Exhaled nitric oxide : Variability and association with bronchial hyperresponsiveness and atopy

Airway inflammation is a key feature of bronchial asthma. In asthma management, according to international guidelines, the gold standard is anti-inflammatory treatment. Currently, only conventional procedures (i.e., symptoms, use of rescue medication, PEF-variability, and lung function tests) were used to both diagnose and evaluate the results of treatment with anti-inflammatory drugs. New methods for evaluation of degree of airway inflammation are required. Nitric oxide (NO) is a gas which is produced in the airways of healthy subjects and especially produced in asthmatic airways. Measurement of NO from the airways is possible, and NO can be measured from exhaled air. Fractional exhaled NO (FENO) is increased in asthma, and the highest concentrations are measured in asthmatic patients not treated with inhaled corticosteroids (ICS). Steroid-treated patients with asthma had levels of FENO similar to those of healthy controls. Atopic asthmatics had higher levels of FENO than did nonatopic asthmatics, indicating that level of atopy affected FENO level. Associations between FENO and bronchial hyperresponsiveness (BHR) occur in asthma. The present study demonstrated that measurement of FENO had good reproducibility, and the FENO variability was reasonable both short- and long-term in both healthy subjects and patients with respiratory symptoms or asthma. We demonstrated the upper normal limit for healthy subjects, which was 12 ppb calculated from two different healthy study populations. We showed that patients with respiratory symptoms who did not fulfil the diagnostic criteria of asthma had FENO values significantly higher than in healthy subjects, but significantly lower than in asthma patients. These findings suggest that BHR to histamine is a sensitive indicator of the effect of ICS and a valuable tool for adjustment of corticosteroid treatment in mild asthma. The findings further suggest that intermittent treatment periods of a few weeks’ duration are insufficient to provide long-term control of BHR in patients with mild persistent asthma. Moreover, during the treatment with ICS changes in BHR and changes in FENO were associated. FENO level was associated with BHR measured by a direct (histamine challenge) or indirect method (exercise challenge) in steroid-naïve symptomatic, non-smoking asthmatics. Although these associations could be found only in atopics, FENO level in nonatopic asthma was also increased. It can thus be concluded that assessment of airway inflammation by measuring FENO can be useful for clinical purposes. The methodology of FENO measurements is now validated. Especially in those patients with respiratory symptoms who did not fulfil the diagnostic criteria of asthma, FENO measurement can aid in treatment decisions. Serial measurement of FENO during treatment with ICS can be a complementary or an alternative method for evaluation in patients with asthma.

Long time, no see? (DIY walking)

Building on the launch of an early prototype at Balance Unbalance 2013, we now offer a fully realised experience of the ‘Long Time, No See?’ site specific walking/visualisation project for conference users to engage with on a do it yourself basis, either before, during or after the event. ‘Long Time, No See?’ is a new form of participatory, environmental futures project, designed for individuals and groups. It uses a smartphone APP to guide processes of individual or group walking at any chosen location—encouraging walkers to think in radical new ways about how to best prepare for ‘stormy’ environmental futures ahead. As part of their personal journeys participants’ contribute site-specific micro narratives in the form of texts, images and sounds, captured via the APP during the loosely ‘guided’ walk. These responses are then uploaded and synthesised into an ever-building audiovisual and generative artwork/‘map’ of future-thinking affinities, viewable both online at long-time-no-see.org (in Chrome) (and at the same time on a large screen visualisations at QUT’s Cube Centre in Brisbane Australia). The artwork therefore spans both participants’ mobile devices and laptops. If desired outcomes can also be presented publicly in large screen format at the conference. ‘Long Time, No See?’ has been developed over the past two years by a team of leading Australian artists, designers, urban/environmental planners and programmers.

