Radiative Rotational Lifetimes and State-Resolved Relative Detachment Cross Sections from Photodetachment Thermometry of Molecular Anions in a Cryogenic Storage Ring.

Photodetachment thermometry on a beam of OH^{-} in a cryogenic storage ring cooled to below 10 K is carried out using two-dimensional frequency- and time-dependent photodetachment spectroscopy over 20 min of ion storage. In equilibrium with the low-level blackbody field, we find an effective radiative temperature near 15 K with about 90% of all ions in the rotational ground state. We measure the J=1 natural lifetime (about 193 s) and determine the OH^{-} rotational transition dipole moment with 1.5% uncertainty. We also measure rotationally dependent relative near-threshold photodetachment cross sections for photodetachment thermometry.

The cryogenic storage ring CSR.

An electrostatic cryogenic storage ring, CSR, for beams of anions and cations with up to 300 keV kinetic energy per unit charge has been designed, constructed, and put into operation. With a circumference of 35 m, the ion-beam vacuum chambers and all beam optics are in a cryostat and cooled by a closed-cycle liquid helium system. At temperatures as low as (5.5 ± 1) K inside the ring, storage time constants of several minutes up to almost an hour were observed for atomic and molecular, anion and cation beams at an energy of 60 keV. The ion-beam intensity, energy-dependent closed-orbit shifts (dispersion), and the focusing properties of the machine were studied by a system of capacitive pickups. The Schottky-noise spectrum of the stored ions revealed a broadening of the momentum distribution on a time scale of 1000 s. Photodetachment of stored anions was used in the beam lifetime measurements. The detachment rate by anion collisions with residual-gas molecules was found to be extremely low. A residual-gas density below 140 cm(-3) is derived, equivalent to a room-temperature pressure below 10(-14) mbar. Fast atomic, molecular, and cluster ion beams stored for long periods of time in a cryogenic environment will allow experiments on collision- and radiation-induced fragmentation processes of ions in known internal quantum states with merged and crossed photon and particle beams.

Photodissociation of an Internally Cold Beam of CH

We have studied the photodissociation of CH^{+} in the Cryogenic Storage Ring at ambient temperatures below 10 K. Owing to the extremely high vacuum of the cryogenic environment, we were able to store CH^{+} beams with a kinetic energy of ∼60 keV for several minutes. Using a pulsed laser, we observed Feshbach-type near-threshold photodissociation resonances for the rotational levels J=0-2 of CH^{+}, exclusively. In comparison to updated, state-of-the-art calculations, we find excellent agreement in the relative intensities of the resonances for a given J, and we can extract time-dependent level populations. Thus, we can monitor the spontaneous relaxation of CH^{+} to its lowest rotational states and demonstrate the preparation of an internally cold beam of molecular ions.

Integrated pharmacokinetic, pharmacodynamic and immunogenicity profiling of an anti-CCL21 monoclonal antibody in cynomolgus monkeys.

QBP359 is an IgG1 human monoclonal antibody that binds with high affinity to human CCL21, a chemokine hypothesized to play a role in inflammatory disease conditions through activation of resident CCR7-expressing fibroblasts/myofibroblasts. The pharmacokinetics (PK) and pharmacodynamics (PD) of QBP359 in non-human primates were characterized through an integrated approach, combining PK, PD, immunogenicity, immunohistochemistry (IHC) and tissue profiling data from single- and multiple-dose experiments in cynomolgus monkeys. When compared with regular immunoglobulin typical kinetics, faster drug clearance was observed in serum following intravenous administration of 10 mg/kg and 50 mg/kg of QBP359. We have shown by means of PK/PD modeling that clearance of mAb-ligand complex is the most likely explanation for the rapid clearance of QBP359 in cynomolgus monkey. IHC and liquid chromatography mass spectrometry data suggested a high turnover and synthesis rate of CCL21 in tissues. Although lymphoid tissue was expected to accumulate drug due to the high levels of CCL21 present, bioavailability following subcutaneous administration in monkeys was 52%. In human disease states, where CCL21 expression is believed to be expressed at 10-fold higher concentrations compared with cynomolgus monkeys, the PK/PD model of QBP359 and its binding to CCL21 suggested that very large doses requiring frequent administration of mAb would be required to maintain suppression of CCL21 in the clinical setting. This highlights the difficulty in targeting soluble proteins with high synthesis rates.

