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Peter D Sly

Publications and source records attributed to Peter D Sly.

At least 55 records · Page 3Linked to original sources

Sensitivity analysis of respiratory parameter estimates in the constant-phase model.

The constant-phase model is increasingly used to fit low-frequency respiratory input impedance (Zrs), highlighting the need for a better understanding of the use of the model. Of particular interest is the extent to which Zrs would be affected by changes in parameters of the model, and conversely, how reliable are parameters estimated from model fits to the measured Zrs. We performed sensitivity analysis on respiratory data from 6 adult mice, at functional residual capacity (FRC), total lung capacity (TLC), and during bronchoconstriction, obtained using a 1-25 Hz oscillatory signal. The partial derivatives of Zrs with respect to each parameter were first examined. The limits of the 95% confidence intervals, 2-dimensional pairwise and p-dimensional joint confidence regions were then calculated. It was found that airway resistance was better estimated at FRC, as determined by the confidence region limits, whereas tissue damping and elastance were better estimated at TLC. Airway inertance was poorly estimated at this frequency range, as expected. During methacholine-evoked pulmonary constriction, there was an increase in the uncertainty of airway resistance and tissue damping, but this can be compensated for by using the relative (weighted residuals) in preference over the absolute (unweighted residuals) fitting criterion. These results are consistent with experimental observation and physiological understanding.

Airway Resistance↗

Drug development strategies for asthma: in search of a new paradigm.

The spiraling costs of asthma treatment seem set to continue rising, given the equivocal performance of the latest generation of specific anti-inflammatory drugs in trials in adult asthmatics. We argue that the continuation of this trend is inevitable unless there is a substantial realignment of entrenched drug development policy in the pharmaceutical industry and a parallel shift in licensing policy by regulatory authorities to encourage the development of drugs capable of halting the progression from acute to chronic asthma when the disease first manifests in childhood. The theoretical framework for such an approach, including proof-of-principle data from studies in children with early-stage disease and a range of candidate drugs, already exists. What is needed is informed debate on the risks versus potential benefits of this approach.

Animals↗

Monitoring of lung volume recruitment and derecruitment using oscillatory mechanics during high-frequency oscillatory ventilation in the preterm lamb.

OBJECTIVES: To determine whether the low-frequency forced oscillation technique (LFOT) can track changes in lung mechanics resulting from prophylactic intratracheal surfactant and a volume recruitment-derecruitment maneuver during high-frequency oscillatory ventilation (HFOV) and how this relates to the damping of the tracheal pressure waveform (P(tr)). DESIGN: Interventional laboratory study. SETTING: Rural animal research facility in Western Australia. SUBJECTS: Sedated newborn preterm lambs. INTERVENTIONS: Two separate studies were performed. Study 1 involved a volume recruitment-derecruitment maneuver during HFOV using stepwise changes (4 cm H(2)O) in mean airway opening pressure (P(ao), n = 5). Study 2 involved instillation of 4 mL/kg fetal lung fluid (n = 5) or exogenous surfactant (n = 8) at birth and subsequent intermittent mandatory ventilation for 40 mins. MEASUREMENTS AND MAIN RESULTS: Arterial blood gases were recorded every 10 mins and ventilation was appropriately adjusted to achieve moderate hypercarbia (Paco(2), 50-60 mm Hg). Lung mechanics were measured using LFOT 10 mins following each adjustment in P(ao) in parallel with measurements of P(tr) and tidal volume (study 1) or after 40 mins (study 2). Both the recruitment-derecruitment maneuver and prophylactic surfactant administration achieved similar improvements (decrease) in tissue impedance (Z(ti)). The coefficient of tissue resistance (G) decreased more than the coefficient of tissue elastance (H), consistent with improved homogeneity of the lung tissue compartment as lung volume was recruited. Minimum Z(ti) coincided with minimum tracheal pressure amplitude (DeltaP(tr)) on the deflation limb of the volume recruitment-derecruitment maneuver during HFOV. There was a linear relationship between DeltaP(tr) and H. CONCLUSIONS: In the preterm lamb, the LFOT can successfully detect changes in lung mechanics resulting from volume recruitment maneuvers during both HFOV and ventilation at conventional rates and may provide information on ventilation inhomogeneity. Minimization of Z(ti) is crucial to damping of P(tr) and may limit potential barotrauma to proximal alveolar units during establishment of HFOV.

