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Structural variants are associated with cancers and developmental disorders, but challenges with estimating population frequency remain a barrier to prioritizing mutations over inherited variants. In particular, variability in variant calling heuristics and filtering limits the use of current structural variant catalogs. We present STIX, a method that, instead of relying on variant calls, indexes and searches the raw alignments from thousands of samples to enable more comprehensive allele frequency estimation.

Background Anti-vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKI) combined with mTOR inhibitors, like everolimus, result in significant responses and prolonged progression-free survival (PFS) among patients with renal cell carcinoma (RCC) [1]. However, everolimus doses >5 mg are often not tolerated when combined with other TKIs2,3. Vorolanib (X-82), an oral anti-VEGFR/platelet derived growth factor receptor (PDGFR)/colony stimulating factor 1 receptor (CSF1R) multitarget TKI, has a short half-life and limited tissue accumulation. We conducted a Phase 1 study of vorolanib with everolimus (10 mg daily) in patients with solid tumors. Methods A 3 + 3 dose escalation design was utilized to determine dose limiting toxicities (DLT) and recommended Phase 2 dose (RP2D) of vorolanib/everolimus. Oral vorolanib at 100, 150, 200, 300, or 400 mg was combined with 10 mg oral everolimus daily. The phase 2 portion was terminated after enrolling two patients due to funding. Results Eighteen patients were evaluable for DLT among 22 treated subjects. Observed DLTs were grade 3 fatigue, hypophosphatemia, and mucositis. The RP2D is vorolanib 300 mg with everolimus 10 mg daily. In 15 patients evaluable for response, three had partial response (PR; 2 RCC, 1 neuroendocrine tumor [NET]) and eight had stable disease (SD; 2 RCC, 6 NET). Conclusions Vorolanib can safely be combined with everolimus. Encouraging activity is seen in RCC and NET. Further studies are warranted. Trial Registration Number: NCT01784861.

Programmed cell death 1 (PD-1) inhibitors have limited effect in pancreatic ductal adenocarcinoma (PDAC), underscoring the need to co-target alternative pathways. CXC chemokine receptor 4 (CXCR4) blockade promotes T cell tumor infiltration and is synergistic with anti-PD-1 therapy in PDAC mouse models. We conducted a phase IIa, open-label, two-cohort study to assess the safety, efficacy and immunobiological effects of the CXCR4 antagonist BL-8040 (motixafortide) with pembrolizumab and chemotherapy in metastatic PDAC (NCT02826486). The primary outcome was objective response rate (ORR). Secondary outcomes were overall survival (OS), disease control rate (DCR) and safety. In cohort 1, 37 patients with chemotherapy-resistant disease received BL-8040 and pembrolizumab. The DCR was 34.5% in the evaluable population (modified intention to treat, mITT; N = 29), including nine patients (31%) with stable disease and one patient (3.4%) with partial response. Median OS (mOS) was 3.3 months in the ITT population. Notably, in patients receiving study drugs as second-line therapy, the mOS was 7.5 months. BL-8040 increased CD8+ effector T cell tumor infiltration, decreased myeloid-derived suppressor cells (MDSCs) and further decreased circulating regulatory T cells. In cohort 2, 22 patients received BL-8040 and pembrolizumab with chemotherapy, with an ORR, DCR and median duration of response of 32%, 77% and 7.8 months, respectively. These data suggest that combined CXCR4 and PD-1 blockade may expand the benefit of chemotherapy in PDAC and warrants confirmation in subsequent randomized trials. Results from the phase IIa COMBAT trial combining CXCR4 and PD-1 inhibition in patients with metastatic cancer show encouraging clinical responses in association with enhanced antitumor immune activation.

The population of raccoon dogs (Nyctereutes procyonoides) in Denmark has increased rapidly from 1995 when the first was recorded until today where 3291 raccoon dogs are trapped, shot by hunters or road killed. The aims of this study are to present the first data on reproduction and life tables of raccoon dogs in Denmark and to compare mortality from modelled life tables with game bag records and sampled raccoon dogs in different age groups. In this study, the uteri of 89 adult females (> 10 months) were examined for placental scars (PSC), and 561 individuals (289 males, 272 females) were aged using pulp cavity width and dental lines in canine teeth. The litter size of raccoon dogs in Denmark is to date the largest litter size recorded in the wild (mean ± SE) 10.8 ± 0.4, range 1–16 pubs and fecundity 8.4 ± 0.6 pubs. The percent-reproducing females are 78–83%, based on dark and all PSC, respectively. A significant difference was found between the proportion of individuals composing the different age groups based on age determination of individuals collected (Ntage) and the modelled number of individuals in age groups based on fecundity and different mortality rate (Ntmodel), X2 = 8, p < 0.05. The discrepancy between the relatively high reproduction and lifetables may be due to older and more experienced animals that avoid culling. A low population density in a newly founded Danish population of raccoon dogs, together with a milder climate where raccoon dogs can forage during the winter, may cause an exceptionally high reproduction in Danish raccoon dogs.

Background When interpreting sequencing data from multiple spatial or longitudinal biopsies, detecting sample mix-ups is essential, yet more difficult than in studies of germline variation. In most genomic studies of tumors, genetic variation is detected through pairwise comparisons of the tumor and a matched normal tissue from the sample donor. In many cases, only somatic variants are reported, which hinders the use of existing tools that detect sample swaps solely based on genotypes of inherited variants. To address this problem, we have developed Somalier, a tool that operates directly on alignments and does not require jointly called germline variants. Instead, Somalier extracts a small sketch of informative genetic variation for each sample. Sketches from hundreds of germline or somatic samples can then be compared in under a second, making Somalier a useful tool for measuring relatedness in large cohorts. Somalier produces both text output and an interactive visual report that facilitates the detection and correction of sample swaps using multiple relatedness metrics. Results We introduce the tool and demonstrate its utility on a cohort of five glioma samples each with a normal, tumor, and cell-free DNA sample. Applying Somalier to high-coverage sequence data from the 1000 Genomes Project also identifies several related samples. We also demonstrate that it can distinguish pairs of whole-genome and RNA-seq samples from the same individuals in the Genotype-Tissue Expression (GTEx) project. Conclusions Somalier is a tool that can rapidly evaluate relatedness from sequencing data. It can be applied to diverse sequencing data types and genome builds and is available under an MIT license at github.com/brentp/somalier.