Nasal nitric oxide is associated with exhaled NO, bronchial responsiveness and poor asthma control.

The fraction of exhaled nitric oxide (FeNO) is an established marker of airway inflammation in asthma. Nasal nitric oxide (nNO) has initially been regarded as a promising marker of inflammation of nasal mucosa. However, due to its dual origins, paranasal sinuses and nasal mucosa, the clinical use of nNO is controversial. There is an inflammatory link between inflammation in the upper and lower airways within the united airways' paradigm, but the study of the clinical value of nNO in asthma has been limited. The objective of this study is to analyse nNO in asthmatics and its relationship to FeNO, bronchial hyperresponsiveness, allergic sensitization and asthma control. A total of 371 children and young adults from an asthma cohort were included in this study, which performed measurements of nNO (through aspiration at 5 mL s(-1)), FeNO, bronchial responsiveness to methacholine, blood eosinophil count (B-Eos) and IgE sensitization. The asthma control test (ACT) and a questionnaire regarding medical treatment, symptoms of asthma, rhinitis and chronic rhinosinusitis were completed by all subjects. An association was found between higher nNO levels and increased bronchial responsiveness (p < 0.001), FeNO (p < 0.001) and B-Eos (p = 0.002). Sensitization to furry animals related to higher levels of nNO (p < 0.001). Subjects with poorly controlled asthma (ACT < 15) had lower levels of nNO than subjects with a higher ACT score (619 ± 278 ppb, versus 807 ± 274 ppb, p = 0.002). Loss of smell showed the strongest association with lower nNO levels among the upper airway symptoms recorded. In patients with asthma, nNO was positively correlated with exhaled NO, bronchial responsiveness and asthma control. This study suggests clinical utility of nNO in subjects with asthma, but in order to get better understanding of the nNO determinants, simultaneous mapping of upper airway comorbidities by clinical examination is appropriate.

Role of projectile coherence in close heavy ion-atom collisions.

We have measured fully differential cross sections for single ionization and transfer ionization (TI) in 16 MeV O(7+)+He collisions. The impact parameters mostly contributing to single ionization are about an order of magnitude larger than for TI. Therefore, the projectile beam was much more coherent for the latter compared to the former process. The measured data suggest that, as a result, TI is significantly affected by interference effects which are not present in single ionization.

Hot water molecules from dissociative recombination of D3O+ with cold electrons.

Individual product channels in the dissociative recombination of deuterated hydronium ions and cold electrons are studied in an ion storage ring by velocity imaging using spatial and mass-sensitive detection of the neutral reaction fragments. Initial and final molecular excitation are analyzed, finding the outgoing water molecules to carry internal excitation of more than 3 eV in 90% of the recombination events. Initial rotation is found to be substantial and in three-body breakup strongly asymmetric energy repartition among the deuterium products is enhanced for hot parent ions.

Ultraviolet and visible light photodissociation of H3+ in an ion storage ring.

Ultraviolet and visible photodissociation of a vibrationally excited H(3)(+) ion beam, as produced by standard ion sources, was successfully implemented in an ion storage ring with the aim of investigating the decay of the excited molecular levels. A collinear beams configuration was used to measure the photodissociation of H(3)(+) into H(2)(+) + H fragments by transitions into the first excited singlet state with 266 and 532 nm laser beams. A clear signal could be observed up to 5 ms of storage, indicating that enough highly excited rovibrational states survive on the millisecond time scale of the experiment. The decay into H(2)(+) + H shows an effective time constant between about 1 and 1.5 ms. The initial photodissociating states are estimated to lie roughly 1 eV below the dissociation limit of 4.4 eV. The expected low population of these levels gives rise to an effective cross section of several 10(-20) cm(2) for ultraviolet and some 10(-21) cm(2) for visible light. For using multistep resonant dissociation schemes to monitor rotational populations of cold H(3)(+) in low-density environments, these measurements open promising perspectives.