Animals↗

The relation of breastfeeding and body mass index to asthma and atopy in children: a prospective cohort study to age 6 years.

OBJECTIVES: We investigated the relationship between breastfeeding, asthma and atopy, and child body mass index (BMI). METHODS: From a prospective birth cohort (n = 2860) in Perth, Western Australia, 2195 children were followed up to age 6 years. Asthma was defined as doctor-diagnosed asthma and wheeze in the last year, and atopy was determined by skin prick test of 1596 children. Breastfeeding, BMI, asthma, and atopy were regressed allowing for confounders and the propensity score for overweight. RESULTS: Using fractional polynomials, we found no association between breastfeeding and overweight. Less exclusive breastfeeding was associated with increased asthma and atopy, and BMI increased with asthma. CONCLUSIONS: Less exclusive breastfeeding leads to increases in child asthma and atopy and a higher BMI is a risk factor for asthma.

Asthma↗

Site of inflammation influences site of hyperresponsiveness in experimental asthma.

BACKGROUND: Our recently developed murine asthma model is capable of inducing airway-specific chronic inflammatory changes and remodeling, features of human asthma commonly missing in conventional animal models. OBJECTIVES: To validate this model by site-specific physiological evaluation of hyperresponsiveness. METHODS: Non-sensitized and sensitized mice received either short-term uncontrolled or long-term controlled low-level exposures to aerosolized ovalbumin (OVA). Respiratory impedance (Zrs) was measured in response to increasing doses of methacholine (Mch). The constant-phase model was fitted to Zrs spectra to determine the specific site of hyperresponsiveness. RESULTS: Sensitized acutely exposed mice had significantly increased tissue damping (G), tissue elastance (H) and hysteresivity (eta) in response to Mch, but no significant increase in airway resistance (Raw), indicating tissue-specific hyperresponsiveness. In contrast, sensitized chronically exposed mice had significantly elevated Raw at all concentrations of Mch but no increases in G, H or eta indicating airway-specific hyperresponsiveness. CONCLUSIONS: Chronic inhalational exposure of sensitized mice to low-mass concentrations of OVA induces airway-specific hyperresponsiveness.

Aerosols↗

Bidirectional interactions between antigen-bearing respiratory tract dendritic cells (DCs) and T cells precede the late phase reaction in experimental asthma: DC activation occurs in the airway mucosa but not in the lung parenchyma.

The airway mucosal response to allergen in asthma involves influx of activated T helper type 2 cells and eosinophils, transient airflow obstruction, and airways hyperresponsiveness (AHR). The mechanism(s) underlying transient T cell activation during this inflammatory response is unclear. We present evidence that this response is regulated via bidirectional interactions between airway mucosal dendritic cells (AMDC) and T memory cells. After aerosol challenge, resident AMDC acquire antigen and rapidly mature into potent antigen-presenting cells (APCs) after cognate interactions with T memory cells. This process is restricted to dendritic cells (DCs) in the mucosae of the conducting airways, and is not seen in peripheral lung. Within 24 h, antigen-bearing mature DCs disappear from the airway wall, leaving in their wake activated interleukin 2R+ T cells and AHR. Antigen-bearing activated DCs appear in regional lymph nodes at 24 h, suggesting onward migration from the airway. Transient up-regulation of CD86 on AMDC accompanies this process, which can be reproduced by coculture of resting AMDC with T memory cells plus antigen. The APC activity of AMDC can be partially inhibited by anti-CD86, suggesting that CD86 may play an active role in this process and/or is a surrogate for other relevant costimulators. These findings provide a plausible model for local T cell activation at the lesional site in asthma, and for the transient nature of this inflammatory response.

Animals↗

Tracking of airway and tissue mechanics during TLC maneuvers in mice.

