits. RESULTS: : Dust samples were collected in 165 of the 200 subjects completing both visits. Mean length of follow-up was 47 months. Bronchial hyperresponsiveness, measured at both visits in 86 subjects, deteriorated in those exposed to high mite allergen levels compared with those not exposed [mean (95% CI) doubling dose change PD20 = -0.44 (-1.07 to 0.19) vs 0.82 (0.27 to 1.36)], but improved in those exposed to high dog allergen levels compared with those not exposed [1.10 (0.33 to 1.86) vs 0.10 (-0.39 to 0.58)]. The associations were significant in the multivariate models. Cat allergen exposure was not associated with any changes in lung function, exhaled nitric oxide, or bronchial hyperresponsiveness. CONCLUSIONS: : In a 4-year prospective cohort of persons with asthma, exposure to high levels of dust mite allergens at baseline was associated with a subsequent increase in bronchial hyperresponsiveness

Recurring patterns in stationary intervals of abdominal uterine electromyograms during gestation

Abdominal uterine electromyograms (uEMG) studies have focused on uterine contractions to describe the evolution of uterine activity and preterm birth (PTB) prediction. Stationary, non-contracting uEMG has not been studied. The aim of the study was to investigate the recurring patterns in stationary uEMG, their relationship with gestation age and PTB, and PTB predictivity. A public database of 300 (38 PTB) three-channel (S1-S3) uEMG recordings of 30 min, collected between 22 and 35 weeks' gestation, was used. Motion and labour contraction-free intervals in uEMG were identified as 5-min weak-sense stationarity intervals in 268 (34 PTB) recordings. Sample entropy (SampEn), percentage recurrence (PR), percentage determinism (PD), entropy (ER), and maximum length (L MAX) of recurrence were calculated and analysed according to the time to delivery and PTB. Random time series were generated by random shuffle (RS) of actual data. Recurrence was present in actual data (p<0.001) but not RS. In S3, PR (p<0.005), PD (p<0.01), ER (p<0.005), and L MAX (p<0.05) were higher, and SampEn lower (p<0.005) in PTB. Recurrence indices increased (all p<0.001) and SampEn decreased (p<0.01) with decreasing time to delivery, suggesting increasingly regular and recurring patterns with gestation progression. All indices predicted PTB with AUC≥0.62 (p<0.05). Recurring patterns in stationary non-contracting uEMG were associated with time to delivery but were relatively poor predictors of PTB

Rigid Quantum Monte Carlo Simulations of Condensed Molecular Matter: Water Clusters in the n=2 ―˃ 8 Range

The numerical advantage of quantum Monte Carlo simulations of rigid bodies relative to the flexible simulations is investigated for some simple systems. The results show that if high frequency modes in molecular condensed matter are predominantly in the ground state, the convergence of path integral simulations becomes nonuniform. Rigid body quantum parallel tempering simulations are necessary to accurately capture thermodynamic phenomena in the temperature range where the dynamics are influenced by intermolecular degrees of freedom; the stereographic projection path integral adapted for quantum simulations of asymmetric tops is a significantly more efficient strategy compared with Cartesian coordinate simulations for molecular condensed matter under these conditions. The reweighted random series approach for stereographic path integral Monte Carlo is refined and implemented for the quantum simulation of water clusters treated as an assembly of rigid asymmetric tops

Objective cough frequency, airway inflammation, and disease control in asthma

Background Cough is recognized as an important troublesome symptom in the diagnosis and monitoring of asthma. Asthma control is thought to be determined by the degree of airway inflammation and hyperresponsiveness but how these factors relate to cough frequency is unclear. The goal of this study was to investigate the relationships between objective cough frequency, disease control, airflow obstruction, and airway inflammation in asthma. Methods Participants with asthma underwent 24-h ambulatory cough monitoring and assessment of exhaled nitric oxide, spirometry, methacholine challenge, and sputum induction (cell counts and inflammatory mediator levels). Asthma control was assessed by using the Global Initiative for Asthma (GINA) classification and the Asthma Control Questionnaire (ACQ). The number of cough sounds was manually counted and expressed as coughs per hour (c/h). Results Eighty-nine subjects with asthma (mean ± SD age, 57 ± 12 years; 57% female) were recruited. According to GINA criteria, 18 (20.2%) patients were classified as controlled, 39 (43.8%) partly controlled, and 32 (36%) uncontrolled; the median ACQ score was 1 (range, 0.0-4.4). The 6-item ACQ correlated with 24-h cough frequency (r = 0.40; P < .001), and patients with uncontrolled asthma (per GINA criteria) had higher median 24-h cough frequency (4.2 c/h; range, 0.3-27.6) compared with partially controlled asthma (1.8 c/h; range, 0.2-25.3; P = .01) and controlled asthma (1.7 c/h; range, 0.3-6.7; P = .002). Measures of airway inflammation were not significantly different between GINA categories and were not correlated with ACQ. In multivariate analyses, increasing cough frequency and worsening FEV1 independently predicted measures of asthma control. Conclusions Ambulatory cough frequency monitoring provides an objective assessment of asthma symptoms that correlates with standard measures of asthma control but not airflow obstruction or airway inflammation. Moreover, cough frequency and airflow obstruction represent independent dimensions of asthma control

The c-kit Ligand, Stem Cell Factor, Can Enhance Innate Immunity Through Effects on Mast Cells

