Relationship between cardiorespiratory phase coherence during hypoxia and genetic polymorphism in humans.

KEY POINTS: High altitude-induced hypoxia in humans evokes a pattern of breathing known as periodic breathing (PB), in which the regular oscillations corresponding to rhythmic expiration and inspiration are modulated by slow periodic oscillations. The phase coherence between instantaneous heart rate and respiration is shown to increase significantly at the frequency of periodic breathing during acute and sustained normobaric and hypobaric hypoxia. It is also shown that polymorphism in specific genes, NOTCH4 and CAT, is significantly correlated with this coherence, and thus with the incidence of PB. Differences in phase shifts between blood flow signals and respiratory and PB oscillations clearly demonstrate contrasting origins of the mechanisms underlying normal respiration and PB. These novel findings provide a better understanding of both the genetic and the physiological mechanisms responsible for respiratory control during hypoxia at altitude, by linking genetic factors with cardiovascular dynamics, as evaluated by phase coherence. ABSTRACT: Periodic breathing (PB) occurs in most humans at high altitudes and is characterised by low-frequency periodic alternation between hyperventilation and apnoea. In hypoxia-induced PB the dynamics and coherence between heart rate and respiration and their relationship to underlying genetic factors is still poorly understood. The aim of this study was to investigate, through novel usage of time-frequency analysis methods, the dynamics of hypoxia-induced PB in healthy individuals genotyped for a selection of antioxidative and neurodevelopmental genes. Breathing, ECG and microvascular blood flow were simultaneously monitored for 30 min in 22 healthy males. The same measurements were repeated under normoxic and hypoxic (normobaric (NH) and hypobaric (HH)) conditions, at real and simulated altitudes of up to 3800 m. Wavelet phase coherence and phase difference around the frequency of breathing (approximately 0.3 Hz) and around the frequency of PB (approximately 0.06 Hz) were evaluated. Subjects were genotyped for common functional polymorphisms in antioxidative and neurodevelopmental genes. During hypoxia, PB resulted in increased cardiorespiratory coherence at the PB frequency. This coherence was significantly higher in subjects with NOTCH4 polymorphism, and significantly lower in those with CAT polymorphism (HH only). Study of the phase shifts clearly indicates that the physiological mechanism of PB is different from that of the normal respiratory cycle. The results illustrate the power of time-evolving oscillatory analysis content in obtaining important insight into high altitude physiology. In particular, it provides further evidence for a genetic predisposition to PB and may partly explain the heterogeneity in the hypoxic response.

Urine and Fecal 1H-NMR Metabolomes Differ Significantly between Pre-Term and Full-Term Born Physically Fit Healthy Adult Males.

Preterm birth (before 37 weeks gestation) accounts for ~10% of births worldwide and remains one of the leading causes of death in children under 5 years of age. Preterm born adults have been consistently shown to be at an increased risk for chronic disorders including cardiovascular, endocrine/metabolic, respiratory, renal, neurologic, and psychiatric disorders that result in increased death risk. Oxidative stress was shown to be an important risk factor for hypertension, metabolic syndrome and lung disease (reduced pulmonary function, long-term obstructive pulmonary disease, respiratory infections, and sleep disturbances). The aim of this study was to explore the differences between preterm and full-term male participants' levels of urine and fecal proton nuclear magnetic resonance (1H-NMR) metabolomes, during rest and exercise in normoxia and hypoxia and to assess general differences in human gut-microbiomes through metagenomics at the level of taxonomy, diversity, functional genes, enzymatic reactions, metabolic pathways and predicted gut metabolites. Significant differences existed between the two groups based on the analysis of 1H-NMR urine and fecal metabolomes and their respective metabolic pathways, enabling the elucidation of a complex set of microbiome related metabolic biomarkers, supporting the idea of distinct host-microbiome interactions between the two groups and enabling the efficient classification of samples; however, this could not be directed to specific taxonomic characteristics.

FragViz: visualization of fragmented networks.

BACKGROUND: Researchers in systems biology use network visualization to summarize the results of their analysis. Such networks often include unconnected components, which popular network alignment algorithms place arbitrarily with respect to the rest of the network. This can lead to misinterpretations due to the proximity of otherwise unrelated elements. RESULTS: We propose a new network layout optimization technique called FragViz which can incorporate additional information on relations between unconnected network components. It uses a two-step approach by first arranging the nodes within each of the components and then placing the components so that their proximity in the network corresponds to their relatedness. In the experimental study with the leukemia gene networks we demonstrate that FragViz can obtain network layouts which are more interpretable and hold additional information that could not be exposed using classical network layout optimization algorithms. CONCLUSIONS: Network visualization relies on computational techniques for proper placement of objects under consideration. These algorithms need to be fast so that they can be incorporated in responsive interfaces required by the explorative data analysis environments. Our layout optimization technique FragViz meets these requirements and specifically addresses the visualization of fragmented networks, for which standard algorithms do not consider similarities between unconnected components. The experiments confirmed the claims on speed and accuracy of the proposed solution.