Reconstruction of past UV radiation

Solar ultraviolet (UV) radiation has a broad range of effects concerning life on Earth. Soon after the mid-1980s, it was recognized that the stratospheric ozone content was declining over large areas of the globe. Because the stratospheric ozone layer protects life on Earth from harmful UV radiation, this lead to concern about possible changes in the UV radiation due to anthropogenic activity. Initiated by this concern, many stations for monitoring of the surface UV radiation were founded in the late 1980s and early 1990s. As a consequence, there is an apparent lack of information on UV radiation further in the past: measurements cannot tell us how the UV radiation levels have changed on time scales of, for instance, several decades. The aim of this thesis was to improve our understanding of past variations in the surface UV radiation by developing techniques for UV reconstruction. Such techniques utilize commonly available meteorological data together with measurements of the total ozone column for reconstructing, or estimating, the amount of UV radiation reaching Earth's surface in the past. Two different techniques for UV reconstruction were developed. Both are based on first calculating the clear-sky UV radiation using a radiative transfer model. The clear-sky value is then corrected for the effect of clouds based on either (i) sunshine duration or (ii) pyranometer measurements. Both techniques account also for the variations in the surface albedo caused by snow, whereas aerosols are included as a typical climatological aerosol load. Using these methods, long time series of reconstructed UV radiation were produced for five European locations, namely Sodankylä and Jokioinen in Finland, Bergen in Norway, Norrköping in Sweden, and Davos in Switzerland. Both UV reconstruction techniques developed in this thesis account for the greater part of the factors affecting the amount of UV radiation reaching the Earth's surface. Thus, they are considered reliable and trustworthy, as suggested also by the good performance of the methods. The pyranometer-based method shows better performance than the sunshine-based method, especially for daily values. For monthly values, the difference between the performances of the methods is smaller, indicating that the sunshine-based method is roughly as good as the pyranometer-based for assessing long-term changes in the surface UV radiation. The time series of reconstructed UV radiation produced in this thesis provide new insight into the past UV radiation climate and how the UV radiation has varied throughout the years. Especially the sunshine-based UV time series, extending back to 1926 and 1950 at Davos and Sodankylä, respectively, also put the recent changes driven by the ozone decline observed over the last few decades into perspective. At Davos, the reconstructed UV over the period 1926-2003 shows considerable variation throughout the entire period, with high values in the mid-1940s, early 1960s, and in the 1990s. Moreover, the variations prior to 1980 were found to be caused primarily by variations in the cloudiness, while the increase of 4.5 %/decade over the period 1979-1999 was supported by both the decline in the total ozone column and changes in the cloudiness. Of the other stations included in this work, both Sodankylä and Norrköping show a clear increase in the UV radiation since the early 1980s (3-4 %/decade), driven primarily by changes in the cloudiness, and to a lesser extent by the diminution of the total ozone. At Jokioinen, a weak increase was found, while at Bergen there was no considerable overall change in the UV radiation level.

Involvement of Ca2+-dependent hyperpolarization in sleep duration in mammals

The detailed molecular mechanisms underlying the regulation of sleep duration in mammals are still elusive. To address this challenge, we constructed a simple computational model, which recapitulates the electrophysiological characteristics of the slow-wave sleep and awake states. Comprehensive bifurcation analysis predicted that a Ca2+-dependent hyperpolarization pathway may play a role in slow-wave sleep and hence in the regulation of sleep duration. To experimentally validate the prediction, we generate and analyze 21 KO mice. Here we found that impaired Ca2+-dependent K+ channels (Kcnn2 and Kcnn3), voltage-gated Ca2+ channels (Cacna1g and Cacna1h), or Ca2+/calmodulin-dependent kinases (Camk2a and Camk2b) decrease sleep duration, while impaired plasma membrane Ca2+ ATPase (Atp2b3) increases sleep duration. Pharmacological intervention and whole-brain imaging validated that impaired NMDA receptors reduce sleep duration and directly increase the excitability of cells. Based on these results, we propose a hypothesis that a Ca2+-dependent hyperpolarization pathway underlies the regulation of sleep duration in mammals.

