Biomedical subjects

J Vaughan

Publications and source records attributed to J Vaughan.

At least 19 recordsLinked to original sources

PubMed2005

Exhaled breath condensate pH assays are not influenced by oral ammonia.

BACKGROUND: Measurement of pH in exhaled breath condensate (EBC) is robust and simple. Acidic source fluid (airway lining fluid) traps bases while volatilising acids, leading to EBC acidification in many lung diseases. Lower airway ammonia is one determinant of airway lining fluid pH, raising the concern that addition of the base ammonia by contamination from the mouth might confound EBC pH assays. METHODS: Three discrete methods were used to limit oral ammonia contamination of EBC collections: endotracheal intubation, oral rinsing, and -40 degrees C condenser temperatures. Separately, ammonia was removed from collected EBC samples by lyophilisation and resuspension. Intraweek and intraday variability of ammonia concentration was determined in 76 subjects, and ammonia and pH from a further 235 samples were graphically compared. Ammonia was assayed spectrophotometrically and pH was assessed after deaeration. RESULTS: Data from 1091 samples are presented. Ammonia was reduced in EBC by all methods. Endotracheal intubation decreased EBC ammonia from a mean (SD) of 619 (124) microM to 80 (24) microM (p<0.001, n=32). Oral rinsing before collection also led to a decline in EBC ammonia from 573 (307) microM to 224 (80) microM (p=0.016, n=7). The colder the condensation temperature used, the less ammonia was trapped in the EBC. Lyophilisation removed 99.4 (1.9)% of ammonia. Most importantly, the pH of EBC never decreased after removal of ammonia by any of these methods. Intraweek and intraday coefficients of variation for ammonia were 64 (27)% and 60 (32)%, which is substantially more variable than EBC pH assays. CONCLUSIONS: Although ammonia and pH appear to correlate in EBC, the oral ammonia concentration is not an important determinant of EBC pH. No precautions need to be taken to exclude oral ammonia when EBC pH is of interest. The low pH and low ammonia found in EBC from patients with lung diseases appear to be independent effects of volatile compounds arising from the airway.

Adult↗

PubMed2004

A staff perspective of early warning signs intervention for individuals with psychosis: clinical and service implications.

Research has established the benefits of early warnings signs monitoring in the prevention of relapse for individuals with psychosis. This study explored staff views (n = 8) of the implementation of an early warning signs clinic within a day hospital of an adult mental health service. A qualitative methodology using focus groups was adopted and content analysis was used to discover themes arising from the data. Overall, the data indicated a positive view of the early warning signs clinic, with benefits for clients, staff and their relationship; and for service delivery and resources. The clinical and service implications are discussed.

Adult↗

PubMed2003

Exhaled breath condensate pH is a robust and reproducible assay of airway acidity.

Exhaled breath condensate (EBC) pH is low in several lung diseases and it normalises with therapy. The current study examined factors relevant to EBC pH monitoring. Intraday and intraweek variability were studied in 76 subjects. The pH of EBC collected orally and from isolated lower airways was compared in an additional 32 subjects. Effects of ventilatory pattern (hyperventilation/hypoventilation), airway obstruction after methacholine, temperature (-44 to +13 degrees C) and duration of collection (2-7 min), and duration of sample storage (up to 2 yrs) were examined. All samples were collected with a disposable condensing device, and de-aerated with argon until pH measurement stabilised. Mean EBC pH (n=76 subjects, total samples=741) was 7.7+/-0.49 (mean+/-SD). Mean intraweek and intraday coefficients of variation were 4.5% and 3.5%. Control of EBC pH appears to be at the level of the lower airway. Temperature of collection, duration of collection and storage, acute airway obstruction, subject age, saliva pH, and profound hyperventilation and hypoventilation had no effect on EBC pH. The current authors conclude that in health, exhaled breath condensate pH is slightly alkaline, held in a narrow range, and is controlled by lower airway source fluid. Measurement of exhaled breath condensate pH is a simple, robust, reproducible and relevant marker of disease.