PURPOSE: Patient-reported health-related quality of life is a complementary healthcare outcome and important when assessing treatment efficacy. Using COSMIN methodological recommendations, this study evaluates the validity and reliability of a core heart disease-specific health-related quality of life questionnaire, the HeartQoL questionnaire (Danish version) in a sample of patients following heart valve surgery.DESIGN: This project involved a cross-sectional validity study and a test-retest reliability study.METHODS: Eligible patients completed the HeartQoL, the SF-36 health survey questionnaire, and the Hospital Anxiety and Depression Scale following heart valve surgery. Construct validity was tested using a priori hypotheses. Internal consistency reliability was assessed with Cronbach's alpha. An independent sample of patients participated in the test-retest study and reproducibility was determined with relative [intra-class correlation coefficient (ICC)] and absolute reliability [standard error of measurement (SEM) and smallest detectable change (SDC)].RESULTS: Internal consistency was high with Cronbach's alpha ≥ 0.87. ICC was 0.86-0.92. SEM ranged from 0.17 to 0.26 points and SDC ranged from 0.5 to 0.7 points. Construct validity was confirmed with 87% of all a priori hypotheses for predicted variables.CONCLUSIONS: The HeartQoL questionnaire demonstrates acceptable construct validity, internal consistency, and test-retest reproducibility in patients following heart valve surgery. Future studies should focus on assessing the responsiveness of the HeartQoL questionnaire over time and following heart valve surgery.

The invasive garden ant, Lasius neglectus, is the most recently detected pest ant and the first known invasive ant able to become established and thrive in the temperate regions of Eurasia. In this study, we aim to reconstruct the invasion history of this ant in Europe analysing 14 populations with three complementary approaches: genetic microsatellite analysis, chemical analysis of cuticular hydrocarbon profiles and behavioural observations of aggression behaviour. We evaluate the relative informative power of the three methodological approaches and estimate both the number of independent introduction events from a yet unknown native range somewhere in the Black Sea area, and the invasive potential of the existing introduced populations.Three clusters of genetically similar populations were detected, and all but one population had a similar chemical profile. Aggression between populations could be predicted from their genetic and chemical distance, and two major clusters of non-aggressive groups of populations were found. However, populations of L. neglectus did not separate into clear supercolonial associations, as is typical for other invasive ants.The three methodological approaches gave consistent and complementary results. All joint evidence supports the inference that the 14 introduced populations of L. neglectus in Europe likely arose from only very few independent introductions from the native range, and that new infestations were typically started through introductions from other invasive populations. This indicates that existing introduced populations have a very high invasive potential when the ants are inadvertently spread by human transport.

BACKGROUND: Factors associated with development of medication-overuse headache (MOH) in migraine patients are not fully understood, but with respect to prevention, the ability to predict the onset of MOH is clinically important. The aims were to examine if personality characteristics, disability and physical activity level are associated with the onset of MOH in a group of migraine patients and explore to which extend these factors combined can predict the onset of MOH.METHODS: The study was a single-center prospective observational study of migraine patients. At inclusion, all patients completed questionnaires evaluating 1) personality (NEO Five-Factor Inventory), 2) disability (Migraine Disability Assessment), and 3) physical activity level (Physical Activity Scale 2.1). Diagnostic codes from patients' electronic health records confirmed if they had developed MOH during the study period of 20 months. Analyses of associations were performed and to identify which of the variables predict onset MOH, a multivariable least absolute shrinkage and selection operator (LASSO) logistic regression model was fitted to predict presence or absence of MOH.RESULTS: Out of 131 participants, 12 % (n=16) developed MOH. Migraine disability score (OR=1.02, 95 % CI: 1.00 to 1.04), intensity of headache (OR=1.49, 95 % CI: 1.03 to 2.15) and headache frequency (OR=1.02, 95 % CI: 1.00 to 1.04) were associated with the onset of MOH adjusting for age and gender. To identify which of the variables predict onset MOH, we used a LASSO regression model, and evaluating the predictive performance of the LASSO-mode (containing the predictors MIDAS score, MIDAS-intensity and -frequency, neuroticism score, time with moderate physical activity, educational level, hours of sleep daily and number of contacts to the headache clinic) in terms of area under the curve (AUC) was weak (apparent AUC=0.62, 95% CI: 0.41-0.82).CONCLUSION: Disability, headache intensity and frequency were associated with the onset of MOH whereas personality and the level of physical activity were not. The multivariable LASSO model based on personality, disability and physical activity is applicable despite moderate study size, however it can be considered as a weak classifier for discriminating between absence and presence of MOH.

© 2015, Springer Science+Business Media New York. Ag triangular nanoplates are known to generate strong plasmonic resonances when excited by both light and electron beams. Experimental electron energy-loss spectra (EELS) and maps were acquired using an aberration-corrected JEOL-ARM microscope. The corner, edge and centre modes that are often observed in such structures were also observed in these measurements. In addition, novel higher order internal modes were observed and were found to be well reproduced by theoretical calculations using boundary element method (BEM). These modes are “dark modes” so are not observed in the optical extinction spectra. They are confined surface propagating modes and are analogous to laser cavity modes.

Background: Changes in the coagulation system in patients undergoing surgery for lung cancer have been sparsely investigated and the impact of the surgical trauma on the coagulation system is largely unknown in these patients. An increased knowledge could potentially improve the thromboprophylaxis regimes. The aim of this study was to assess the coagulation profile evoked in patients undergoing curative surgery by Video-Assisted Thoracoscopic Surgery (VATS) lobectomy for primary lung cancer.Methods: Thirty-one patients diagnosed with primary lung cancer undergoing VATS lobectomy were prospectively included. The coagulation profile was assessed preoperatively and in the first two days postoperatively using a wide range of standard coagulation tests, dynamic whole blood coagulation measured by rotational thromboelastometry (ROTEM®) and thrombin generation evaluated by calibrated automated thrombography. Patients did not receive thromboprophylactic treatment. Data was analyzed using repeated measures one-way ANOVA.Results: The standard coagulation parameters displayed only subtle changes after surgery and the ROTEM® and thrombin generation results remained largely unchanged.Conclusions: Patients undergoing VATS lobectomy are normocoagulable in the preoperative state and a VATS lobectomy does not significantly influence the coagulation.Trial registration: The trial is registered at ClinicalTrials.gov (Identifier: NCT01741506) and at EudraCTno. 2012-002409-23. Registered December 2012.