A tracking impedance estimation technique was developed to follow the changes in total respiratory impedance (Zrs) during slow total lung capacity maneuvers in six anesthetized and mechanically ventilated BALB/c mice. Zrs was measured with the wave-tube technique and pseudorandom forced oscillations at nine frequencies between 4 and 38 Hz during inflation from a transrespiratory pressure of 0-20 cmH2O and subsequent deflation, each lasting for approximately 20 s. Zrs was averaged for 0.125 s and fitted by a model featuring airway resistance (Raw) and inertance, and tissue damping and elastance (H). Lower airway conductance (Glaw) was linearly related to volume above functional residual capacity (V) between 0 and 75-95% maximum V, with a mean slope of dGlaw/dV = 13.6 +/- 4.6 cmH2O-1. s-1. The interdependence of Raw and H was characterized by two distinct and closely linear relationships for the low- and high-volume regions, separated at approximately 40% maximum V. Comparison of Raw with the highest-frequency resistance of the total respiratory system revealed a marked volume-dependent contribution of tissue resistance to total respiratory system resistance, resulting in the overestimation of Raw by 19 +/- 8 and 163 +/- 40% at functional residual capacity and total lung capacity, respectively, whereas the lowest frequency reactance was proportional to H; these findings indicate that single-frequency resistance values may become inappropriate as surrogates of Raw when tissue impedance is changing.

Airway Resistance↗

Airway and tissue mechanics in anesthetized paralyzed children.

To estimate the mechanical properties of the airways and respiratory tissues, respiratory system impedance (Zrs) was measured with low-frequency forced oscillations in 26 anesthetized, paralyzed children (aged 3 months-10 years) undergoing surgical correction of congenital heart diseases. Zrs was determined from the signals of tracheal flow and pressure between 0.4-12 Hz before surgery at zero mean transrespiratory pressure. The pulmonary (Z(L)) and chest wall (Z(W)) components of Zrs were also determined in 5 children by measuring esophageal pressure. A model containing frequency-independent resistance (R) and inertance (I), and coefficients of tissue-damping (G) and elastance (H), was fitted to the Zrs, Z(L), and Z(W) spectra. The total respiratory parameters normalized to body weights were 82.2 +/- 8.5 (SE) hPa x sec x l(-1) x kg, 0.152 +/- 0.05 hPa x sec(2) x l(-1) x kg, 293.8 +/- 20.0 hPa. l(-1) x kg, and 1,583 +/- 65.5 hPa x l(-1) x kg, for R, I, G, and H, respectively. The measurements of Z(L) and Z(W) revealed the dominance of the lungs in R (91 +/- 4.3%) and I (109 +/- 16%), and the major contribution of the lung parenchyma to G (61 +/- 7.3%) and H (66 +/- 7.4%) of the total respiratory system. It is concluded that anesthesia-paralysis provides an ideal condition for the measurement of low-frequency forced oscillatory impedance and its partitioning into airway and tissue components in mechanically ventilated children. The separation of pulmonary and chest wall mechanics demonstrates that airway properties can be estimated appropriately from Zrs data, while the chest wall may damp the changes in parenchymal properties.

Adolescent↗

In vivo measurements of changes in respiratory mechanics with age in mice deficient in surfactant protein D.

Mice deficient in surfactant protein D [SP-D (-/-)] develop progressive emphysema with age, associated with loss of parenchymal tissue, subpleural fibrosis, and accumulation of abnormal elastin fibers. We measured the changes in lung function, partitioned into components for the airways and lung parenchyma, occurring with age in SP-D (-/-) mice at three ages (n = 8 per group) (5, 8, and 13 wk). Impedance spectra between 0.25 and 19.625 Hz were calculated and a model, consisting of an airway compartment [airway resistance (Raw) and inertance (Iaw)] and a constant-phase tissue compartment [coefficients of tissue damping (G) and elastance (H)], was fitted to the data. Hysteresivity was calculated as G/H. Adult values of Raw, G, and H are reached by 8 wk of age in wild-type controls. Raw and H were lower at all ages in SP-D (-/-) compared with the wild-type controls (p = 0.006 and 0.029, respectively), and a similar trend was seen in G (p = 0.060). The patterns of change in respiratory mechanics were similar in both SP-D (+/+) and (-/-) groups. There were no changes in hysteresivity with age and no differences between wild-type and SP-D (-/-) mice. These data demonstrate that the changes in lung structure in SP-D (-/-) mice are reflected in the mechanical properties of both airway and lung parenchyma measured in vivo.