Acid-Base Equilibrium↗

PubMed2003

Residues in the C-terminal region of activin A determine specificity for follistatin and type II receptor binding.

Activin is a secreted growth factor that signals by binding two related classes of single transmembrane receptors at the cell surface. The interaction of activin with its receptors is highly regulated by other cell surface receptors, antagonistic ligands, and high affinity extracellular binding proteins such as follistatin. Two activin A mutants, the deletion mutant des[85-109]-activin A and the point mutant K102E-activin A (K102E), were investigated with respect to their ability to bind cell surface receptors and the binding protein follistatin. The deletion mutant exhibits low affinity for both receptors and follistatin whereas the point mutant fails to bind cell surface receptors but binds follistatin-288 with high affinity. K102E is able to compete with wild type activin to bind to follistatin and can thus increase the concentration of activin available for receptor binding and signaling. These findings underline the importance of the C-terminal region of activin for binding interactions and show that different residues in this region are involved in cell surface receptor and follistatin interactions.

Activins↗

PubMed2002

Potent and long-acting corticotropin releasing factor (CRF) receptor 2 selective peptide competitive antagonists.

We present evidence that members of the corticotropin releasing factor (CRF) family assume distinct structures when interacting with the CRF(1) and CRF(2) receptors. Predictive methods, physicochemical measurements, and structure-activity relationship studies have suggested that CRF, its family members, and competitive antagonists such as astressin [cyclo(30-33)[DPhe(12),Nle(21),Glu(30),Lys(33),Nle(38)]hCRF((12-41))] assume an alpha-helical conformation when interacting with their receptors. We had shown that alpha-helical CRF((9-41)) and sauvagine showed some selectivity for CRF receptors other than that responsible for ACTH secretion(1) and later for CRF2.(2) More recently, we suggested the possibility of a helix-turn-helix motif around a turn encompassing residues 30-33(3) that would confer high affinity for both CRF(1) and CRF(2)(2,4) in agonists and antagonists of all members of the CRF family.(3) On the other hand, the substitutions that conferred ca. 100-fold CRF(2) selectivity to the antagonist antisauvagine-30 [[DPhe(11),His(12)]sauvagine((11-40))] did not confer such property to the corresponding N-terminally extended agonists. We find here that a Glu(32)-Lys(35) side chain to side chain covalent lactam constraint in hCRF and the corresponding Glu(31)-Lys(34) side chain to side chain covalent lactam constraint in sauvagine yield potent ligands that are selective for CRF(2). Additionally, we introduced deletions and substitutions known to increase duration of action to yield antagonists such as cyclo(31-34)[DPhe(11),His(12),C(alpha)MeLeu(13,39),Nle(17),Glu(31),Lys(34)]Ac-sauvagine((8-40)) (astressin(2)-B) with CRF(2) selectivities greater than 100-fold. CRF receptor autoradiography was performed in rat tissue known to express CRF(2) and CRF(1) in order to confirm that astressin(2)-B could indeed bind to established CRF(2) but not CRF(1) receptor-expressing tissues. Extended duration of action of astressin(2)-B vs that of antisauvagine-30 is demonstrated in the CRF(2)-mediated animal model whereby the inhibition of gastric emptying of a solid meal in mice by urocortin administered intraperitoneally at time zero is antagonized by the administration of astressin(2)-B but not by antisauvagine-30 at times -3 and -6 h while both peptides are effective when given 10 min before urocortin.

Animals↗

PubMed2001

No pathogenic mutations in the synphilin-1 gene in Parkinson's disease.

alpha-Synuclein is mutated in rare autosomal dominant forms of Parkinson's disease and is a major component of Lewy bodies and neurites. Synphilin-1, a novel protein interacts in vivo and co-localises with alpha-synuclein in Lewy bodies. We analysed the synphilin-1 gene in familial Parkinson's disease by single-strand conformation polymorphism (SSCP) and automated sequencing but found no coding mutations. However, we identified two novel intronic polymorphisms; an A/T polymorphism in intron 2, resulting in the introduction of an Alu1 site and a second G/T polymorphism in intron 4. We analysed the intron 2 polymorphism for allelic association as it was conducive to rapid screening but observed no changes in frequency between Parkinson's disease cases and controls.