Ant supercolonies (large networks of interconnected nests) represent the most extreme form of multi-queen breeding (polygyny) and have been found across ant lineages, usually in specific long-term stable populations. Many studies on the genetic population structure and demography of ant supercolonies have been done in recent decades, but they have lacked multicolonial control patches with separated colonies headed by a single or few queens so the origin of the supercolonial trait syndrome has remained enigmatic. Here, we set out to compare sympatric supercolonial and multicolonial patches in two natural Danish populations of the common red ant Myrmica rubra. We used DNA microsatellites to reconstruct genetic colony/population structure and obtained morphological and density measurements to estimate life history and ecology covariates. We found that supercolonies in both populations completely dominated their patches whereas colonies in multicolonial patches coexisted with other ant species. Supercolony patches had very low genetic differentiation between nests, negligible relatedness within nests, and lower inbreeding than multicolonial patches, but there were no significant morphological differences. One population also had nests that approached true outbred monogyny with larger workers and males but smaller queens than in the two other social nest types. Our results suggest that once smaller colonies start to adopt additional queens, they also gain the potential to ultimately become supercolonial when the habitat allows rapid expansion through nest budding. This is relevant for understanding obligate polygyny in ants and for appreciating how and why introduced North American populations of M. rubra have recently become invasive.

Due to aging of the population and cardiotoxic cancer treatment, there is an increasing group of patients with cancer and co-morbid cardiovascular disease (CVD). In order to find a balance between the risk of undertreating the malignancy on the one hand and inducing CVD on the other hand, CVD risk stratification at the time of cancer diagnosis and knowledge on the pathway for developing incident CVD in cancer patients is vital. In this paper, we propose an adapted multiple-hit hypothesis for developing CVD in cancer patients describing that patients with cancer are exposed to a series of sequential or concurrent events that together make them more vulnerable to reduced cardiovascular reserves, development of incident CVD and ultimately death. We highlight the possible impact of psychological distress secondary to a cancer diagnosis and/or treatment, which in turn may increase the risk of incident CVD in patients diagnosed with cancer. Furthermore, we discuss potential behavioral and pathophysiological mechanisms underlying the link between psychological distress and the pathophysiology of incident CVD. In addition, key unanswered questions for future research are posed. In the future, researching the adapted multiple-hit hypothesis for developing CVD among cancer patients will hopefully advance the care of cancer patients by finding some of the missing pieces of the puzzle. To do so, we need to focus on minimizing cardiovascular risk and promoting cardiovascular health in cancer patients by addressing the knowledge gaps formulated in this paper.

The shrub Rosa rugosa (Japanese Rose), native to East Asia, is considered one of the most troublesome invasive plant species in natural or semi- natural habitats of northern Europe and has proven very difficult to control. We aimed at disentangling the species' invasion history in Europe, including deter- mining the number of introductions and their geo- graphic origin, and at investigating whether populations in the introduced and native ranges differ in genetic diversity, structure and degree of differentiation. We found that introduced (n = 16) and native (n = 16) populations had similar levels of genetic diversity at seven nuclear SSR (microsatellite) loci. European populations lack isolation by distance and are less genetically differentiated than are populations in East Asia. Multiple and at least three independent coloniza- tion events, one of which was particularly successful, gave rise to current R. rugosa populations in Europe. The geographic distribution patterns of these three genetic clusters could not be explained by natural dispersal alone, indicating that human mediated sec- ondary dispersal is driving the expansion in Europe. One cluster representing three of the European popu- lations was most likely derived from NW Japan, whereas the origin of the remaining thirteen populations could not clearly be resolved. The introduction and expansion in Europe occurred with no significant loss of genetic diversity. We conclude that high propagule pressure at the primary establishment phase is the most parsimonious explanation for this pattern. A potential for long distance seed dispersal, coastal habitat con- nectivity and an outcrossing breeding system are factors likely to have enabled populations of R. rugosa to avoid detrimental effects of genetic bottlenecks and will further increase the species' range size and abundance in Europe. We recommend that human-mediated dis- persal should be prevented in order to halt the continued expansion.

To determine via meta-analysis the diagnostic accuracy of 64-slice computed tomography coronary angiography (CTA) for assessment of significant obstructive coronary artery stenosis at different coronary artery calcium score (CACS) levels. Data of 12,053 versus 5,890 segments, 906 versus 758 arteries and 1,120 versus 514 patients in low versus high CACS subgroups from 19 eligible studies were compared. The per-patient prevalence of coronary artery disease was 48% versus 68%, respectively. Subgroups were stratified by different CACS thresholds ranging from 100 to 400. Meta-analyses of per-patient data comparing overall low versus high CACS subgroups resulted in a sensitivity of 97.5 (95.5–99)% versus 97 (94.5–98.5)%, specificity of 85 (82–88)% versus 66.5 (58–74.5)%, diagnostic odds ratio of 153 (81–290) versus 40 (20–83), positive predictive value of 85 (82–87)% versus 86 (84–88)%, negative predictive value of 97.5 (95–99)% versus 91 (88–94)% and overall accuracy of 91% versus 89% with 95% confidence interval, respectively. The drop in specificity was significant (P = 0.035), while the sensitivity and overall accuracy were insignificantly changed (P > 0.05). Meta-analyses of independent subgroups at CACS levels ≤10 and ≤100 demonstrated high specificities of 90 (94–100)% and 88.5 (81–91.5)%, whereas at CACS levels ≥400 the specificity declined significantly to 42 (28–56)% but with consistently retained high sensitivity of 97.5 (94–99)%. The specificity of CTA decreases with increasing CACS, while the sensitivity remains high independent of that. The suggested CACS thresholds are arbitrary and do not necessarily warrant cancelling angiography. Diagnostic studies are needed to explore whether a specific CACS threshold may serve as a pre-angiographic gatekeeper to prevent likely equivocal angiographies.

