AQP1 in the Gastrointestinal Tract of Mice: Expression Pattern and Impact of AQP1 Knockout on Colonic Function.

Aquaporin 1 (AQP1) is one of thirteen known mammalian aquaporins. Its main function is the transport of water across cell membranes. Lately, a role of AQP has been attributed to other physiological and pathological functions including cell migration and peripheral pain perception. AQP1 has been found in several parts of the enteric nervous system, e.g., in the rat ileum and in the ovine duodenum. Its function in the intestine appears to be multifaceted and is still not completely understood. The aim of the study was to analyze the distribution and localization of AQP1 in the entire intestinal tract of mice. AQP1 expression was correlated with the hypoxic expression profile of the various intestinal segments, intestinal wall thickness and edema, as well as other aspects of colon function including the ability of mice to concentrate stools and their microbiome composition. AQP1 was found in a specific pattern in the serosa, the mucosa, and the enteric nervous system throughout the gastrointestinal tract. The highest amount of AQP1 in the gastrointestinal tract was found in the small intestine. AQP1 expression correlated with the expression profiles of hypoxia-dependent proteins such as HIF-1α and PGK1. Loss of AQP1 through knockout of AQP1 in these mice led to a reduced amount of bacteroidetes and firmicutes but an increased amount of the rest of the phyla, especially deferribacteres, proteobacteria, and verrucomicrobia. Although AQP-KO mice retained gastrointestinal function, distinct changes regarding the anatomy of the intestinal wall including intestinal wall thickness and edema were observed. Loss of AQP1 might interfere with the ability of the mice to concentrate their stool and it is associated with a significantly different composition of the of the bacterial stool microbiome.

Lung function fluctuation patterns unveil asthma and COPD phenotypes unrelated to type 2 inflammation.

BACKGROUND: In all chronic airway diseases, the dynamics of airway function are influenced by underlying airway inflammation and bronchial hyperresponsiveness along with limitations in reversibility owing to airway and lung remodeling as well as mucous plugging. The relative contribution of each component translates into specific clinical patterns of symptoms, quality of life, exacerbation risk, and treatment success. OBJECTIVE: We aimed to evaluate whether subgrouping of patients with obstructive airway diseases according to patterns of fluctuation in lung function allows identification of specific phenotypes with distinct clinical characteristics. METHODS: We applied the novel method of fluctuation-based clustering (FBC) to twice-daily FEV1 measurements recorded over a 1-year period in a mixed group of 134 adults with mild-to-moderate asthma, severe asthma, or chronic obstructive pulmonary disease from the European BIOAIR cohort. RESULTS: Independently of clinical diagnosis, FBC divided patients into 4 fluctuation-based clusters with progressively increasing alterations in lung function that corresponded to patterns of increasing clinical severity, risk of exacerbation, and lower quality of life. Clusters of patients with airway disease with significantly elevated levels of biomarkers relating to remodeling (osteonectin) and cellular senescence (plasminogen activator inhibitor-1), accompanied by a loss of airway reversibility, pulmonary hyperinflation, and loss of diffusion capacity, were identified. The 4 clusters generated were stable over time and revealed no differences in levels of markers of type 2 inflammation (blood eosinophils and periostin). CONCLUSION: FBC-based phenotyping provides another level of information that is complementary to clinical diagnosis and unrelated to eosinophilic inflammation, which could identify patients who may benefit from specific treatment strategies or closer monitoring.

Functional phenotypes determined by fluctuation-based clustering of lung function measurements in healthy and asthmatic cohort participants.

