A Rapid, Handheld Device to Assess Respiratory Resistance: Clinical and Normative Evidence

Introduction: Following reports of respiratory symptoms among service members returning from deployment to South West Asia (SWA), an expert panel recommended pre-deployment spirometry be used to assess disease burden. Unfortunately, testing with spirometry is high cost and time-consuming. The airflow perturbation device (APD) is a handheld monitor that rapidly measures respiratory resistance (APD-Rr) and has promising but limited clinical data. Its speed and portability make it ideally suited for large volume pre-deployment screening. We conducted a pilot study to assess APD performance characteristics and develop normative values. Materials and Methods: We prospectively enrolled subjects and derived reference equations for the APD from those without respiratory symptoms, pulmonary disease, or tobacco exposure. APD testing was conducted by medical technicians who received a 10-min in-service on its use. A subset of subjects performed spirometry and impulse oscillometry (iOS), administered by trained respiratory therapists. APD measures were compared with spirometry and iOS. Results: The total study population included 199 subjects (55.8% males, body mass index 27.7 ± 6.0 kg/m2, age 49.9 ± 18.7 yr). Across the three APD trials, mean inspiratory (APD-Ri), expiratory (APD-Re), and average (APD-Ravg) resistances were 3.30 ± 1.0, 3.69 ± 1.2, and 3.50 ± 1.1 cm H2O/L/s. Reference equations were derived from 142 clinically normal volunteers. Height, weight, and body mass index were independently associated with APD-Ri, APD-Re, and APD-Ravg and were combined with age and gender in linear regression models. APD-Ri, APD-Re, and APD-Ravg were significantly inversely correlated with FEV1 (r = −0.39 to −0.42), FVC (r = −0.37 to −0.40), and FEF25–75 (r = −0.31 to −0.35) and positively correlated with R5 (r = 0.61–0.62), R20 (r = 0.50–0.52), X5 (r = −0.57 to −0.59), and FRES (r = 0.42–0.43). Bland–Altman plots showed that the APD-Rr closely approximates iOS when resistance is normal. Conclusion: Rapid testing was achieved with minimal training required, and reference equations were constructed. APD-Rr correlated moderately with iOS and weakly with spirometry. More testing is required to determine whether the APD has value for pre- and post-deployment respiratory assessment

Cortisol as an Acute Stress Biomarker in Young Hematopoietic Cell Transplant Patients/Caregivers: Active Music Engagement Protocol

Objective: Primary aims of the proposed protocol are to determine the feasibility/acceptability of the active music engagement intervention protocol during hematopoietic stem cell transplantation (HSCT) and clinical feasibility/acceptability of the biological sample collection schedule. Design: The authors propose a single-case, alternating treatment design to compare levels of child and caregiver cortisol in blood and saliva collected on alternating days, when the dyad receives and does not receive AME sessions. Included are the scientific rationale for this design and detailed intervention and sample collection schedules based on transplant type. Setting/Location: Pediatric inpatient HSCT unit. Subjects: Eligible participants are dyads of children 3-8 years old, hospitalized for HSCT, and their caregiver. Children with malignant and nonmalignant conditions will be eligible, regardless of transplant type. Intervention: AME intervention is delivered by a board-certified music therapist who tailors music-based play experiences to encourage active engagement in, and independent use of, music play to manage the inter-related emotional distress experienced by children and their caregivers during HSCT. Dyads will receive two 45-min AME sessions each week during hospitalization. Outcome Measures: Eight collections of blood (child) and saliva (child/caregiver) will be performed for cortisol measurement. The authors will also collect self-report and caregiver proxy measures for dyad emotional distress, quality of life, and family function. At study conclusion, qualitative caregiver interviews will be conducted. Results: Planned analyses will be descriptive and evaluate the feasibility of participant recruitment, cortisol collection, planned evaluations, and AME delivery. Analysis of qualitative interviews will be used to gain an understanding about the ease/burden of biological sample collection and any perceived benefit of AME. Conclusions: Behavioral intervention studies examining biological mechanisms of action in pediatric transplant populations are rare. Findings will provide important information about the feasibility/acceptability of collecting cortisol samples during a high-intensity treatment and advance understanding about the use of active music interventions to mitigate child/caregiver distress during the transplant period

Recent results in relativistic heavy ion collisions: from ``a new state of matter'' to "the perfect fluid"