Mast cells are thought to contribute significantly to the pathology and mortality associated with anaphylaxis and other allergic disorders. However, studies using genetically mast cell–deficient WBB6F1-KitW/KitW-v and congenic wild-type (WBB6F1-+/+) mice indicate that mast cells can also promote health, by participating in natural immune responses to bacterial infection. We previously reported that repetitive administration of the c-kit ligand, stem cell factor (SCF), can increase mast cell numbers in normal mice in vivo. In vitro studies have indicated that SCF can also modulate mast cell effector function. We now report that treatment with SCF can significantly improve the survival of normal C57BL/6 mice in a model of acute bacterial peritonitis, cecal ligation and puncture (CLP). Experiments in mast cell–reconstituted WBB6F1-KitW/KitW-v mice indicate that this effect of SCF treatment reflects, at least in part, the actions of SCF on mast cells. Repetitive administration of SCF also can enhance survival in mice that genetically lack tumor necrosis factor (TNF)-α, demonstrating that the ability of SCF treatment to improve survival after CLP does not solely reflect effects of SCF on mast cell– dependent (or –independent) production of TNF-α. These findings identify c-kit and mast cells as potential therapeutic targets for enhancing innate immune responses

Infectious disease and health systems modelling for local decision making to control neglected tropical diseases

Most neglected tropical diseases (NTDs) have complex life cycles and are challenging to control. The “2020 goals” of control and elimination as a public health programme for a number of NTDs are the subject of significant international efforts and investments. Beyond 2020 there will be a drive to maintain these gains and to push for true local elimination of transmission. However, these diseases are affected by variations in vectors, human demography, access to water and sanitation, access to interventions and local health systems. We therefore argue that there will be a need to develop local quantitative expertise to support elimination efforts. If available now, quantitative analyses would provide updated estimates of the burden of disease, assist in the design of locally appropriate control programmes, estimate the effectiveness of current interventions and support ‘real-time’ updates to local operations. Such quantitative tools are increasingly available at an international scale for NTDs, but are rarely tailored to local scenarios. Localised expertise not only provides an opportunity for more relevant analyses, but also has a greater chance of developing positive feedback between data collection and analysis by demonstrating the value of data. This is essential as rational program design relies on good quality data collection. It is also likely that if such infrastructure is provided for NTDs there will be an additional impact on the health system more broadly. Locally tailored quantitative analyses can help achieve sustainable and effective control of NTDs, but also underpin the development of local health care systems

Psychiatric gene discoveries shape evidence on ADHD\u27s biology

A strong motivation for undertaking psychiatric gene discovery studies is to provide novel insights into unknown biology. Although attention-deficit hyperactivity disorder (ADHD) is highly heritable, and large, rare copy number variants (CNVs) contribute to risk, little is known about its pathogenesis and it remains commonly misunderstood. We assembled and pooled five ADHD and control CNV data sets from the United Kingdom, Ireland, United States of America, Northern Europe and Canada. Our aim was to test for enrichment of neurodevelopmental gene sets, implicated by recent exome-sequencing studies of (a) schizophrenia and (b) autism as a means of testing the hypothesis that common pathogenic mechanisms underlie ADHD and these other neurodevelopmental disorders. We also undertook hypothesis-free testing of all biological pathways. We observed significant enrichment of individual genes previously found to harbour schizophrenia de novo non-synonymous single-nucleotide variants (SNVs; P=5.4 x 10-4) and targets of the Fragile X mental retardation protein (P=0.0018). No enrichment was observed for activity-regulated cytoskeleton-associated protein (P=0.23) or N-methyl-D-aspartate receptor (P=0.74) post-synaptic signalling gene sets previously implicated in schizophrenia. Enrichment of ADHD CNV hits for genes impacted by autism de novo SNVs (P=0.019 for non-synonymous SNV genes) did not survive Bonferroni correction. Hypothesis-free testing yielded several highly significantly enriched biological pathways, including ion channel pathways. Enrichment findings were robust to multiple testing corrections and to sensitivity analyses that excluded the most significant sample. The findings reveal that CNVs in ADHD converge on biologically meaningful gene clusters, including ones now established as conferring risk of other neurodevelopmental disorders

Aortic valve replacement in a young patient with essential thrombocytosis

Essential Thrombocythcythaemia (ET) is an uncommon type of myeloproliferative disorder, characterised by both thrombotic and haemorrhagic diathesis. No clear guidelines exist for the pre- and post-operative management of patients undergoing cardiac surgery in the haematological and surgical literature. This condition has profound implications in patients undergoing cardiac surgery with the use of cardiopulmonary bypass, where heparin is used for anti-coagulation. This dilemma is further compounded in the setting of a young patient undergoing aortic valve replacement (AVR), where insertion of a mechanical prosthesis would be the procedure of choice. This would require life-long anticoagulation with warfarin which can predispose these patients to catastrophic bleeding. Using a tissue valve will subject the patient to multiple redo operations in the patient's lifetime. We report a young patient with ET requiring AVR and discuss the dilemmas surrounding the choice of prosthesis in this patient

Worldwide Prevalence of Lentivirus Infection in Wild Feline Species: Epidemiologic and Phylogenetic Aspects

The natural occurrence of lentiviruses closely related to feline immunodeficiency virus (FIV) in nondomestic felid species is shown here to be worldwide. Cross-reactive antibodies to FIV were common in several free-ranging populations of large cats, including East African lions and cheetahs of the Serengeti ecosystem and in puma (also called cougar or mountain lion) populations throughout North America. Infectious puma lentivirus (PLV) was isolated from several Florida panthers, a severely endangered relict puma subspecies inhabiting the Big Cypress Swamp and Everglades ecosystems in southern Florida. Phylogenetic analysis of PLV genomic sequences from disparate geographic isolates revealed appreciable divergence from domestic cat FIV sequences as well as between PLV sequences found in different North American locales. The level of sequence divergence between PLV and FIV was greater than the level of divergence between human and certain simian immunodeficiency viruses, suggesting that the transmission of FIV between feline species is infrequent and parallels in time the emergence of HIV from simian ancestors