RATIONALE: Asthma is characterised by inflammation and reversible airway obstruction. However, these features are not always closely related. Fluctuations of daily lung function contain information on asthma phenotypes, exacerbation risk and response to long-acting ß-agonists. OBJECTIVES: In search of subgroups of asthmatic participants with specific lung functional features, we developed and validated a novel clustering approach to asthma phenotyping, which exploits the information contained within the fluctuating behaviour of twice-daily lung function measurements. METHODS: Forced expiratory volume during the first second (FEV1) and peak expiratory flow (PEF) were prospectively measured over 4 weeks in 696 healthy and asthmatic school children (Protection Against Allergy - Study in Rural Environments (PASTURE)/EFRAIM cohort), and over 1 year in 138 asthmatic adults with mild-to-moderate or severe asthma (Pan-European Longitudinal Assessment of Clinical Course and BIOmarkers in Severe Chronic AIRway Disease (BIOAIR) cohort). Using enrichment analysis, we explored whether the method identifies clinically meaningful, distinct clusters of participants with different lung functional fluctuation patterns. MEASUREMENTS AND MAIN RESULTS: In the PASTURE/EFRAIM dataset, we found four distinct clusters. Two clusters were enriched in children with well-known clinical characteristics of asthma. In cluster 3, children from a farming environment predominated, whereas cluster 4 mainly consisted of healthy controls. About 79% of cluster 3 carried the asthma-risk allele rs7216389 of the 17q21 locus. In the BIOAIR dataset, we found two distinct clusters clearly discriminating between individuals with mild-to-moderate and severe asthma. CONCLUSIONS: Our method identified dynamic functional asthma and healthy phenotypes, partly independent of atopy and inflammation but related to genetic markers on the 17q21 locus. The method can be used for disease phenotyping and possibly endotyping. It may identify participants with specific functional abnormalities, potentially needing a different therapeutic approach.

Electronic monitoring of adherence to inhaled corticosteroids: an essential tool in identifying severe asthma in children.

International guidelines recommend that severe asthma can only be diagnosed after contributory factors, including adherence, have been addressed. Accurate assessment of adherence is difficult in clinical practice. We hypothesised that electronic monitoring in children would identify nonadherence, thus delineating the small number with true severe asthma.Asthmatic children already prescribed inhaled corticosteroids were prospectively recruited and persistence of adherence assessed using electronic monitoring devices. Spirometry, airway inflammation and asthma control were measured at the start and end of the monitoring period.93 children (62 male; median age 12.4 years) were monitored for a median of 92 days. Median (range) monitored adherence was 74% (21-99%). We identified four groups: 1) good adherence during monitoring with improved control, 24% (likely previous poor adherence); 2) good adherence with poor control, 18% (severe therapy-resistant asthma); 3) poor adherence with good control, 26% (likely overtreated); and 4) poor adherence with poor control, 32%. No clinical parameter prior to monitoring distinguished these groups.Electronic monitoring is a useful tool for identifying children in whom a step up in treatment is indicated. Different approaches are needed in those who are controlled when adherent or who are nonadherent. Electronic monitoring is essential in a paediatric severe asthma clinic.

Immediate effects of phototherapy on sleep in very preterm neonates: an observational study.

Process C (internal clock) and Process S (sleep-wake homeostasis) are the basis of sleep-wake regulation. In the last trimester of pregnancy, foetal heart rate is synchronized with the maternal circadian rhythm. At birth, this interaction fails and an ultradian rhythm appears. Light exposure is a strong factor influencing the synchronization of sleep-wake processes. However, little is known about the effects of phototherapy on the sleep rhythm of premature babies. It was hypothesized that sleep in preterm infants would not differ during phototherapy, but that a maturation effect would be seen. Sleep states were studied in 38 infants born < 32 weeks gestational age and/or < 1 500 g birth weight. Videos of 3 h were taken over the first 5 days of life. Based on breathing and movement patterns, behavioural states were defined as: awake; active sleep; or quiet sleep. Videos with and without phototherapy were compared for amounts of quiet sleep and active states (awake + active sleep). No significant association between phototherapy and amount of quiet sleep was found (P = 0.083). Analysis of videos in infants not under phototherapy revealed an increase in time spent awake with increasing gestational age. The current data suggest that the ultradian rhythm of preterm infants seems to be independent of phototherapy, supporting the notion that sleep rhythm in this population is mainly driven by their internal clock.

Air pollution modelling for birth cohorts: a time-space regression model.