Experimental Physics with Relativistic Heavy Ions dates from 1992 when a beam of 197Au of energy greater than 10A GeV/c first became available at the Alternating Gradient Synchrotron (AGS) at Brookhaven National Laboratory (BNL) soon followed in 1994 by a 208Pb beam of 158A GeV/c at the Super Proton Synchrotron (SPS) at CERN (European Center for Nuclear Research). Previous pioneering measurements at the Berkeley Bevalac in the late 1970's and early 1980's were at much lower bombarding energies (~ 1 A GeV/c) where nuclear breakup rather than particle production is the dominant inelastic process in A+A collisions. More recently, starting in 2000, the Relativistic Heavy Ion Collider (RHIC) at BNL has produced head-on collisions of two 100A GeV beams of fully stripped Au ions, corresponding to nucleon-nucleon center-of-mass energy, sqrt(sNN)=200 GeV, total c.m. energy 200A GeV. The objective of this research program is to produce nuclear matter with extreme density and temperature, possibly resulting in a state of matter where the quarks and gluons normally confined inside individual nucleons (r < 1 fm) are free to act over distances an order of magnitude larger. Progress from the period 1992 to the present will be reviewed, with reference to previous results from light ion and proton-proton collisions where appropriate. Emphasis will be placed on the measurements which formed the basis for the announcements by the two major laboratories: "A new state of matter", by CERN on Feb 10, 2000 and "The perfect fluid", by BNL on April 19, 2005.Comment: 62 pages, 39 figures. Review article published in Reports on Progress in Physics on June 23, 2006. In this published version, mistakes, typographical errors, and citations have been corrected and a subsection has been adde

Current challenges in software solutions for mass spectrometry-based quantitative proteomics

This work was in part supported by the PRIME-XS project, grant agreement number 262067, funded by the European Union seventh Framework Programme; The Netherlands Proteomics Centre, embedded in The Netherlands Genomics Initiative; The Netherlands Bioinformatics Centre; and the Centre for Biomedical Genetics (to S.C., B.B. and A.J.R.H); by NIH grants NCRR RR001614 and RR019934 (to the UCSF Mass Spectrometry Facility, director: A.L. Burlingame, P.B.); and by grants from the MRC, CR-UK, BBSRC and Barts and the London Charity (to P.C.

A Software Tool to Model Genetic Regulatory Networks. Applications to the Modeling of Threshold Phenomena and of Spatial Patterning in Drosophila

We present a general methodology in order to build mathematical models of genetic regulatory networks. This approach is based on the mass action law and on the Jacob and Monod operon model. The mathematical models are built symbolically by the Mathematica software package GeneticNetworks. This package accepts as input the interaction graphs of the transcriptional activators and repressors of a biological process and, as output, gives the mathematical model in the form of a system of ordinary differential equations. All the relevant biological parameters are chosen automatically by the software. Within this framework, we show that concentration dependent threshold effects in biology emerge from the catalytic properties of genes and its associated conservation laws. We apply this methodology to the segment patterning in Drosophila early development and we calibrate the genetic transcriptional network responsible for the patterning of the gap gene proteins Hunchback and Knirps, along the antero-posterior axis of the Drosophila embryo. In this approach, the zygotically produced proteins Hunchback and Knirps do not diffuse along the antero-posterior axis of the embryo of Drosophila, developing a spatial pattern due to concentration dependent thresholds. This shows that patterning at the gap genes stage can be explained by the concentration gradients along the embryo of the transcriptional regulators

Visual cortical plasticity and the risk for psychosis: An interim analysis of the North American Prodrome Longitudinal Study

Background: Adolescence/early adulthood coincides with accelerated pruning of cortical synapses and the onset of schizophrenia. Cortical gray matter reduction and dysconnectivity in schizophrenia are hypothesized to result from impaired synaptic plasticity mechanisms, including long-term potentiation (LTP), since deficient LTP may result in too many weak synapses that are then subject to over-pruning. Deficient plasticity has already been observed in schizophrenia. Here, we assessed whether such deficits are present in the psychosis risk syndrome (PRS), particularly those who subsequently convert to full psychosis. Methods: An interim analysis was performed on a sub-sample from the NAPLS-3 study, including 46 healthy controls (HC) and 246 PRS participants. All participants performed an LTP-like visual cortical plasticity paradigm involving assessment of visual evoked potentials (VEPs) elicited by vertical and horizontal line gratings before and after high frequency (“tetanizing”) visual stimulation with one of the gratings to induce “input-specific” neuroplasticity (i.e., VEP changes specific to the tetanized stimulus). Non-parametric, cluster-based permutation testing was used to identify electrodes and timepoints that demonstrated input-specific plasticity effects. Results: Input-specific pre-post VEP changes (i.e., increased negative voltage) were found in a single spatio-temporal cluster covering multiple occipital electrodes in a 126–223 ms time window. This plasticity effect was deficient in PRS individuals who subsequently converted to psychosis, relative to PRS non-converters and HC. Conclusions: Input-specific LTP-like visual plasticity can be measured from VEPs in adolescents and young adults. Interim analyses suggest that deficient visual cortical plasticity is evident in those PRS individuals at greatest risk for transition to psychosis