Age Factors↗

Environmental threats to children's health in Southeast Asia and the Western Pacific.

The Southeast Asia and Western Pacific regions contain half of the world's children and are among the most rapidly industrializing regions of the globe. Environmental threats to children's health are widespread and are multiplying as nations in the area undergo industrial development and pass through the epidemiologic transition. These environmental hazards range from traditional threats such as bacterial contamination of drinking water and wood smoke in poorly ventilated dwellings to more recently introduced chemical threats such as asbestos construction materials; arsenic in groundwater; methyl isocyanate in Bhopal, India; untreated manufacturing wastes released to landfills; chlorinated hydrocarbon and organophosphorous pesticides; and atmospheric lead emissions from the combustion of leaded gasoline. To address these problems, pediatricians, environmental health scientists, and public health workers throughout Southeast Asia and the Western Pacific have begun to build local and national research and prevention programs in children's environmental health. Successes have been achieved as a result of these efforts: A cost-effective system for producing safe drinking water at the village level has been devised in India; many nations have launched aggressive antismoking campaigns; and Thailand, the Philippines, India, and Pakistan have all begun to reduce their use of lead in gasoline, with resultant declines in children's blood lead levels. The International Conference on Environmental Threats to the Health of Children, held in Bangkok, Thailand, in March 2002, brought together more than 300 representatives from 35 countries and organizations to increase awareness on environmental health hazards affecting children in these regions and throughout the world. The conference, a direct result of the Environmental Threats to the Health of Children meeting held in Manila in April 2000, provided participants with the latest scientific data on children's vulnerability to environmental hazards and models for future policy and public health discussions on ways to improve children's health. The Bangkok Statement, a pledge resulting from the conference proceedings, is an important first step in creating a global alliance committed to developing active and innovative national and international networks to promote and protect children's environmental health.

Asia, Southeastern↗

Volume dependence of airway and tissue impedances in mice.

We measured respiratory input impedance (1-25 Hz) in mice and obtained parameters for airway and tissue mechanics by model fitting. Lung volume was varied by inflating to airway opening pressure (Pao) between 0 and 20 cm H2O. The expected pattern of changes in respiratory mechanics with increasing lung volume was seen: a progressive fall in airway resistance and increases in the coefficients of tissue damping and elastance. A surprising pattern was seen in hysteresivity (eta), with a plateau at low lung volumes (Pao < 10 cm H2O), a sharp fall occurring between 10 and 15 cm H2O, and eta approaching a second (lower) plateau at higher lung volumes. Studies designed to elucidate the mechanism(s) behind this behavior revealed that this was not due to chest wall properties, differences in volume history at low lung volume, time dependence of volume recruitment, or surface-acting forces. Our data are consistent with the notion that at low lung volumes the mechanics of the tissue matrix determine eta, whereas at high lung volumes the properties of individual fibers (collagen) become more important.

Airway Resistance↗

Association of IL12B promoter polymorphism with severity of atopic and non-atopic asthma in children.

BACKGROUND: Severe asthma is a frequent cause of hospital admission, especially among children. The main environmental triggers of airway inflammation in asthma are viruses and aeroallergens. These agents elicit reciprocal immune responses, characterised by production of T helper 1 and T helper 2 cytokines, respectively. There is no genetic explanation for how hyper-responsiveness to these disparate environmental stimuli develops among individuals with asthma. Our aim was to assess relation between an IL12B promoter polymorphism and asthma. METHODS: We did a cohort study in which we initially genotyped 411 6-year olds for the IL12B promoter polymorphism. We then assessed the relation between this polymorphism and asthma severity. A further 85 asthmatic children in an additional sample of 433 children from the same cohort were then assessed to confirm these findings. We also examined in-vitro interleukin-12 responses in a subgroup of individuals. FINDINGS: Heterozygosity for the IL12B promoter polymorphism was observed in 76% (16) of atopic and non-atopic individuals with severe asthma in the initial sample. By comparison, heterozygotes comprised only 31% (17) of the moderate asthma group, and 48% (20) of individuals with mild asthma were heterozygous, as were unaffected controls. These findings were confirmed in the second sample (overall p<0.0001). Our data suggest that IL12B promoter heterozygosity contributes to asthma severity rather than susceptibility per se. The severity-predisposing genotype was associated with reduced interleukin 12 p40 gene transcription and decreased interleukin 12 p70 secretion. INTERPRETATION: Interleukin 12 plays a key part in antagonism of T helper 2 differentiation, and in induction of antiviral host defense. Genetically determined attenuation of interleukin-12 response capacity would, therefore, provide a plausible common immunological pathway to disease severity for the two major forms of asthma.