BACKGROUND: To investigate air pollution effects during pregnancy or in the first weeks of life, models are needed that capture both the spatial and temporal variability of air pollution exposures. METHODS: We developed a time-space exposure model for ambient NO2 concentrations in Bern, Switzerland. We used NO2 data from passive monitoring conducted between 1998 and 2009: 101 rural sites (24,499 biweekly measurements) and 45 urban sites (4350 monthly measurements). We evaluated spatial predictors (land use; roads; traffic; population; annual NO2 from a dispersion model) and temporal predictors (meteorological conditions; NO2 from continuous monitoring station). Separate rural and urban models were developed by multivariable regression techniques. We performed ten-fold internal cross-validation, and an external validation using 57 NO2 passive measurements obtained at study participant's homes. RESULTS: Traffic related explanatory variables and fixed site NO2 measurements were the most relevant predictors in both models. The coefficient of determination (R(2)) for the log transformed models were 0.63 (rural) and 0.54 (urban); cross-validation R(2)s were unchanged indicating robust coefficient estimates. External validation showed R(2)s of 0.54 (rural) and 0.67 (urban). CONCLUSIONS: This approach is suitable for air pollution exposure prediction in epidemiologic research with time-vulnerable health effects such as those occurring during pregnancy or in the first weeks of life.

The cycle of EBV infection explains persistence, the sizes of the infected cell populations and which come under CTL regulation.

Previous analysis of Epstein-Barr virus (EBV) persistent infection has involved biological and immunological studies to identify and quantify infected cell populations and the immune response to them. This led to a biological model whereby EBV infects and activates naive B-cells, which then transit through the germinal center to become resting memory B-cells where the virus resides quiescently. Occasionally the virus reactivates from these memory cells to produce infectious virions. Some of this virus infects new naive B-cells, completing a cycle of infection. What has been lacking is an understanding of the dynamic interactions between these components and how their regulation by the immune response produces the observed pattern of viral persistence. We have recently provided a mathematical analysis of a pathogen which, like EBV, has a cycle of infected stages. In this paper we have developed biologically credible values for all of the parameters governing this model and show that with these values, it successfully recapitulates persistent EBV infection with remarkable accuracy. This includes correctly predicting the observed patterns of cytotoxic T-cell regulation (which and by how much each infected population is regulated by the immune response) and the size of the infected germinal center and memory populations. Furthermore, we find that viral quiescence in the memory compartment dictates the pattern of regulation but is not required for persistence; it is the cycle of infection that explains persistence and provides the stability that allows EBV to persist at extremely low levels. This shifts the focus away from a single infected stage, the memory B-cell, to the whole cycle of infection. We conclude that the mathematical description of the biological model of EBV persistence provides a sound basis for quantitative analysis of viral persistence and provides testable predictions about the nature of EBV-associated diseases and how to curb or prevent them.

Long-term smoking cessation and heart rate dynamics in an aging healthy cohort: Is it possible to fully recover?

AIM: To evaluate the long-term influence of smoking cessation on the regulation of the autonomic cardiovascular system in an aging general population, using the subpopulation of lifelong non-smokers as control group. METHODS: We analyzed 1481 participants aged ≥50 years from the SAPALDIA cohort. In each participant, heart rate variability and heart rate dynamics were characterized by means of various quantitative analyzes of the inter-beat interval time series generated from 24-hour electrocardiogram recordings. Each parameter obtained was then used as the outcome variable in multivariable linear regression models in order to evaluate the association with smoking status and time elapsed since smoking cessation. The models were adjusted for known confounding factors and stratified by the time elapsed since smoking cessation. RESULTS: Our findings indicate that smoking triggers adverse changes in the regulation of the cardiovascular system, even at low levels of exposure since current light smokers exhibited significant changes as compared to lifelong non-smokers. Moreover, there was evidence for a dose-response effect. Indeed, the changes observed in current heavy smokers were more marked as compared to current light smokers. Furthermore, full recovery was achieved in former smokers (i.e., normalization to the level of lifelong non-smokers). However, while light smokers fully recovered within the 15 first years of cessation, heavy former smokers might need up to 15-25 years to fully recover. CONCLUSION: This study supports the substantial benefits of smoking cessation, but also warns of important long-term alterations caused by heavy smoking.

Volumetric capnography in infants with bronchopulmonary dysplasia.