Long-term effects of physical activity level on changes in healthy body mass index over 12 years in young adult women

Objectives To examine the effects of overall level and timing of physical activity (PA) on changes from a healthy body mass index (BMI) category over 12 years in young adult women. Patients and Methods Participants in the Australian Longitudinal Study on Women's Health (younger cohort, born 1973-1978) completed surveys between 2000 (age 22-27 years) and 2012 (age 34-39 years). Physical activity was measured in 2000, 2003, 2006, and 2009 and was categorized as very low, low, active, or very active at each survey, and a cumulative PA score for this 9-year period was created. Logistic regression was used to examine relationships between PA accumulated across all surveys (cumulative PA model) and PA at each survey (critical periods PA model), with change in BMI category (from healthy to overweight or healthy to obese) from 2000 to 2012. Results In women with a healthy BMI in 2000, there were clear dose-response relationships between accumulated PA and transition to overweight (P=.03) and obesity (P<.01) between 2000 and 2012. The critical periods analysis indicated that very active levels of PA at the 2006 survey (when the women were 28-33 years old) and active or very active PA at the 2009 survey (age 31-36 years) were most protective against transitioning to overweight and obesity. Conclusion These findings confirm that maintenance of very high PA levels throughout young adulthood will significantly reduce the risk of becoming overweight or obese. There seems to be a critical period for maintaining high levels of activity at the life stage when many women face competing demands of caring for infants and young children.

The relationships between work stressors and organizational performance in long-term care for elderly residents

This study investigates the relationships between work stressors and organizational performance in terms of the quality of care provided by the long-term care facilities. Work stressors are first examined in relation to the unit's structural factors, resident characteristics, and to the unit specialization. The study is completed by an investigation into the associations of work stressors such as job demands or time pressure, role ambiguity, resident-related stress, and procedural injustice to organizational performance. Also the moderating effect of job control in the job demands organizational performance relationship is examined. The study was carried out in the National Research and Development Centre for Welfare and Health (STAKES). Survey data were drawn from 1194 nursing employees in 107 residential-home and health-center inpatient units in 1999 and from 977 employees in 91 units in 2002. Information on the unit resident characteristics and the quality of care was provided by the Resident Assessment Instrument (RAI). The results showed that large unit size or lower staffing levels were not consistently related to work stressors, whereas the impairments in residents' physical functioning in particular initiated stressful working conditions for employees. However, unit specialization into dementia and psychiatric residents was found to buffer the effects that the resident characteristics had on employee appraisals of work stressors, in that a high proportion of behavioral problems was related to less time pressure and role conflicts for employees in specialized units. Unit specialization was also related to improved team climates and the organizational commitment of employees. Work stressors associated with problems in care quality. Time pressure explained most of the differences between units in how the employees perceived the quality of physical and psychosocial care they provide for the residents. A high level of job demands in the unit was also found to be related to some increases in all clinical quality problems. High job control buffered the effects of job demands on the quality of care in terms of the use of restraints on elderly residents. Physical restraint and especially antipsychotic drug use were less prevalent in units that combined both high job demands and high control for employees. In contrast, in high strain units where heavy job demands coincided with a lack of control for employees, quality was poor in terms of the frequent use of physical restraints. In addition, procedural injustice was related to the frequent use of antianxiety of hypnotic drugs for elderly residents. The results suggest that both job control and procedural justice may have improved employees' abilities to cope when caring for the elderly residents, resulting in better organizational performance.

Visual performance at passive level crossings with long sighting distances

The third edition of the Australian Standard AS1742 Manual of Uniform Traffic Control Devices Part 7 provides a method of calculating the sighting distance required to safely proceed at passive level crossings based on the physics of moving vehicles. This required distance becomes greater with higher line speeds and slower, heavier vehicles so that it may return quite a long sighting distance. However, at such distances, there are also concerns around whether drivers would be able to reliably identify a train in order to make an informed decision regarding whether it would be safe to proceed across the level crossing. In order to determine whether drivers are able to make reliable judgements to proceed in these circumstances, this study assessed the distance at which a train first becomes identifiable to a driver as well as their, ability to detect the movement of the train. A site was selected in Victoria, and 36 participants with good visual acuity observed 4 trains in the 100-140 km/h range. While most participants could detect the train from a very long distance (2.2 km on average), they could only detect that the train was moving at much shorter distances (1.3 km on average). Large variability was observed between participants, with 4 participants consistently detecting trains later than other participants. Participants tended to improve in their capacity to detect the presence of the train with practice, but a similar trend was not observed for detection of the movement of the train. Participants were consistently poor at accurately judging the approach speed of trains, with large underestimations at all investigated distances.