Aged↗

PubMed2001

Identification of urocortin III, an additional member of the corticotropin-releasing factor (CRF) family with high affinity for the CRF2 receptor.

The corticotropin-releasing factor (CRF) family of neuropeptides includes the mammalian peptides CRF, urocortin, and urocortin II, as well as piscine urotensin I and frog sauvagine. The mammalian peptides signal through two G protein-coupled receptor types to modulate endocrine, autonomic, and behavioral responses to stress, as well as a range of peripheral (cardiovascular, gastrointestinal, and immune) activities. The three previously known ligands are differentially distributed anatomically and have distinct specificities for the two major receptor types. Here we describe the characterization of an additional CRF-related peptide, urocortin III, in the human and mouse. In searching the public human genome databases we found a partial expressed sequence tagged (EST) clone with significant sequence identity to mammalian and fish urocortin-related peptides. By using primers based on the human EST sequence, a full-length human clone was isolated from genomic DNA that encodes a protein that includes a predicted putative 38-aa peptide structurally related to other known family members. With a human probe, we then cloned the mouse ortholog from a genomic library. Human and mouse urocortin III share 90% identity in the 38-aa putative mature peptide. In the peptide coding region, both human and mouse urocortin III are 76% identical to pufferfish urocortin-related peptide and more distantly related to urocortin II, CRF, and urocortin from other mammalian species. Mouse urocortin III mRNA expression is found in areas of the brain including the hypothalamus, amygdala, and brainstem, but is not evident in the cerebellum, pituitary, or cerebral cortex; it is also expressed peripherally in small intestine and skin. Urocortin III is selective for type 2 CRF receptors and thus represents another potential endogenous ligand for these receptors.

Amino Acid Sequence↗

PubMed2001

S-nitrosoglutathione increases cystic fibrosis transmembrane regulator maturation.

Endogenous S-nitrosoglutathione (GSNO) is known to increase the expression of certain proteins at concentrations present in the normal human airway. We hypothesized that GSNO would increase expression and maturation of the cystic fibrosis transmembrane conductance regulator (CFTR). Cells expressing DeltaF508 and wild type CFTR were exposed to GSNO and analyzed for expression and maturation by Western blot analysis. Physiologically relevant concentrations of GSNO resulted in dose- and time-dependent increases in expression. The GSNO-induced increases were eliminated by cycloheximide, suggesting a posttranscriptional effect. Unlike proteasome inhibitors, GSNO resulted in an increase CFTR maturation. The GSNO effect could be reversed by dithiothreitol and inhibited by acivicin, a gamma glutamyl transpeptidase inhibitor. These observations suggest that GSNO leads to maturation of mutated DeltaF508 CFTR, a process associated with restoration of CFTR function. Because endogenous levels of GSNO are low in the cystic fibrosis (CF) airway, these results raise the possibility that GSNO replacement therapy could be an effective treatment for CF.

Animals↗

PubMed2001

Sensitisation, asthma, and a modified Th2 response in children exposed to cat allergen: a population-based cross-sectional study.