OBJECTIVES: To assess the feasibility of using volumetric capnography in spontaneously breathing small infants and its ability to discriminate between infants with and without bronchopulmonary dysplasia (BPD). STUDY DESIGN: Lung function variables for 231 infants (102 term, 52 healthy preterm, 77 BPD), matched for post-conceptional age of 44 weeks, were collected. BPD was defined as supplemental oxygen requirement at 36 weeks post-menstrual age. Tidal breath-by-breath volume capnograms were obtained by mainstream capnography. The capnographic slope of phase II (SII) and slope of phase III (SIII) were calculated and compared between study groups. The effect of BPD, tidal volume (VT), respiratory rate (RR), and prematurity on the magnitude of the slopes was assessed. RESULTS: SII was steeper in infants with BPD (100 ± 28/L) compared with healthy preterm (88 ± 22/L; P = .007) and term infants (79 ± 18/L; P < .001), but this finding was attributed to differences in VT, RR, and gestational age. SIII was steeper in the BPD group (26.8 ± 14.1/L) compared with healthy preterm (16.2 ± 6.2/L; P < .001) and term controls (14.8 ± 5.4/L; P < .001). BPD was a significant predictor of SIII independently of VT, RR, and gestational age. The ability of SIII to discriminate between BPD and controls was significantly higher compared with lung clearance index (area under the curve 0.83 vs 0.56; P < .001). CONCLUSIONS: Volumetric capnography may provide valuable information regarding functional lung alterations related to BPD and might be considered as an alternative to more involved lung function techniques for monitoring chronic lung disease during early infancy.

Correlation properties of spontaneous motor activity in healthy infants: a new computer-assisted method to evaluate neurological maturation.

Qualitative assessment of spontaneous motor activity in early infancy is widely used in clinical practice. It enables the description of maturational changes of motor behavior in both healthy infants and infants who are at risk for later neurological impairment. These assessments are, however, time-consuming and are dependent upon professional experience. Therefore, a simple physiological method that describes the complex behavior of spontaneous movements (SMs) in infants would be helpful. In this methodological study, we aimed to determine whether time series of motor acceleration measurements at 40-44 weeks and 50-55 weeks gestational age in healthy infants exhibit fractal-like properties and if this self-affinity of the acceleration signal is sensitive to maturation. Healthy motor state was ensured by General Movement assessment. We assessed statistical persistence in the acceleration time series by calculating the scaling exponent α via detrended fluctuation analysis of the time series. In hand trajectories of SMs in infants we found a mean α value of 1.198 (95 % CI 1.167-1.230) at 40-44 weeks. Alpha changed significantly (p = 0.001) at 50-55 weeks to a mean of 1.102 (1.055-1.149). Complementary multilevel regression analysis confirmed a decreasing trend of α with increasing age. Statistical persistence of fluctuation in hand trajectories of SMs is sensitive to neurological maturation and can be characterized by a simple parameter α in an automated and observer-independent fashion. Future studies including children at risk for neurological impairment should evaluate whether this method could be used as an early clinical screening tool for later neurological compromise.

The evolution of virulence in RNA viruses under a competition-colonization trade-off.

RNA viruses exist in large intra-host populations which display great genotypic and phenotypic diversity. We analyze a model of viral competition between two viruses infecting a constantly replenished cell pool. We assume a trade-off between the ability of the virus to colonize new cells (cell killing rate or virulence) and its local competitiveness (replicative success within coinfected cells). We characterize the conditions that allow for viral spread by means of the basic reproductive number and show that a local coexistence equilibrium exists, which is asymptotically stable. At this equilibrium, the less virulent competitor has a reproductive advantage over the more virulent colonizer reflected by a larger equilibrium population size of the competitor. The equilibria at which one virus outcompetes the other one are unstable, i.e., a second virus is always able to permanently invade. We generalize the two-virus model to multiple viral strains, each displaying a different virulence. To account for the large phenotypic diversity in viral populations, we consider a continuous spectrum of virulences and present a continuum limit of this multiple viral strains model that describes the time evolution of an initial continuous distribution of virulence without mutations. We provide a proof of the existence of solutions of the model equations, analytically assess the properties of stationary solutions, and present numerical approximations of solutions for different initial distributions. Our simulations suggest that initial continuous distributions of virulence evolve toward a distribution that is extremely skewed in favor of competitors. At equilibrium, only the least virulent part of the population survives. The discrepancy of this finding in the continuum limit with the two-virus model is attributed to the skewed equilibrium subpopulation sizes and to the transition to a continuum. Consequently, in viral quasispecies with high virulence diversity, the model predicts collective virulence attenuation. This result may contribute to understanding virulence attenuation, which has been reported in several experimental studies.