Stochastic simulations of the origins and implications of long-tailed distributions in gene expression

Gene expression noise results in protein number distributions ranging from long-tailed to Gaussian. We show how long-tailed distributions arise from a stochastic model of the constituent chemical reactions and suggest that, in conjunction with cooperative switches, they lead to more sensitive selection of a subpopulation of cells with high protein number than is possible with Gaussian distributions. Single-cell-tracking experiments are presented to validate some of the assumptions of the stochastic simulations. We also examine the effect of DNA looping on the shape of protein distributions. We further show that when switches are incorporated in the regulation of a gene via a feedback loop, the distributions can become bimodal. This might explain the bimodal distribution of certain morphogens during early embryogenesis.

Ring loading of a long, thin, circular cylindrical shell enclosing a soft, solid core: A recalculation by the love function method of elasticity.

The problem is solved using the Love function and Flügge shell theory. Numerical work has been done with a computer for various values of shell geometry parameters and elastic constants.

Duration of a lightning flash

The mean duration of a lightning flash is observed to exhibit systematic variation with the growth and decay of the activity of a thundercloud and reaches a minimum value when the radio noise level and rate of flashing are at their maximum values.

Search for Long-Lived Massive Charged Particles in 1.96 TeV pp̅ Collisions

We performed a signature-based search for long-lived charged massive particles (CHAMPs) produced in 1.0 $\rm{fb}^{-1}$ of $\bar{p}p$ collisions at $\sqrt{s}=1.96$ TeV, collected with the CDF II detector using a high transverse-momentum ($p_T$) muon trigger. The search used time-of-flight to isolate slowly moving, high-$p_T$ particles. One event passed our selection cuts with an expected background of $1.9 \pm 0.2$ events. We set an upper bound on the production cross section, and, interpreting this result within the context of a stable scalar top quark model, set a lower limit on the particle mass of 249 GeV/$c^2$ at 95% C.L.

Stimulation by thyrotropin, long-acting thyroid stimulator, and dibutyryl 3′, 5′-adenosine monophosphate of protein and ribonucleic acid synthesis and ribonucleic acid polymerase activities in porcine thyroid in Vitro

The in vitro incorporation of [3H]uridine into RNA and [3H]leucine into protein in slices of porcine thyroid was studied. Thyrotropin (10-500 mU/ml of medium), when added with [3H]uridine, inhibited incorporation into RNA, but as little as 10 mU of thyrotropin per ml stimulated incorporation of [3H]orotic acid into RNA. Uridine kinase (EC 2.7.1.48) was found to be inhibited in slices incubated with thyrotropin whereas UMP 5′ nucleotidase (EC 2.1.3.5) was not. Preincubation of slices with thyrotropin (5-50 mU/ml) led to enhanced incorporation of subsequently added [3H]uridine and [3H]leucine. When slices were preincubated with long-acting thyroid stimulator-IgG (2.5 or 5 mg per ml of medium) incorporation of [3H]uridine and [3H]leucine was similarly enhanced, with the smaller concentration being more effective. Without preincubation these stimulatory effects were mimicked by 1 mM dibutyryl 3′,5′-AMP and, to a lesser extent, 1 mM 3′,5′-AMP. AMP and ATP also stimulated [3H]uridine incorporation in this system but only after more prolonged periods of incubation than were required for the other nucleotides. RNA polymerase (EC 2.7.7.6) activity measured in isolated thyroid nuclei had two components, one Mg2+-stimulated and the other requ ring Mn2+ and high salt content [0.4 M (NH4)2SO4]. These activities, and particularly the former, were enhanced if thyroid slices were incubated with thyrotropin (5-100 mU/ml of medium), 2.5 mg or 5.0 mg of long-acting thyroid stimulator-IgG per ml, or 1 mM dibutyryl 3′,5′-AMP, before isolatior of the nuclei and measurement of enzyme activities; 1 mM AMP, ADP, or 2′,3′-GMP had no influence. Added directly to the nuclei, thyrotropin, long-acting thyroid stimulator-IgG, and dibutyryl 3′,5′-AMP had no effect on RNA polymerase activities. These data are seen as affording evidence for mediation by 3′,5′-AMP of effects of thyrotropin and long-acting thyroid stimulator on thyroid RNA and protein synthesis, at least in part through an indirect stimulation of nuclear RNA polymerase activities.