BACKGROUND: Although asthma is strongly associated with immediate hypersensitivity to indoor allergens, several studies have suggested that a cat in the house can decrease the risk of asthma. We investigated the immune response to cat and mite allergens, and asthma among children with a wide range of allergen exposure. METHODS: We did a population-based cross-sectional study of children (aged 12-14 years), some of whom had symptoms of asthma and bronchial hyper-reactivity. Antibodies to mite (Der f 1) and cat (Fel d 1) allergens measured by isotype (IgG and IgG4) specific radioimmunoprecipitation assays were compared with sensitisation and allergen concentrations in house dust. FINDINGS: 226 children were recruited, 47 of whom had symptoms of asthma and bronchial hyper-reactivity. Increasing exposure to mite was associated with increased prevalence of sensitisation and IgG antibody to Der f 1. By contrast, the highest exposure to cat was associated with decreased sensitisation, but a higher prevalence of IgG antibody to Fel d 1. Thus, among children with high exposure, the odds of sensitisation to mite rather than cat was 4.0 (99% CI 1.49-10.00). Furthermore, 31 of 76 children with 23 microg Fel d 1 at home, who were not sensitised to cat allergen had >125 units of IgG antibody to Fel d 1. Antibodies to Fel d 1 of the IgG4 isotype were strongly correlated with IgG antibody in both allergic and non-allergic children (r=0.84 and r=0.66, respectively). Sensitisation to mite or cat allergens was the strongest independent risk factor for asthma (p<0.001). INTERPRETATION: Exposure to cat allergen can produce an IgG and IgG4 antibody response without sensitisation or risk of asthma. This modified T-helper-2 cell response should be regarded as a form of tolerance and may be the correct objective of immunotherapy. The results may also explain the observation that animals in the house can decrease the risk of asthma.

Adolescent↗

PubMed2001

Urocortin II: a member of the corticotropin-releasing factor (CRF) neuropeptide family that is selectively bound by type 2 CRF receptors.

Here we describe the cloning and initial characterization of a previously unidentified CRF-related neuropeptide, urocortin II (Ucn II). Searches of the public human genome database identified a region with significant sequence homology to the CRF neuropeptide family. By using homologous primers deduced from the human sequence, a mouse cDNA was isolated from whole brain poly(A)(+) RNA that encodes a predicted 38-aa peptide, structurally related to the other known mammalian family members, CRF and Ucn. Ucn II binds selectively to the type 2 CRF receptor (CRF-R2), with no appreciable activity on CRF-R1. Transcripts encoding Ucn II are expressed in discrete regions of the rodent central nervous system, including stress-related cell groups in the hypothalamus (paraventricular and arcuate nuclei) and brainstem (locus coeruleus). Central administration of 1-10 microg of peptide elicits activational responses (Fos induction) preferentially within a core circuitry subserving autonomic and neuroendocrine regulation, but whose overall pattern does not broadly mimic the CRF-R2 distribution. Behaviorally, central Ucn II attenuates nighttime feeding, with a time course distinct from that seen in response to CRF. In contrast to CRF, however, central Ucn II failed to increase gross motor activity. These findings identify Ucn II as a new member of the CRF family of neuropeptides, which is expressed centrally and binds selectively to CRF-R2. Initial functional studies are consistent with Ucn II involvement in central autonomic and appetitive control, but not in generalized behavioral activation.

Amino Acid Sequence↗

PubMed2001

Origin of the mutations in the parkin gene in Europe: exon rearrangements are independent recurrent events, whereas point mutations may result from Founder effects.

A wide variety of mutations in the parkin gene, including exon deletions and duplications, as well as point mutations, result in autosomal recessive early-onset parkinsonism. Interestingly, several of these anomalies were found repeatedly in unrelated patients and may therefore result from recurrent, de novo mutational events or from founder effects. In the present study, haplotype analysis, using 10 microsatellite markers covering a 4.7-cM region known to contain the parkin gene, was performed in 48 families, mostly from European countries, with early-onset autosomal recessive parkinsonism. The patients carried 14 distinct mutations in the parkin gene, and each mutation was detected in more than one family. Our results support the hypothesis that exon rearrangements occurred independently, whereas some point mutations, found in families from different geographic origins, may have been transmitted by a common founder.

Age of Onset↗

PubMed2001

Multijoint grasping movements. Simulated and observed effects of object location, object size, and initial aperture.