A model of host response to a multi-stage pathogen.

We model the immune surveillance of a pathogen which passes through n immunologically distinct stages. The biological parameters of this system induce a partial order on the stages, and this, in turn, determines which stages will be subject to immune regulation. This corresponds to the system's unique asymptotically stable fixed point.

Can Measurements of Inflammatory Biomarkers be Used to Spot Respiratory Viral Infections?

Accurate detection of human respiratory viral infections is highly topical. We investigated how strongly inflammatory biomarkers (FeNO, eosinophils, neutrophils, and cytokines in nasal lavage fluid) and lung function parameters change upon rhinovirus 16 infection, in order to explore their potential use for infection detection. To this end, within a longitudinal cohort study, healthy and mildly asthmatic volunteers were experimentally inoculated with rhinovirus 16, and time series of these parameters/biomarkers were systematically recorded and compared between the pre- and post-infection phases of the study, which lasted two months and one month, respectively. We found that the parameters'/biomarkers' ability to discriminate between the infected and the uninfected state varied over the observation time period. Consistently over time, the concentration of cytokines, in nasal lavage fluid, showed moderate to very good discrimination performance, thereby qualifying for disease progression monitoring, whereas lung function and FeNO, while quickly and non-invasively measurable using cheap portable devices (e.g., at airports), performed poorly.

Fluctuation-based clustering reveals phenotypes of patients with different asthma severity.

Serial peak expiratory flow (PEF) measurements can identify phenotypes in severe adult asthma, enabling more targeted treatment. The feasibility of this approach in children has not been investigated. Overall, 105 children (67% male, median age 12.4 years) with a range of asthma severities were recruited and followed up over a median of 92 days. PEF was measured twice daily. Fluctuation-based clustering (FBC) was used to identify clusters based on PEF fluctuations. The patients' clinical characteristics were compared between clusters. Three PEF clusters were identified in 44 children with sufficient measurements. Cluster 1 (27% of patients: n=12) had impaired spirometry (mean forced expiratory volume in 1 s (FEV1) 71% predicted), significantly higher exhaled nitric oxide (≥35 ppb) and uncontrolled asthma (asthma control test (ACT) score <20 of 25). Cluster 2 (45%: n=20) had normal spirometry, the highest proportion of difficult asthma and significantly more patients on a high dose of inhaled corticosteroids (≥800 µg budesonide). Cluster 3 (27%: n=12) had mean FEV1 92% predicted, the highest proportion of patients with no bronchodilator reversibility, a low ICS dose (≤400 µg budesonide), and controlled asthma (ACT scores ≥20 of 25). Three clinically relevant paediatric asthma clusters were identified using FBC analysis on PEF measurements, which could improve telemonitoring diagnostics. The method remains robust even when 80% of measurements were removed. Further research will determine clinical applicability.

A virtual look at Epstein-Barr virus infection: biological interpretations.

The possibility of using computer simulation and mathematical modeling to gain insight into biological and other complex systems is receiving increased attention. However, it is as yet unclear to what extent these techniques will provide useful biological insights or even what the best approach is. Epstein-Barr virus (EBV) provides a good candidate to address these issues. It persistently infects most humans and is associated with several important diseases. In addition, a detailed biological model has been developed that provides an intricate understanding of EBV infection in the naturally infected human host and accounts for most of the virus' diverse and peculiar properties. We have developed an agent-based computer model/simulation (PathSim, Pathogen Simulation) of this biological model. The simulation is performed on a virtual grid that represents the anatomy of the tonsils of the nasopharyngeal cavity (Waldeyer ring) and the peripheral circulation--the sites of EBV infection and persistence. The simulation is presented via a user friendly visual interface and reproduces quantitative and qualitative aspects of acute and persistent EBV infection. The simulation also had predictive power in validation experiments involving certain aspects of viral infection dynamics. Moreover, it allows us to identify switch points in the infection process that direct the disease course towards the end points of persistence, clearance, or death. Lastly, we were able to identify parameter sets that reproduced aspects of EBV-associated diseases. These investigations indicate that such simulations, combined with laboratory and clinical studies and animal models, will provide a powerful approach to investigating and controlling EBV infection, including the design of targeted anti-viral therapies.