Very Low Birth Weight Infants as Young Adults : Focus on aspects of cognition, behavior and sleep

Major advances in the treatment of preterm infants have occurred during the last three decades. Survival rates have increased, and the first generations of preterm infants born at very low birth weight (VLBW; less than 1500 g) who profited from modern neonatal intensive care are now in young adulthood. The literature shows that VLBW children achieve on average lower scores on cognitive tests, even after exclusion of individuals with obvious neurosensory deficits. Evidence also exists for an increased risk in VLBW children for various neuropsychiatric disorders such as attention-deficit hyperactivity disorder (ADHD) and related behavioral symptoms. Up till now, studies extending into adulthood are sparse, and it remains to be seen whether these problems persist into adulthood. The aim of this thesis was to study ADHD-related symptoms and cognitive and executive functioning in young adults born at VLBW. In addition, we aimed to study sleep disturbances, known to adversely affect both cognition and attention. We hypothesized that preterm birth at VLBW interferes with early brain development in a way that alters the neuropsychological phenotype; this may manifest itself as ADHD symptoms and impaired cognitive abilities in young adulthood. In this cohort study from a geographically defined region, we studied 166 VLBW adults and 172 term-born controls born from 1978 through 1985. At ages 18 to 27 years, the study participants took part in a clinic study during which their physical and psychological health was assessed in detail. Three years later, 213 of these individuals participated in a follow-up. The current study is part of a larger research project (The Helsinki Study of Very Low Birth Weight Adults), and the measurements of interest for this particular study include the following: 1) The Adult Problem Questionnaire (APQ), a self-rating scale of ADHD-related symptoms in adults; 2) A computerized cognitive test battery designed for population studies (CogState®) which measures core cognitive abilities such as reaction time, working memory, and visual learning; 3) Sleep assessment by actigraphy, the Basic Nordic Sleep Questionnaire, and the Morningness-Eveningness Questionnaire. Actigraphs are wrist-worn accelerometers that separate sleep from wakefulness by registering body movements. Contrary to expectations, VLBW adults as a group reported no more ADHD-related behavioral symptoms than did controls. Further subdivision of the VLBW group into SGA (small for gestational age) and AGA (appropriate for gestational age) subgroups, however, revealed more symptoms on ADHD subscales pertaining to executive dysfunction and emotional instability among those born SGA. Thus, it seems that intrauterine growth retardation (for which SGA served as a proxy) is a more essential predictor for self-perceived ADHD symptoms in adulthood than is VLBW birth as such. In line with observations from other cohorts, the VLBW adults reported less risk-taking behavior in terms of substance use (alcohol, smoking, and recreational drugs), a finding reassuring for the VLBW individuals and their families. On the cognitive test, VLBW adults free from neurosensory deficits had longer reaction times than did term-born peers on all tasks included in the test battery, and lower accuracy on the learning task, with no discernible effect of SGA status over and above the effect of VLBW. Altogether, on a group level, even high-functioning VLBW adults show subtle deficits in psychomotor processing speed, visual working memory, and learning abilities. The sleep studies provided no evidence for differences in sleep quality or duration between the two groups. The VLBW adults were, however, at more than two-fold higher risk for sleep-disordered breathing (in terms of chronic snoring). Given the link between sleep-disordered breathing and health sequelae, these results suggest that VLBW individuals may benefit from an increased awareness among clinicians of this potential problem area. An unexpected finding from the sleep studies was the suggestion of an advanced sleep phase: The VLBW adults went to bed earlier according to the actigraphy registrations and also reported earlier wake-up times on the questionnaire. In further study of this issue in conjunction with the follow-up three years later, the VLBW group reported higher levels of morningness propensity, further corroborating the preliminary findings of an advanced sleep phase. Although the clinical implications are not entirely clear, the issue may be worth further study, since circadian rhythms are closely related to health and well-being. In sum, we believe that increased understanding of long-term outcomes after VLBW, and identification of areas and subgroups that are particularly vulnerable, will allow earlier recognition of potential problems and ultimately lead to improved prevention strategies.