Studies of human prehension have revealed characteristic patterns of grasping kinematics. We sought to gain insight into the determinants of those patterns by means of a computer simulation and accompanying behavioral experiment concerning multijoint, planar grasping behavior. The simulation was based on a recent theory of posture-based motion planning which hypothesizes that movement preparation entails time-limited, multiple task-constraint satisfaction. Prehension was modeled with a stick-figure animation involving 12 series of 81 grasping movements. Circular objects to be grasped were located at three angles (45 degrees, 90 degrees, and 135 degrees) and at three distances (20 cm, 30 cm, and 40 cm) relative to the initial location of the hand in the workplane. Additionally, three object sizes (2 cm, 4 cm, and 6 cm in diameter) and three initial aperture sizes (0.3 cm, 3.3 cm, and 7.0 cm) were used. Analyses of the simulated grasping movements focused on the time course of the hand opening, the tangential velocity of the wrist, and the rotations of the joints in the arm, hand, and fingers. The results showed that the model accurately mimicked detailed kinematics of prehension observed in earlier studies. With respect to the frequently reported relationship between object size and hand opening, the simulations further revealed an effect of initial aperture. This predicted effect was confirmed in an experiment in which four participants performed analogous planar grasping tasks. An analysis of the time course of the opening of the hand showed that maximum aperture covaried with initial aperture. A conclusion of this work is that a major determinant of grasping kinematics is avoidance of collisions with objects that are to be grasped.

Adult↗

PubMed2001

Posture-based motion planning: applications to grasping.

This article describes a model of motion planning instantiated for grasping. According to the model, one of the most important aspects of motion planning is establishing a constraint hierarchy--a set of prioritized requirements defining the task to be performed. For grasping, constraints include avoiding collisions with to-be-grasped objects and minimizing movement-related effort. These and other constraints are combined with instance retrieval (recall of stored postures) and instance generation (generation of new postures and movements to them) to simulate flexible prehension. Dynamic deadline setting is used to regulate termination of instance generation, and performance of more than one movement at a time with a single effector is used to permit obstacle avoidance. Old and new data are accounted for with the model.

Attention↗

PubMed2001

Three-dimensional (3D) echocardiographic analysis of congenital heart disease in the fetus: comparison with cross-sectional (2D) fetal echocardiography.

OBJECTIVE: We attempted to assess the ability of Doppler-gated three-dimensional (3D) fetal echocardiography to reconstruct and display specific cardiac structures in fetuses with cardiac anomalies and to determine whether any advantage is offered by 3D sonographic cardiac examination over conventional fetal echocardiography. DESIGN: After 2D fetal echocardiographic examination, 3D cardiac data were collected prospectively in 22 fetuses with various congenital heart defects. Their ages ranged from 19 to 35 weeks' gestation. Basic echocardiographic key views of the venoatrial, atrioventricular and ventriculoarterial connections were derived from volume data sets and selected for 3D reconstruction and analysis. Comparisons were made with 2D echocardiographic imaging of the fetal hearts and the diagnostic image quality of visualized structural details was evaluated. RESULTS: The underlying cardiac malformation was well or satisfactorily visualized in 20 fetuses using 2D imaging. Gated 3D volume data sets enabled diagnostically acceptable visualization of all affected cardiac structures in 7 of 22 fetuses. High-quality 3D reconstruction of the site and spatial orientation of ventricular septal defects was obtained in 9 of 13 patients. Two-dimensional imaging remained the principal diagnostic modality in all cases with additional structural detail being obtained by 3D imaging in only two fetuses. CONCLUSIONS: Three-dimensional imaging of fetal heart disease is feasible for a wide range of lesions, and may provide additional information of clinical value in a small number of cases when compared with 2D imaging.

Australia↗

PubMed2001

Planning reaching and grasping movements: the problem of obstacle avoidance.