Association of long-term exposure to traffic-related PM10 with heart rate variability and heart rate dynamics in healthy subjects.

BACKGROUND: Epidemiological evidence on the influence of long-term exposure to traffic-related particulate matter (TPM10) on heart rate variability (HRV) is weak. OBJECTIVE: To evaluate the association of long-term exposure (10 years) with TPM10 on the regulation of the autonomic cardiovascular system and heart rate dynamics (HRD) in an aging general population, as well as potential modifying effects by the a priori selected factors sex, smoking status, obesity, and gene variation in selected glutathione S-transferases (GSTs). METHODS: We analyzed data from 1593 SAPALDIA cohort participants aged ≥ 50 years. For each participant, various HRV and HRD parameters were derived from 24-hour electrocardiogram recordings. Each parameter obtained was then used as the outcome variable in multivariable mixed linear regression models in order to evaluate the association with TPM10. Potential modifying effects were assessed using interaction terms. RESULTS: No association between long-term exposure to TPM10 and HRV/HRD was observed in the entire study population. However, HRD changes were found in subjects without cardiovascular morbidity and both HRD and HRV changes in non-obese subjects without cardiovascular morbidity. Subjects without cardiovascular morbidity with homozygous GSTM1 gene deletion appeared to be more susceptible to the effects of TPM10. CONCLUSION: This study suggests that long-term exposure to TPM10 triggers adverse changes in the regulation of the cardiovascular system. These adverse effects were more visible in the subjects without cardiovascular disease, in whom the overall relationship between TPM10 and HRV/HRD could not be masked by underlying morbidities and the potential counteracting effects of related drug treatments.

Dynamics of respiratory symptoms during infancy and associations with wheezing at school age.

Children with frequent respiratory symptoms in infancy have an increased risk for later wheezing, but the association with symptom dynamics is unknown. We developed an observer-independent method to characterise symptom dynamics and tested their association with subsequent respiratory morbidity. In this birth-cohort of healthy neonates, we prospectively assessed weekly respiratory symptoms during infancy, resulting in a time series of 52 symptom scores. For each infant, we calculated the transition probability between two consecutive symptom scores. We used these transition probabilities to construct a Markov matrix, which characterised symptom dynamics quantitatively using an entropy parameter. Using this parameter, we determined phenotypes by hierarchical clustering. We then studied the association between phenotypes and wheezing at 6 years. In 322 children with complete data for symptom scores during infancy (16 864 observations), we identified three dynamic phenotypes. Compared to the low-risk phenotype, the high-risk phenotype, defined by the highest entropy parameter, was associated with an increased risk of wheezing (odds ratio (OR) 3.01, 95% CI 1.15-7.88) at 6 years. In this phenotype, infants were more often male (64%) and had been exposed to environmental tobacco smoke (31%). In addition, more infants had siblings (67%) and attended childcare (38%). We describe a novel method to objectively characterise dynamics of respiratory symptoms in infancy, which helps identify abnormal clinical susceptibility and recovery patterns of infant airways associated with persistent wheezing.

Breath-to-breath variability of exhaled CO2 as a marker of lung dysmaturity in infancy.