Asthma↗

The role of corticosteroids in the management of childhood asthma.

Preventive treatment: * Inhaled corticosteroids are indicated in children with asthma who have more than mild persistent asthma or are unresponsive to non-steroidal medications after 2-4 weeks. * Initial administration of 400 microg/day of chlorofluorocarbon-beclomethasone dipropionate, or budesonide, or 200 microg/day of fluticasone propionate or hydrofluoroalkane-beclomethasone dipropionate, is suggested, with subsequent titration of the dose to achieve ongoing control with the lowest dose possible. * In situations where asthma control cannot be achieved with the above doses of inhaled corticosteroids, the addition of a long-acting beta2-agonist, theophylline or a leukotriene antagonist should be considered. * Specialist referral is recommended in children requiring high doses of inhaled steroids, regular oral steroids or in whom there is concern about possible steroid side effects. Treatment of acute asthma: * Systemic corticosteroid therapy is recommended for children with moderate to severe acute asthma or if there is incomplete response to beta2-agonists. * Initial administration of 1 mg/kg prednisolone (maximum, 50 mg) orally is suggested, and this may be repeated every 12-24 hours, depending on response. While a course of up to three days is generally sufficient, in more severe cases a prolonged course (with tapering) may occasionally be indicated. * The need for recurrent systemic corticosteroid therapy for acute episodes is an indication for reassessment of the child's interval therapy.

Acute Disease↗

Using imprecise probabilities to address the questions of inference and decision in randomized clinical trials.

Randomized controlled clinical trials play an important role in the development of new medical therapies. There is, however, an ethical issue surrounding the use of randomized treatment allocation when the patient is suffering from a life threatening condition and requires immediate treatment. Such patients can only benefit from the treatment they actually receive and not from the alternative therapy, even if it ultimately proves to be superior. We discuss a novel new way to analyse data from such clinical trials based on the use of the recently developed theory of imprecise probabilities. This work draws an explicit distinction between the related but nevertheless distinct questions of inference and decision in clinical trials. The traditional question of scientific interest asks 'Which treatment offers the greater chance of success?' and is the primary reason for conducting the clinical trial. The question of decision concerns the welfare of the patients in the clinical trial, asking whether the accumulated evidence favours one treatment over the other to such an extent that the next patient should decline randomization and instead express a preference for one treatment. Consideration of the decision question within the framework of imprecise probabilities leads to a mathematical definition of equipoise and a method for governing the randomization protocol of a clinical trial. This paper describes in detail the protocol for the conduct of clinical trials based on this new method of analysis, which is illustrated in a retrospective analysis of data from a clinical trial comparing the anti-emetic drugs ondansetron and droperidol in the treatment of postoperative nausea and vomiting. The proposed methodology is compared quantitatively using computer simulation studies with conventional clinical trial designs and is shown to maintain high statistical power with reduced sample sizes, at the expense of a high type I error rate that we argue is irrelevant in some specific circumstances. Particular emphasis is placed on describing the type of medical conditions and treatment comparisons where the new methodology is expected to provide the greatest benefit.

Antiemetics↗

Development of interleukin-12-producing capacity throughout childhood.