Purpose The effectiveness of cardiac rehabilitation (CR) in patients with coronary artery disease (CAD) is moderated by negative emotions and clinical factors, but no studies evaluated the role of positive emotions. This study examined whether anhedonia (i.e. the lack of positive affect) moderated the effectiveness of CR on health status and somatic and cognitive symptoms. Methods CAD patients (n = 368) filled out the Hospital Anxiety and Depression Scale (HADS) to assess anhedonia at the start of CR, and the Short-Form Health Survey (SF-36) and the Health Complaints Scale (HCS) at the start of CR and at 3 months to assess health status and somatic and cognitive symptoms, respectively. Results Adjusting for clinical and demographic factors, health status improved significantly during the follow-up (F(1,357) = 10.84, P = .001). Anhedonic patients reported poorer health status compared with non-anhedonic patients, with anhedonia exerting a stable effect over time (F(1,358) = 34.80, P

The success of an ant colony depends on the simultaneous presence of reproducing queens and non-reproducing workers in a ratio that will maximize colony growth and reproduction. Despite its presumably crucial role, queen–worker caste ratios (the ratio of adult queens to workers) and the factors affecting this variable remain scarcely studied. Maintaining polygynous pharaoh ant (Monomorium pharaonis) colonies in the laboratory has provided us with the opportunity to experimentally manipulate colony size, one of the key factors that can be expected to affect colony level queen–worker caste ratios and body size of eclosing workers, gynes and males. We found that smaller colonies produced more new queens relative to workers, and that these queens and workers both tended to be larger. However, colony size had no effect on the size of males or on the sex ratio of the individuals reared. Furthermore, for the first time in a social insect, we confirmed the general life history prediction by Smith and Fretwell (Am Nat 108:499–506, 1974) that offspring number varies more than offspring size. Our findings document a high level of plasticity in energy allocation toward female castes and suggest that polygynous species with budding colonies may adaptively adjust caste ratios to ensure rapid growth.

We find great value in the genomes from the nonmodel organisms papaya and grape. These genomes help us understand the chromosomal history of the super-order rosids. Essential to this process are new, online genomics tools that allow researchers to easily perform their own experiments, such as identifying and evaluating syntenic regions and estimating the degree of post-tetraploidy gene fractionation (diploidization); this process is exemplified here using the online comparative genomics toolset CoGe. Using case studies, we show that two of the three genomes within the rosid paleohexaploid are more fractionated with respect to one another than to a third genome. This indicates a shared history derived from a [tetraploid]-then-[wide cross to generate a triploid]-then-[whole genome duplication to generate the hexaploid,] or similar scenario involving unreduced gametes. Two alternative hypotheses are presented that differ in terms of the mechanism and timing of fractionation.

Udgivelsesdato: November Evolutionary trees describing the relationship for a set of species are central in evolutionary biology, and quantifying differences between evolutionary trees is therefore an important task. The quartet distance is a distance measure between trees previously proposed by Estabrook, McMorris, and Meacham. The quartet distance between two unrooted evolutionary trees is the number of quartet topology differences between the two trees, where a quartet topology is the topological subtree induced by four species. In this paper we present an algorithm for computing the quartet distance between two unrooted evolutionary trees of n species, where all internal nodes have degree three, in time O(n log n. The previous best algorithm for the problem uses time O(n 2).

The emergence of ‘alternative’ investment opportunities, the current bear market and the Wall Street analysts' conflict of interest debacle have put pressure on current investment performance measurement methodologies. This paper presents a survey of classic and modern performance measures and assesses them against objective criteria. Depending upon the market, industry or group of assets studied and the preferences of investors, different measures gain favour, and key questions to address when selecting an appropriate performance measure are proposed. The arguments are demonstrated empirically for the global financial services sector, for which strong evidence in support of using Sharpe ratio-based measures is documented. As a comparison, the paper also looks at firms listed on the UK Alternative Investment Market (AIM), for which a divergence of rankings based on alternative measures is illustrated. General implications for risk management and asset allocations across different asset classes are discussed.

Background In animal studies, perfluorinated alkyl substances affect growth and neuro-behavioural outcomes. Human epidemiological studies are sparse. The aim was to investigate the association between pregnancy serum concentrations of perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) and offspring behaviour and motor development at 5–9 years of age. Methods Maternal sera from the INUENDO cohort (2002–2004) comprising 1,106 mother-child pairs from Greenland, Kharkiv (Ukraine) and Warsaw (Poland) were analysed for PFOS and PFOA, using liquid-chromatography-tandem-mass-spectrometry. Exposures were grouped into country specific as well as pooled tertiles as well as being used as continuous variables for statistical analyses. Child motor development and behaviour at follow-up (2010–2012) were measured by the Developmental Coordination Disorder Questionnaire 2007 (DCDQ) and Strength and Difficulties Questionnaire (SDQ), respectively. Exposure-outcome associations were analysed by multiple logistic and linear regression analyses. Results In the pooled analysis, odds ratio (OR) (95% confidence interval (CI)) for hyperactivity was 3.1 (1.3, 7.2) comparing children prenatally exposed to the highest PFOA tertile with those exposed to the lowest PFOA tertile. Comparing children in the highest PFOS tertile with those in the lowest PFOS tertile showed elevated but statistically non-significant OR of hyperactivity (OR (95% CI) 1.7 (0.9, 3.2)). In Greenland, elevated PFOS was associated with higher SDQ-total scores indicating more behavioural problems (β (95% CI) =1.0 (0.1, 2.0)) and elevated PFOA was associated with higher hyperactivity sub-scale scores indicating more hyperactive behaviour (β (95% CI) = 0.5 (0.1, 0.9)). Prenatal PFOS and PFOA exposures were not associated with motor difficulties. Conclusions Prenatal exposure to PFOS and PFOA may have a small to moderate effect on children’s neuro-behavioural development, specifically in terms of hyperactive behaviour. The associations were strongest in Greenland where exposure contrast is largest. Electronic supplementary material The online version of this article (doi:10.1186/1476-069X-14-2) contains supplementary material, which is available to authorized users.

As wealth increases, preference of one fixed gamble over another typically changes once or not at all. A key question is whether certain assumptions on preferences guarantee such behaviour. Bell [Management Science, 34(12), 1416–1424, 1988; 41, 1145–1150, 1995a; 41(1), 23–30, 1995b] has addressed this difficult question and characterised the specific functional form of utility functions which allow a finite number of switches between two arbitrary gambles over the entire range of initial wealth. By extending this analysis, and linking the discussion to more recent works, the authors characterise conditions under which a large set of utility functions with respect to their switching characteristics, and discuss the results in the context of the classical notion of decreasing absolute risk aversion. The Geneva Papers on Risk and Insurance Theory (2001) 26, 175–193. doi:10.1023/A:1015225616695

Differential Scanning Calorimetric measurements were performed for accurate determination of the solidus and liquidus temperature of Sn–Pb alloys. The difference between onset and end temperature of the melting peak depended clearly on alloy composition. The results obtained were found to be in good agreement with the existing equilibrium phase diagram for the Sn–Pb system, although the data suggested a slight correction of the eutectic composition. Under cooling conditions a large variation in the onset temperature for solidification was found. A large number of heating and cooling cycles were performed in order to investigate the statistical variation of the solid nucleation process.