Effect of pre-term birth on oxidative stress responses to normoxic and hypoxic exercise.

Pre-term birth is a major health concern that occurs in approximately 10% of births worldwide. Despite high incidence rate, long-term consequences of pre-term birth remain unclear. Recent evidence suggests that elevated oxidative stress observed in pre-term born infants could persist into adulthood. Given that oxidative stress is known to play an important role in response to physical activity and hypoxia, we investigated whether oxidative stress responses to acute exercise in normoxia and hypoxia may be differently modulated in pre-term vs. full-term born adults. Twenty-two pre-term born and fifteen age-matched full-term born controls performed maximal incremental cycling tests in both normoxia (FiO2: 0.21) and normobaric hypoxia (FiO2: 0.13; simulated altitude of 3800 m) in blinded and randomized manner. Plasma levels of oxidative stress (advanced oxidation protein products [AOPP] and malondialdehyde), antioxidant (ferric reducing antioxidant power, glutathione peroxidase, catalase [CAT] and superoxide dismutase [SOD]) and nitrosative stress markers (nitrotyrosine, nitrite and total nitrite and nitrate [NOx]) were measured before and immediately after each test. AOPP (+24%, P<0.001), CAT (+38%, P<0.001) and SOD (+12%, P=0.018) and NOx (+17%, P=0.024) significantly increased in response to exercise independently of condition and birth status. No difference in response to acute exercise in normoxia was noted between pre-term and full-term born adults in any of measured markers. Hypoxic exposure during exercise resulted in significant increase in AOPP (+45%, P=0.008), CAT (+55%, P=0.019) and a trend for an increase in nitrite/nitrate content (+35%, P=0.107) only in full-term and not pre-term born individuals. These results suggest that prematurely born adult individuals exhibit higher resistance to oxidative stress response to exercise in hypoxia.

Exercise Overrides Blunted Hypoxic Ventilatory Response in Prematurely Born Men.

PURPOSE: Pre-term birth provokes life-long anatomical and functional respiratory system sequelae. Although blunted hypoxic ventilatory response (HVR) is consistently observed in pre-term infants, it remains unclear if it persists with aging and, moreover, if it influences hypoxic exercise capacity. In addition, it remains unresolved whether the previously observed prematurity-related alterations in redox balance could contribute to HVR modulation. METHODS: Twenty-one prematurely born adult males (gestational age = 29 ± 4 weeks], and 14 age matched controls born at full term (gestational age = 39 ± 2 weeks) underwent three tests in a randomized manner: (1) hypoxia chemo-sensitivity test to determine the resting and exercise poikilocapnic HVR and a graded exercise test to volitional exhaustion in (2) normoxia (FiO2 = 0.21), and (3) normobaric hypoxia (FiO2 = 0.13) to compare the hypoxia-related effects on maximal aerobic power (MAP). Selected prooxidant and antioxidant markers were analyzed from venous samples obtained before and after the HVR tests. RESULTS: Resting HVR was lower in the pre-term (0.21 ± 0.21 L ⋅ min-1 ⋅ kg-1) compared to full-term born individuals (0.47 ± 0.23 L ⋅ min-1 ⋅ kg-1; p < 0.05). No differences were noted in the exercise HVR or in any of the measured oxidative stress markers before or after the HVR test. Hypoxia-related reduction of MAP was comparable between the groups. CONCLUSION: These findings indicate that blunted resting HVR in prematurely born men persists into adulthood. Also, active adults born prematurely seem to tolerate hypoxic exercise well and should, hence, not be discouraged to engage in physical activities in hypoxic environments. Nevertheless, the blunted resting HVR and greater desaturation observed in the pre-term born individuals warrant caution especially during prolonged hypoxic exposures.

Visualization-based cancer microarray data classification analysis.

MOTIVATION: Methods for analyzing cancer microarray data often face two distinct challenges: the models they infer need to perform well when classifying new tissue samples while at the same time providing an insight into the patterns and gene interactions hidden in the data. State-of-the-art supervised data mining methods often cover well only one of these aspects, motivating the development of methods where predictive models with a solid classification performance would be easily communicated to the domain expert. RESULTS: Data visualization may provide for an excellent approach to knowledge discovery and analysis of class-labeled data. We have previously developed an approach called VizRank that can score and rank point-based visualizations according to degree of separation of data instances of different class. We here extend VizRank with techniques to uncover outliers, score features (genes) and perform classification, as well as to demonstrate that the proposed approach is well suited for cancer microarray analysis. Using VizRank and radviz visualization on a set of previously published cancer microarray data sets, we were able to find simple, interpretable data projections that include only a small subset of genes yet do clearly differentiate among different cancer types. We also report that our approach to classification through visualization achieves performance that is comparable to state-of-the-art supervised data mining techniques. AVAILABILITY: VizRank and radviz are implemented as part of the Orange data mining suite (http://www.ailab.si/orange). SUPPLEMENTARY INFORMATION: Supplementary data are available from http://www.ailab.si/supp/bi-cancer.