Increasing evidence indicates that the capacity to induce protective Th1 immune responses is impaired in early childhood, an observation that can be partially attributed to deficiencies in antigen-presenting-cell function. Synthesis of interleukin 12 (IL-12), a key Th1-trophic cytokine, is markedly reduced in the neonatal period, though there is a paucity of knowledge concerning the ontogeny of IL-12-synthetic capacity throughout the childhood years. Hence, we examined the production of bioactive IL-12 p70 by circulating mononuclear cells in a population of healthy individuals. As expected, the capacity to synthesize IL-12 p70 in response to either lipopolysaccharide or heat-killed Staphylococcus aureus was markedly impaired at birth, even after priming of cells with gamma interferon. Surprisingly however, IL-12 p70 synthesis by peripheral blood mononuclear cells from both 5- and 12-year-old children was still substantially below that seen in adults, and this did not appear to be related to excessive production of IL-10. In contrast, dendritic cells from adults and neonates, derived from monocytes with granulocyte-macrophage colony-stimulating factor and IL-4, synthesized equivalent amounts of IL-12 p70 in response to microbial stimulation. This indicates that the impaired capacity for IL-12 synthesis in childhood is not an intrinsic property of circulating mononuclear cells but rather can be readily overcome in response to appropriate maturational stimuli. Because IL-12 arose predominantly from circulating HLA-DR(+) cells that lacked B-cell- and monocyte-specific markers, we propose that the slow maturation of IL-12-synthetic capacity in the childhood years can be attributed to deficiencies in the number and/or function of dendritic cells.

Adult↗

Intra-amniotic injection of IL-1 induces inflammation and maturation in fetal sheep lung.

Antenatal inflammation may be an important triggering event in the pathogenesis of bronchopulmonary dysplasia but may also accelerate fetal lung maturation. We examined the effects of intra-amniotic (IA) interleukin (IL)-1 alpha and IL-1 beta on maturation of the fetal sheep lung. These cytokine effects were compared with IA endotoxin, a potent proinflammatory stimulus that accelerated lung maturation. Date-bred ewes received 15 or 150 microg recombinant ovine IL-1 alpha or IL-1 beta or 10 mg Escherichia coli endotoxin by IA injection at 118 days gestation (term = 150 days), and fetuses were delivered at 125 days. IL-1 alpha and IL-1 beta improved lung function and increased alveolar saturated phosphatidylcholine (Sat PC) and surfactant protein mRNA expression at the higher dose. The maturation response to IL-1 alpha was greater than that to IL-1 beta, which was similar to endotoxin response. Inflammation was also more pronounced after IL-1 alpha treatment. Only endotoxin animals had residual inflammation of the fetal membranes at 7 days. Lung compliance, lung volume, and alveolar Sat PC were positively correlated with residual alveolar wash leukocyte numbers 7 days after IL-1 treatment, suggesting a link between lung inflammation and maturation.

Amnion↗

Effects of pulmonary vascular pressures and flow on airway and parenchymal mechanics in isolated rat lungs.

Changes in pulmonary hemodynamics have been shown to alter the mechanical properties of the lungs, but the exact mechanisms are not clear. We therefore investigated the effects of alterations in pulmonary vascular pressure and flow (Q(p)) on the mechanical properties of the airways and the parenchyma by varying these parameters independently in three groups of isolated perfused normal rat lungs. The pulmonary capillary pressure (Pc(est)), estimated from the pulmonary arterial (Ppa) and left atrial pressure (Pla), was increased at constant Q(p) (n = 7), or Q(p) was changed at Pc(est) = 10 mmHg (n = 7) and at Pc(est) = 20 mmHg (n = 6). In each condition, the airway resistance (Raw) and parenchymal damping (G) and elastance (H) were identified from the low-frequency pulmonary input impedance spectra. The results of measurements made under isogravimetric conditions were analyzed. The changes observed in the mechanical parameters were consistent with an altered Pla: monotonous increases in Raw were observed with increasing Pla, whereas G and H were minimal at Pla of approximately 7-10 mmHg and increased at lower and higher Pla. The results indicate that Pla, and not Ppa or Q(p), is the primary determinant of the mechanical condition of the lungs after acute changes in pulmonary hemodynamics: the parenchymal mechanics are impaired if Pla is lower or higher than physiological, whereas airway narrowing occurs at high Pla.

Airway Resistance↗