Standard geostatistical methods for simulation of heterogeneity were applied to the Romeriksporten tunnel in Norway, where water was leaking through high-permeable fracture zones into the tunnel while it was under construction, causing drainage problems on the surface. After the tunnel was completed, artificial infiltration of water into wells drilled from the tunnel was implemented to control the leakage. Synthetic heterogeneity was generated at a scale sufficiently small to simulate the effects of remedial actions that were proposed to control the leakage. The flow field depends on the variance of permeabilities and the covariance model used to generate the heterogeneity. Flow channeling is the most important flow mechanism if the variance of the permeability field is large compared to the expected value. This condition makes the tunnel leakage difficult to control. The main effects of permeability changes due to sealing injection are simulated by a simple perturbation of the log-normal probability density function of the permeability. If flow channeling is the major transport mechanism of water into the tunnel, implementation of artificial infiltration of water to control the leakage requires previous chemical-sealing injection to be successful.

Udgivelsesdato: 2000-Oct We have determined the cDNA sequence and exon/intron structure of the human CLPX gene encoding a human ortholog of the E. coli ClpX chaperone and protease subunit. The CLPX gene comprises 14 exons and encodes a 633-amino acid-long precursor polypeptide. The polypeptide contains an N-terminal putative mitochondrial transit peptide, and expression of a full-length ClpX cDNA tagged at its C-terminus (Myc-His) shows that the polypeptide is transported into mitochondria. FISH analysis localized the CLPX gene to human Chromosome (Chr) 15q22.1-22.32. This localization was refined by radiation hybrid mapping placing the CLPX gene 4.6 cR distal to D15S159. Murine ClpX cDNA was sequenced, and the mouse Clpx locus was mapped to a position between 31 and 42 cM offset from the centromere on mouse Chr 9. Experimental observations indicate the presence of a pseudogene in the mouse genome and sequence variability between mouse ClpX cDNAs from different strains. Alignment of the human and mouse ClpX amino acid sequences with ClpX sequences from other organisms shows that they display the typical modular organization of domains with one AAA(+) domain common to a large group of ATPases and several other domains conserved in ClpX orthologs linked by non-conserved sequences. Notably, a C-4 zinc finger type motif is recognized in human and mouse ClpX. This motif of so far unknown function is present only in a subset of the known ClpX sequences.

New S-DABOs with a long alkylating S-alkyl substituent showing antiretroviral activity against HIV-1 in the micromolar range were prepared from 5,6-disubstituted 4-oxo-2-thiopyrimidines and 1,7-dibromo-3,5-dioxaheptane. The analogues with an ethyl group in position 5 also showed activity in the micromolar range against a Tyr/8/Cys mutant strain of HIV-1. The S-DABO analogues showing activity against the HIV-1 RT mutant strain were transformed to the N-3 and N-1 ring closed 7-oxo-pyrimidino-1,3,5-oxathiazepines which surprisingly all showed activity against HIV-1 in the micromolar range, as well as against a Tyr/8/Cys mutant strain of HIV-1. Some analogues of S-DABO with a thien-2-ylmethyl residue in position 6 were synthesized and tested against HIV-1 wild type, but they showed less or comparable activities to those of the corresponding 6-benzyl analogues.

Detailed knowledge of the mating system in specific social insect populations is essential for testing general evolutionary hypotheses of multiple paternity in eusocial Hymenoptera. We have studied the mating frequency of queens in a polygynous population of the red ant Myrmica sulcinodis. Genetic mother-offspring analysis showed that double mating occurred at a considerable frequency, but that the effective number of queen-mates remained close to one. After quantifying the effects of multiple maternity (polygyny) and multiple paternity (polyandry) on the genetic diversity of workers, we conclude that multiple paternity in M. sulcinodis did not evolve as an adaptation to increase genetic variation within colonies. Contrary to the predictions from `genetic variability' hypotheses, we found a positive correlation between colony-specific queen number and the average number of mates per queen. Such positive association of queen number and frequency of multiple mating was also found after analysing comparative data across six species of Myrmica ants. These results suggest that resticted dispersal of young queens may be a common factor promoting both polygyny and polyandry at the same time, and that moderate degrees of multiple mating may be an unselected consequence of (1) mating at low cost when mating occurs close to the nest and (2) mating in swarms with a highly male biased operational sex ratio. Future comparative tests of genetic-variability hypotheses should therefore not include species with such evolutionary derived mating system characteristics.

Background Increased navicular drop is associated with increased risk of lower extremity overuse injuries and foot orthoses are often prescribed to reduce navicular drop. For laboratory studies, transparent shoes may be used to monitor the effect of orthoses but no clinically feasible methods exist. We have developed a stretch-sensor that allows for in-shoe measurement of navicular drop but the reliability and validity is unknown. The purpose of this study was to investigate: 1) the reliability of the stretch-sensor for measuring navicular drop, and 2) the concurrent validity of the stretch-sensor compared to the static navicular drop test. Methods Intra- and inter-rater reliability was tested on 27 participants walking on a treadmill on two separate days. The stretch-sensor was positioned 20 mm posterior to the tip of the medial malleolus and 20 mm posterior to the navicular tuberosity. The participants walked six minutes on the treadmill before navicular drop was measured. Reliability was quantified by the Intraclass Correlation Coefficient (ICC 2.1) and agreement was quantified by Limits of Agreement (LOA). To assess concurrent validity, static navicular drop was measured with the stretch-sensor and compared with static navicular drop measured with a ruler on 27 new participants. Linear regression was used to measure concurrent validity. Results The reliability of the stretch-sensor was acceptable for barefoot measurement (intra- and inter-rater ICC: 0.76-0.84) but lower for in-shoe measurement (ICC: 0.65). There was a significant association between static navicular drop measured with the stretch-sensor compared with a ruler (r = 0.745, p Conclusion This study suggests that the stretch-sensor has acceptable reliability for dynamic barefoot measurement of navicular drop. Furthermore, the stretch-sensor shows concurrent validity compared with the static navicular drop test as performed by Brody. This new simple method may hold promise for both clinical assessment and research but more work is needed before the method can be recommended.