In this article, we review a model of the movement-planning processes that people use for direct reaching, reaching around obstacles, and grasping, and we present observations of subjects' repeated movements of the hand to touch 2 target locations, circumventing an intervening obstacle. The model defines an obstacle as a posture that, if adopted, would intersect with any part of the environment (including the actor himself or herself). The model finds a trajectory that is likely to bring the end-effector to the target by means of a one-or two- stage planning process. Each stage exploits the principles of instance retrieval and instance generation. In the first stage, a goal posture is identified, and the trajectory of a direct transition to that posture is tested for collision. If the direct movement has no collision, the movement to the target is immediately executed in joint space. If, however, the direct movement is foreseen to result in a collision, a second planning stage is invoked. The second planing stage identifies a via posture, movement through which will probably avoid the collision. Movement to and from the via posture is then superimposed on the main movement to the target so that the combined movement reaches the target without colliding with intervening obstacles. We describe the details of instance retrieval and instance generation for each of these planning stages and compare the model's performance with the observed kinematics of direct movements as well as movements around an obstacle. Then we suggest how the model might contribute to the study of movements in people with motor disorders such as spastic hemiparesis.

Adult↗

PubMed2001

Planning reaching and grasping movements: simulating reduced movement capabilities in spastic hemiparesis.

In this paper we describe how a theory of posture-based motion planning recently applied to human grasping may contribute to the understanding of grasping pathology. The theory is implemented as a computer model rendered as a stick-figure animation capable of generating realistic multi-joint grasping movements. As shown here, the model can also be used to simulate grasping movements whose kinematics resemble those of grasps performed by people with spastic hemiparesis. The simulations demonstrate effects of: (a) reduced ranges of motion of arm joints on the size of the reachable workspace, (b) awkward starting postures on the time course of the hand closing around an object, (c) increased costs of joint rotations on movement time, and (d) addition of noise to biphasic joint rotations on the low-velocity phase of wrist transport.

Arm↗

PubMed2001

Planning reaching and grasping movements: theoretical premises and practical implications.

This paper presents the background, premises, and results of a model of movement planning. The model's central claims are fourfold: (a) A task is defined by a set of prioritized requirements, or what we call a constraint hierarchy; (b) movement planning works first by specifying a goal posture and then by specifying a movement to that goal posture; (c) movements have characteristic forms; and (d) movements can be shaped through simultaneous performance of different movements, even by the same effector. We review the model and then speculate on its implications for clinical concerns, especially spasticity

Arm↗

PubMed2001

Age and alarm symptoms do not predict endoscopic findings among patients with dyspepsia: a multicentre database study.

INTRODUCTION: Symptoms of dyspepsia are common but most patients do not have major upper gastrointestinal pathology. Endoscopy is recommended for dyspeptic patients over the age of 45, or those with certain "alarm" symptoms. We have evaluated the effectiveness of age and "alarm" symptoms for predicting major endoscopic findings in six practising endoscopy centres. METHODS: Clinical variables of consecutive patients with dyspepsia symptoms undergoing upper endoscopy examinations were recorded using a common endoscopy database. Patients who had no previous upper endoscopy or barium radiography were included. Stepwise multivariate logistic regression was used to identify predictors of endoscopic findings. The accuracy of these for predicting endoscopic findings was evaluated with receiver operating characteristic analysis. The sensitivity and specificity of age thresholds from 30 to 70 years were evaluated. RESULTS: Major pathology (tumour, ulcer, or stricture) was found at endoscopy in 787/3815 (21%) patients with dyspepsia. Age, male sex, bleeding, and anaemia were found to be significant but weak independent predictors of endoscopic findings. A multivariate prediction rule based on these factors had poor predictive accuracy (c statistic=0.62). Using a simplified prediction rule of age > or =45 years or the presence of any "alarm" symptom, sensitivity was 87% and specificity was 26%. Increasing or decreasing the age cut off did not significantly improve the predictive accuracy. CONCLUSIONS: Age and the presence of "alarm" symptoms are not effective predictors of endoscopic findings among patients with dyspepsia. Better clinical prediction strategies are needed to identify patients with significant upper gastrointestinal pathology.

Adult↗