GABAA receptors as molecular targets of general anesthetics: identification of binding sites provides clues to allosteric modulation

PurposeThe purpose of this review is to summarize current knowledge of detailed biochemical evidence for the role of γ-aminobutyric acid type A receptors (GABA(A)-Rs) in the mechanisms of general anesthesia.Principal findingsWith the knowledge that all general anesthetics positively modulate GABA(A)-R-mediated inhibitory transmission, site-directed mutagenesis comparing sequences of GABA(A)-R subunits of varying sensitivity led to identification of amino acid residues in the transmembrane domain that are critical for the drug actions in vitro. Using a photo incorporable analogue of the general anesthetic, R(+)etomidate, we identified two transmembrane amino acids that were affinity labelled in purified bovine brain GABA(A)-R. Homology protein structural modelling positions these two residues, αM1-11' and βM3-4', close to each other in a single type of intersubunit etomidate binding pocket at the β/α interface. This position would be appropriate for modulation of agonist channel gating. Overall, available information suggests that these two etomidate binding residues are allosterically coupled to sites of action of steroids, barbiturates, volatile agents, and propofol, but not alcohols. Residue α/βM2-15' is probably not a binding site but allosterically coupled to action of volatile agents, alcohols, and intravenous agents, and α/βM1-(-2') is coupled to action of intravenous agents.ConclusionsEstablishment of a coherent and consistent structural model of the GABA(A)-R lends support to the conclusion that general anesthetics can modulate function by binding to appropriate domains on the protein. Genetic engineering of mice with mutation in some of these GABA(A)-R residues are insensitive to general anesthetics in vivo, suggesting that further analysis of these domains could lead to development of more potent and specific drugs

Quantitative Epistasis Analysis and Pathway Inference from Genetic Interaction Data

Inferring regulatory and metabolic network models from quantitative genetic interaction data remains a major challenge in systems biology. Here, we present a novel quantitative model for interpreting epistasis within pathways responding to an external signal. The model provides the basis of an experimental method to determine the architecture of such pathways, and establishes a new set of rules to infer the order of genes within them. The method also allows the extraction of quantitative parameters enabling a new level of information to be added to genetic network models. It is applicable to any system where the impact of combinatorial loss-of-function mutations can be quantified with sufficient accuracy. We test the method by conducting a systematic analysis of a thoroughly characterized eukaryotic gene network, the galactose utilization pathway in Saccharomyces cerevisiae. For this purpose, we quantify the effects of single and double gene deletions on two phenotypic traits, fitness and reporter gene expression. We show that applying our method to fitness traits reveals the order of metabolic enzymes and the effects of accumulating metabolic intermediates. Conversely, the analysis of expression traits reveals the order of transcriptional regulatory genes, secondary regulatory signals and their relative strength. Strikingly, when the analyses of the two traits are combined, the method correctly infers ∼80% of the known relationships without any false positives

A TRPV Channel Modulates C. elegans Neurosecretion, Larval Starvation Survival, and Adult Lifespan

For most organisms, food is only intermittently available; therefore, molecular mechanisms that couple sensation of nutrient availability to growth and development are critical for survival. These mechanisms, however, remain poorly defined. In the absence of nutrients, newly hatched first larval (L1) stage Caenorhabditis elegans halt development and survive in this state for several weeks. We isolated mutations in unc-31, encoding a calcium-activated regulator of neural dense-core vesicle release, which conferred enhanced starvation survival. This extended survival was reminiscent of that seen in daf-2 insulin-signaling deficient mutants and was ultimately dependent on daf-16, which encodes a FOXO transcription factor whose activity is inhibited by insulin signaling. While insulin signaling modulates metabolism, adult lifespan, and dauer formation, insulin-independent mechanisms that also regulate these processes did not promote starvation survival, indicating that regulation of starvation survival is a distinct program. Cell-specific rescue experiments identified a small subset of primary sensory neurons where unc-31 reconstitution modulated starvation survival, suggesting that these neurons mediate perception of food availability. We found that OCR-2, a transient receptor potential vanilloid (TRPV) channel that localizes to the cilia of this subset of neurons, regulates peptide-hormone secretion and L1 starvation survival. Moreover, inactivation of ocr-2 caused a significant extension in adult lifespan. These findings indicate that TRPV channels, which mediate sensation of diverse noxious, thermal, osmotic, and mechanical stimuli, couple nutrient availability to larval starvation survival and adult lifespan through modulation of neural dense-core vesicle secretion