In children with asthma, twice daily administration of salmeterol 25 micrograms, salmeterol 50 micrograms and salbutamol 200 micrograms were compared in two, 3-month, double-blind, parallel group studies, one using metered dose inhalers (MDIs), the other using dry powder inhalers (Diskhaler, DPIs). Both studies were continued for a further 9 months during which time exacerbation rates, lung function at the clinic and adverse events were monitored. Similarities in design and methodology of the two studies justified a combined analysis. Eight hundred and forty-seven asthmatic children aged between 4 and 16 (mean 10.1) years, requiring inhaled beta 2-agonist treatment were randomised to treatment. After a 2 week run-in when all bronchodilator therapy was withdrawn, 279 patients received salmeterol 25 micrograms bd, 290 patients salmeterol 50 micrograms bd and 278 patients salbutamol 200 micrograms bd. After 3 months' treatment the change from baseline in daily morning and evening peak expiratory flow (PEF) was significantly greater with salmeterol 50 micrograms bd than with salbutamol 200 micrograms bd (P0.001). Salmeterol 50 micrograms bd was also significantly better than salmeterol 25 micrograms bd at improving mean morning PEF (P = 0.017) but both treatments had a similar effect on evening PEF. Analysis of variance showed an interaction between baseline PEF less than 100% predicted normal value and treatment outcome. Analysis of this sub-set of patients with lower lung function revealed similar results to the total population although the improvements in PEF from baseline were greater. Data from both studies, showed that the improvement in lung function was maintained throughout 12 months' treatment. Patients receiving salmeterol 50 micrograms bd had significantly more symptom-free nights (P0.01) and a higher percentage of rescue bronchodilator-free days (P = 0.01). The incidence of asthma exacerbations was evenly distributed between the three treatment groups and there was no evidence of any change in the rate of occurrence of exacerbations over the 12 month period. Adverse events were no different across treatment groups or across age groups and were primarily related to the patients' disease state.Salmeterol 50 micrograms bd is the appropriate dose for the treatment of children with mild to moderate asthma.

It is difficult to accurately interpret chromosomal correspondences such as true orthology and paralogy due to significant divergence of genomes from a common ancestor. Analyses are particularly problematic among lineages that have repeatedly experienced whole genome duplication (WGD) events. To compare multiple "subgenomes" derived from genome duplications, we need to relax the traditional requirements of "one-to-one" syntenic matchings of genomic regions in order to reflect "one-to-many" or more generally "many-to-many" matchings. However this relaxation may result in the identification of synteny blocks that are derived from ancient shared WGDs that are not of interest. For many downstream analyses, we need to eliminate weak, low scoring alignments from pairwise genome comparisons. Our goal is to objectively select subset of synteny blocks whose total scores are maximized while respecting the duplication history of the genomes in comparison. We call this "quota-based" screening of synteny blocks in order to appropriately fill a quota of syntenic relationships within one genome or between two genomes having WGD events. We have formulated the synteny block screening as an optimization problem known as "Binary Integer Programming" (BIP), which is solved using existing linear programming solvers. The computer program QUOTA-ALIGN performs this task by creating a clear objective function that maximizes the compatible set of synteny blocks under given constraints on overlaps and depths (corresponding to the duplication history in respective genomes). Such a procedure is useful for any pairwise synteny alignments, but is most useful in lineages affected by multiple WGDs, like plants or fish lineages. For example, there should be a 1:2 ploidy relationship between genome A and B if genome B had an independent WGD subsequent to the divergence of the two genomes. We show through simulations and real examples using plant genomes in the rosid superorder that the quota-based screening can eliminate ambiguous synteny blocks and focus on specific genomic evolutionary events, like the divergence of lineages (in cross-species comparisons) and the most recent WGD (in self comparisons). The QUOTA-ALIGN algorithm screens a set of synteny blocks to retain only those compatible with a user specified ploidy relationship between two genomes. These blocks, in turn, may be used for additional downstream analyses such as identifying true orthologous regions in interspecific comparisons. There are two major contributions of QUOTA-ALIGN: 1) reducing the block screening task to a BIP problem, which is novel; 2) providing an efficient software pipeline starting from all-against-all BLAST to the screened synteny blocks with dot plot visualizations. Python codes and full documentations are publicly available http://github.com/tanghaibao/quota-alignment . QUOTA-ALIGN program is also integrated as a major component in SynMap http://genomevolution.com/CoGe/SynMap.pl , offering easier access to thousands of genomes for non-programmers.

The purpose of this study was to characterize the ion conductances, in particular those for Cl- and K+, of human sweat duct cells grown in primary culture. Sweat duct cells from healthy individuals were grown to confluence on a dialysis membrane, which was then mounted in a mini-Ussing chamber and transepithelial and intracellular potentials were measured under open-circuit conditions. Under control conditions the epithelia developed mucosa-negative transepithelial potentials, Vte, of about -10 mV. The apical membrane potential, Va, was -25 mV to -30 mV (n = 97) in most cells, but several cells had a higher potential of about -55 mV (n = 29). Mucosal amiloride (10 mumol/l) hyperpolarized Va from -31 +/- 1 mV to a new sustained level of -46 +/- 2 mV (n = 36). These changes were accompanied by increase in the fractional resistance of the apical membrane, fRa, and decreases of Vte and the equivalent short-circuit current, Isc. In amiloride-treated tissues an increase in mucosal K+ concentration (5 mmol/l to 25 mmol/l) depolarized Va by 5 +/- 1 mV (n = 8), while the same step on the serosal side depolarized Va by 20 +/- 2 mV (n = 8). A Cl- channel blocker 3',5-dichlorodiphenylamine-2-carboxylate DCl-DPC; 10 mumol/l) depolarized Va by 5 +/- 1 mV (n = 6), an effect that was lost after amiloride application. The blocker had no effect from the serosal side. Reduction of mucosal Cl- (from 120 to 30 or 10 mmol/l) depolarized Va by 9-11 mV (n = 35), an effect that was often followed by a secondary hyperpolarization of 10-30 mV (n = 27).(ABSTRACT TRUNCATED AT 250 WORDS)

In addition to a single queen and workers, colonies of the ant Crematogaster smithi from the Chiricahua Mts., Arizona, may contain one or several "large workers". These are specialized for laying viable, unfertilized eggs. However, it is unclear whether in queenright colonies these eggs are all eaten or some of them develop into males. Using microsatellite markers we investigated the genetic structure of colonies of C. smithi. The effective mating frequency of queens is close to one. At least in one of four colonies that contained both a queen and "large workers" and produced males in the laboratory, the genotype of some males suggested worker reproduction.