The concept of diffusional screening implies that breath-to-breath variations in CO2 clearance, when related to the variability of breathing, may contain information on the quality and utilization of the available alveolar surface. We explored the validity of the above hypothesis in a cohort of young infants of comparable postmenstrual age but born at different stages of lung maturity, namely, in term-born infants ( n = 128), preterm-born infants without chronic lung disease of infancy (CLDI; n = 53), and preterm infants with moderate/severe CLDI ( n = 87). Exhaled CO2 volume (VE,CO2) and concentration (FE,CO2) were determined by volumetric capnography, whereas their variance was assessed by linear and nonlinear variability metrics. The relationship between relative breath-to-breath change of VE,CO2 (ΔVE,CO2) and the corresponding change of tidal volume (ΔVT) was also analyzed. Nonlinear FE,CO2 variability was lower in CLDI compared with term and non-CLDI preterm group ( P < 0.001 for both comparisons). In CLDI infants, most of the VE,CO2 variability was attributed to the variability of VT ( r2 = 0.749), whereas in term and healthy preterm infants this relationship was weaker ( r2 = 0.507 and 0.630, respectively). The ΔVE,CO2 - ΔVT slope was less steep in the CLDI group (1.06 ± 0.07) compared with non-CLDI preterm (1.16 ± 0.07; P < 0.001) and term infants (1.20 ± 0.10; P < 0.001), suggesting that the more dysmature the infant lung, the less efficiently it eliminates CO2 under tidal breathing conditions. We conclude that the temporal variation of CO2 clearance may be related to the degree of lung dysmaturity in early infancy. NEW & NOTEWORTHY Young infants exhibit appreciable breath-to-breath CO2 variability that can be quantified by nonlinear variability metrics and may reflect the degree of lung dysmaturity. In infants with moderate/severe chronic lung disease of infancy (CLDI), the variability of the exhaled CO2 is mainly driven by the variability of breathing, whereas in term-born and healthy preterm infants this relationship is less strong. The slope of the relative CO2-to-volume change is less steep in CLDI infants, suggesting that dysmature lungs are less efficient in eliminating CO2 under tidal breathing conditions.

Dynamics and complexity of body temperature in preterm infants nursed in incubators.

BACKGROUND: Poor control of body temperature is associated with mortality and major morbidity in preterm infants. We aimed to quantify its dynamics and complexity to evaluate whether indices from fluctuation analyses of temperature time series obtained within the first five days of life are associated with gestational age (GA) and body size at birth, and presence and severity of typical comorbidities of preterm birth. METHODS: We recorded 3h-time series of body temperature using a skin electrode in incubator-nursed preterm infants. We calculated mean and coefficient of variation of body temperature, scaling exponent alpha (Talpha) derived from detrended fluctuation analysis, and sample entropy (TSampEn) of temperature fluctuations. Data were analysed by multilevel multivariable linear regression. RESULTS: Data of satisfactory technical quality were obtained from 285/357 measurements (80%) in 73/90 infants (81%) with a mean (range) GA of 30.1 (24.0-34.0) weeks. We found a positive association of Talpha with increasing levels of respiratory support after adjusting for GA and birth weight z-score (p<0.001; R2 = 0.38). CONCLUSION: Dynamics and complexity of body temperature in incubator-nursed preterm infants show considerable associations with GA and respiratory morbidity. Talpha may be a useful marker of autonomic maturity and severity of disease in preterm infants.

Sigh-induced changes of breathing pattern in preterm infants.

Sighs are thought to play an important role in control of breathing. It is unclear how sighs are triggered, and whether preterm birth and lung disease influence breathing pattern prior to and after a sigh in infants. To assess whether frequency, morphology, size, and short-term variability in tidal volume (VT) before, during, and after a sigh are influenced by gestational age at birth and lung disease (bronchopulmonary dysplasia, BPD) in former preterm infants and healthy term controls measured at equivalent postconceptional age (PCA). We performed tidal breathing measurements in 143 infants during quiet natural sleep at a mean (SD) PCA of 44.8 (1.3) weeks. A total of 233 sighs were analyzed using multilevel, multivariable regression. Sigh frequency in preterm infants increased with the degree of prematurity and severity of BPD, but was not different from that of term controls when normalized to respiratory rate. After a sigh, VT decreased remarkably in all infants (paired t-test: P < 0.001). There was no major effect of prematurity or BPD on various indices of sigh morphology and changes in VT prior to or after a sigh. Short-term variability in VT modestly increased with maturity at birth and infants with BPD showed an earlier return to baseline variability in VT following a sigh. In early infancy, sigh-induced changes in breathing pattern are moderately influenced by prematurity and BPD in preterm infants. The major determinants of sigh-related breathing pattern in these infants remain to be investigated, ideally using a longitudinal study design.