Background Identifying the genetic components of common diseases has long been an important area of research. Recently, genotyping technology has reached the level where it is cost effective to genotype single nucleotide polymorphism (SNP) markers covering the entire genome, in thousands of individuals, and analyse such data for markers associated with a diseases. The statistical power to detect association, however, is limited when markers are analysed one at a time. This can be alleviated by considering multiple markers simultaneously. The Haplotype Pattern Mining (HPM) method is a machine learning approach to do exactly this. Results We present a new, faster algorithm for the HPM method. The new approach use patterns of haplotype diversity in the genome: locally in the genome, the number of observed haplotypes is much smaller than the total number of possible haplotypes. We show that the new approach speeds up the HPM method with a factor of 2 on a genome-wide dataset with 5009 individuals typed in 491208 markers using default parameters and more if the pattern length is increased. Conclusion The new algorithm speeds up the HPM method and we show that it is feasible to apply HPM to whole genome association mapping with thousands of individuals and hundreds of thousands of markers.

Background The study is part of a collaborative project (Inuendo), aiming to assess the impact of dietary persistent organochlorine pollutants (POPs) on human fertility. The aims with the present study are to analyze inter-population variations in serum concentrations of 2,2',4,4',5,5'-hexachlorobiphenyl (CB-153) and 1,1-dichloro-2,2-bis (p-chlorophenyl)-ethylene (p,p'-DDE), to assess inter-population variations in biomarker correlations, and to evaluate the relative impact of different determinants for the inter-individual variations in POP-biomarkers. Method In study populations of 3161 adults, comprising Greenlandic Inuits, Swedish fishermen and their wives, and inhabitants from Warsaw, Poland and Kharkiv, Ukraine, serum concentrations of CB-153 and p,p'-DDE, were analysed by gas chromatography-mass spectrometry. Results The median serum concentrations of CB-153 were for male and female Inuits 200 and 110, for Swedish fishermen 190 and their wives 84, for Kharkiv men and women 44 and 27, and for Warsaw men and women 17 and 11 ng/g lipids, respectively. The median serum concentrations of p,p'-DDE were for Kharkiv men and women 930 and 650, for male and female Inuits 560 and 300, for Warsaw men and women 530 and 380, and for Swedish fishermen 240 and their wives 140 ng/g lipids, respectively. The correlation coefficients between CB-153 and p,p'-DDE varied between 0.19 and 0.92, with the highest correlation among Inuits and the lowest among men from Warsaw. Men had averagely higher serum concentrations of CB-153 and p,p'-DDE, and there were positive associations between age and the POP-biomarkers, whereas the associations with BMI and smoking were inconsistent. Dietary seafood was of importance only in the Inuit and Swedish populations. Conclusion CB-153 concentrations were much higher in Inuits and Swedish fishermen's populations than in the populations from Eastern Europe, whereas the pattern was different for p,p'-DDE showing highest concentrations in the Kharkiv population. The correlations between the POP-biomarkers varied considerably between the populations, underlining that exposure sources differ and that the choice of representative biomarkers of overall POP exposure has to be based on an analysis of the specific exposure situation for each population. Age and gender were consistent determinants of serum POPs; seafood was of importance only in the Inuit and Swedish populations.

The critical stage in a chemical reaction — the progression through the transition state from reagents to products — occurs in less than a picosecond (10^(−12)s). Using laser pulses of femtosecond (10^(−15)s) duration it is possible to probe the nuclear motions throughout formation and break-up of the transition state. The coherence and very short duration of these femtosecond pulses provides a means to influence the course of the reaction during this stage if the time resolution is made sufficiently short. Here we describe a demonstration of such control of a chemical reaction on the femtosecond timescale. Using two sequential coherent laser pulses, we can control the reaction of iodine molecules with xenon atoms to form the product XeI by exciting the reactants through the transition state, in a two-step process. The yield of product XeI is modulated as the delay between the pulses is varied, reflecting its dependence on the nuclear motions of the reactants.

Background and aims: Greenland is a hepatitis B (HBV) high-endemic country, but the only preventive measure against HBV is routine HBsAg testing of pregnant women and HBV vaccination of children born to HBsAg positive mothers. Methods: This national wide study evaluated the effectiveness of the Hepatitis B vaccination program in Greenland by examine the frequency of HBsAg testing during pregnancy of all live-births from 1992 to 2000. Secondly we followed-up children born to HBsAg positive mothers in Greenland in the period 1992 to 2007 and determined their vaccination- and HBV status. Results: The survey revealed more challenges in the Greenlandic HBV vaccination program. Firstly, only 65% of all live births were preceded by HBV testing of the mother during pregnancy. Secondly in the follow up study of children born to HBsAg positive mothers, we found that 20% had received no vaccination at all, and that only 58% of the children had received three or four vaccinations. Thirdly, 3% of the children born to HBsAg positive mothers were immune and 3% were chronically infected. Fourthly, the HBsAb level of immunized children was unexpectedly low indicating non responders or an ineffective vaccine. Conclusions: Based on the results in this study we therefore urgently recommend changing the HBV vaccination strategies in Greenland. HB vaccination should be included in the childhood vaccination program and the procedures in the general screening programme of pregnant women should be evaluated and there should be an attenuated awareness of atrisk children born to HBsAg positive mothers.

Background Ants typically distinguish nestmates from non-nestmates based on the perception of colony-specific chemicals, particularly cuticular hydrocarbons present on the surface of the ants' exoskeleton. These recognition cues are believed to play an important role in the formation of vast so-called supercolonies that have been described for some invasive ant species, but general conclusions about the role of these cues are hampered by only few species being studied. Here we use data on cuticular hydrocarbons, aggression and microsatellite genetic markers to investigate the interdependence of chemical recognition cues, genetic distance and nestmate discrimination in the pharaoh ant (Monomorium pharaonis), a widespread pest species, and ask whether introduced populations of this species are genetically differentiated and exhibit intraspecific aggression. Results Microsatellite analyses of a total of 35 colonies from four continents revealed extremely high levels of genetic differentiation between almost all colonies (FST = 0.751 ± 0.006 SE) and very low within-colony diversity. This implies that at least 34 and likely hundreds more independent lineages of this ant have spread worldwide. Aggression tests involving workers from 14 different colonies showed only low levels of aggression, even between colonies that were geographically and/or genetically very distant. Chemical analyses of groups of worker ants showed that all colonies had the same cuticular compounds, which varied only quantitatively among colonies. There was a positive correlation between geographical and genetic distance, but no other significant relationships were detected between aggression, chemical profile, genetic distance and geographical distance. Conclusions The pharaoh ant has a global invasion history of numerous independent introductions resulting in genetically highly differentiated colonies typically displaying surprisingly low levels of intraspecific aggression, a behaviour that may have evolved in the native range or by lineage selection in the introduced range.

An example of diffusion in a natural solid rock is described using 87Sr as a tracer. The distribution of excess radiogenic 87Sr across the contact of a metamorphosed basic dyke in a granodioritic gneiss is shown to fit closely to a mathematically modelled theoretical diffusion curve. It is suggested that the excess radiogenic Sr was generated by the breakdown of older Rb-rich biotite in the country rock to form chlorite during a late-stage greenschist facies metamorphism, and then taken up into a fluid phase migrating along the country rock — dyke interface. This fluid introduced silica, alkalies, light REE, H2O, CO2, N and Cl into the marginal zone of the dyke, probably during fluid migration along grain boundaries. The present irregular distribution of the volatile constituents across the contact and in the dyke excludes a diffusion controlled distribution. The distribution of volatiles probably reflects the influence of the existing mineralogy on the geochemical anomaly actually recorded from a post magmatic process. Evidence is presented that the diffusivity of radiogenic Sr was enhanced by the presence of a volatile phase.

The sites of replication and of accumulation of viral macromolecules were examined using fluorescent antibodies to viral products and to cell organelles. Synthesis of envelope protein and its accumulation in a narrow rim around the nucleus were detected at 4 hours post infection; concurrently, a progressive change was observed in the rough endoplasmic reticulum from a fine to a coarse network emanating from around the nucleus. This change in the network was visible by light microscopy. The immunofluorescent sites of viral RNA synthesis, located by use of anti-double stranded RNA, extended from the perinuclear region in another fine network which included many small foci or vesicles; these sites were also visible by light microscopy late in infection. None of these changes were associated with any visible redistribution of actin, intermediate filaments or microtubules, and no nuclear involvement was detected. However, when microtubules were disrupted by vinblastine treatment of cells, the distribution of the immunofluorescent sites of viral RNA synthesis was modified and the virus yield was reduced by at least 10-fold. These results confirmed our biochemical studies showing separation of viral sites of RNA synthesis and translation, and the accumulation of envelope protein in nuclear-associated membranes. The relevance of these observations is discussed in relation to the reports of specific membrane structures induced in flavivirus-infected cells.

In vitro ist14C-Methyl-Phalloidin gut dialysabel; in vivo erwies sich dieser Effekt als ungleich geringer. Bei Ratten fuhrte die Applikation von 2 mg/kg Phalloidin i. v. nach 106 Minuten im Mittel zum Tode. Die Uberlebenszeiten wurden durch eine sofort eingeleitete Hamodialyse gegen Elektrolyt-Glukose-Losung bzw. Plasmaprotein gegenuber der Kontrollgruppe nur insignifikant verandert. Lediglich das Tierkollektiv, das unmittelbar nach Vergiftung gegen Partnertiere dialysiert wurde (Cross-Dialyse), zeigte eine statistisch insignifikante Verlangerung der Uberlebenszeit um 16 Minuten. Der histomorphologische Leberbefund war in allen Kollektiven gleich. Neben einer Phalloidin-spezifischen Vakuolisierung des Zytoplasmas der lappchenperipher gelegenen Hepatozyten und hamorrhagischen Nekrosen fanden sich eine feintropfige periphere Verfettung sowie Pyknosen. Spezifische Phalloidineffekte manifestierten sich auch in der Leber der bei Cross-Dialyse verwendeten Partnertiere.

A plate dialyser requiring an extracorporeal blood volume of 1.5 ml was developed to dialyse conscious rats. In experiments in vitro and in vivo its function was tested. The in vitro clearances of urea, creatinine and potassium were 126+/-9 ml/min/m2, 70.5+/-9 ml/min/m2, and 132.5+/-13 ml/min/m2, respectively. The method appears to be suitable for pharmacological and toxicological studies.

The concept of recoverable strain is discussed and measured in connection with extrusion, injection molding and uniaxial tensile deformations at constant jaw speed. The data are treated phenomenologically according to the theory of linear viscoelasticity with a subsequent non-linearization. Recoverable strain for the case of extrusion is given in terms of the shear rate and capillary dimensions together with a knowledge of independently determined material parameters. Estimates of the high shear rate values of the equilibrium elastic compliance,J e , are given.

The clinical efficacy of the conventional aminoglycoside plus beta-lactam treatment was compared to that of monotherapy with oral quinolones in 26 adult cystic fibrosis patients in an open prospective clinical trial in which six two-week courses of antipseudomonas treatment were administered with an interval of approximately three months between treatments. In each patient two courses of conventional treatment were followed by two courses of quinolone treatment and then by another two courses of conventional treatment. The observed improvements in pulmonary function were somewhat higher when the patients received conventional treatments, and in the most seriously affected patients conventional treatment was significantly better than quinolone treatment. On the basis of these findings it is suggested that quinolone monotherapy cannot replace conventional antipseudomonal chemotherapy in patients with severe pulmonary involvement.

In a double-blind cross-over study bepridil 900 mg followed by 300 mg daily for 11 days was given to 37 insulin (Type I) or non-insulin (Type II)-dependent diabetic patients. It did not modify the metabolic control of the patients as levels of glucose in blood and urine, doses of insulin and oral hypoglycaemic drugs, energy intake, and the number of hypoglycaemic attacks during therapy were unchanged. The serum concentration of C-peptide was not modified in either type of diabetic patient, and serum insulin in the Type I but not in the Type II patients was slightly higher during active drug treatment. No adverse organotoxic or arrhythmogenic effects or changes in possible atherogenic lipid fractions in serum could be demonstrated during bepridil therapy.

The pharmacokinetics of the glucocorticoid budesonide was studied in 6 children with asthma after i.v. injection of 0.5 mg and oral inhalation of 1 mg as an aerosol. Budesonide is a 1:1 mixture of the epimers 22 S and 22 R, which were assayed separately by HPLC combined with RIA. All pharmacokinetic parameters of the epimers differed except the half-life of about 1.5 h. It was significantly shorter than that reported in adults. Plasma clearance averaged 103 l X h-1 for epimer 22 R and 74 l X h-1 for epimer 22 S; calculated per kg body weight these values were about 50% higher than in adults. The difference was about 40% when calculated per m2 of body surface area. Since budesonide is a high-clearance drug, the data indicate higher liver blood flow X kg-1 body weight and m2 of body surface area in children. The systemic availability of the aerosol was approximately 30% of nominal dose, i.e. the same as in adults. The high clearance and short half-life of budesonide in children are advantageous in reducing the risk of possible systemic side-effects of prophylactic treatment of asthma in childhood.