Anisotropy and molecular rotation in resonant low-energy dissociative recombination.

Angular fragment distributions from the dissociative recombination (DR) of HD(+) were measured with well directed monochromatic low-energy electrons over a dense grid of collision energies from 7 to 35 meV, where pronounced rovibrational Feshbach resonances occur. Significant higher-order anisotropies are found in the distributions, whose size varies along energy in a partial correlation with the relative DR rate from fast-rotating molecules. This may indicate a breakdown of the nonrotation assumption so far applied to predict angular DR fragment distributions.

Robust association of the APOE epsilon4 allele with premature myocardial infarction especially in patients without hypercholesterolaemia: the Aachen study.

BACKGROUND: Genetic influence on the manifestation of coronary artery disease (CAD) and myocardial infarction (MI) has been shown previously. From many candidate genes the APOE (apolipoprotein E) with the major alleles epsilon2/epsilon3/epsilon4 is in the focus of interest. MATERIALS AND METHODS: In 1817 patients admitted for their first left heart catheterization at a premature age (males < 55 and females < 65) the association of APOE alleles with MI was analysed. Genotyping was done by 5' exonuclease assay (TaqMan). RESULTS APOE was significantly associated with hypercholesterolaemia (epsilon4 72% vs. epsilon3 66% vs. epsilon2 51%; P < 0.0001), and premature MI (epsilon4 57% vs. epsilon3 50% vs. epsilon2 41%; P < 0.0001; hazard ratio 1.41, 95%CI 1.14-1.75). In patients without hypercholesterolaemia, the APOE allele epsilon4 was highly predictive for the presence of premature MI (epsilon4 55% vs. epsilon3 45% vs. epsilon2 28%; P < 0.0001; hazard ratio 1.75, 95%CI 1.19-2.57). CONCLUSION: The APOEepsilon4 allele shows a robust association with premature MI independent of hypercholesterolaemia.

APOE alleles are not associated with calcific aortic stenosis.

OBJECTIVES: To analyse the association of APOE alleles with aortic stenosis (AS) in a large study population. METHODS: Patients with AS (n = 538) and a control group of the same age without heart disease (n = 536) were recruited. Left heart catheterisation was performed and mean gradient, aortic valve area, presence of stenotic coronary artery disease (CAD) and cardiovascular risk factors (hypercholesterolaemia, hypertension, smoking, diabetes mellitus and family history of CAD) were assessed. The frequency of the APOE major alleles e2, e3 and e4 was assessed by genotyping the polymorphisms APOE334 and APOE472 with a 5' exonuclease assay (TaqMan). RESULTS: Mean gradient across the aortic valve in cases was 50 (SD 20) mm Hg corresponding to a mean aortic valve area of 0.84 (SD 0.34) cm(2). 270 patients with AS had stenotic CAD. Among patients with AS, the prevalence of hypercholesterolaemia (64% v 40%, p < 0.001), smoking (43% v 27%, p < 0.001), diabetes (27% v 17%, p < 0.01), family history of CAD (30% v 21%, p 0.10). CONCLUSION: APOE e4 is not associated with AS, reflecting the different genetic backgrounds of CAD and AS.

Childhood fevers: developing an evidence-based anticipatory guidance tool for parents.

Misconceptions about childhood fevers heighten parents' concerns leading to frequent use of health care services. Designing, piloting, and evaluating nursing interventions to demystify parents' phobia of fevers are imperative. An evidence-based fever anticipatory guidance tool was designed to assist parents by: dispelling misconceptions, teaching proper care of their febrile child and appropriate use of antipyretics, and providing a list of serious signs that warrant medical attention. Concepts of the Health Belief Model (HBM) are applied to parent behavior to promote a greater understanding of their actions in the face of childhood fever. Informing consumers with accurate and consistent information has direct implications for changing practice in the hospital and community.

Role of p300-family proteins in E1A oncogene induction of cytolytic susceptibility and tumor cell rejection.

The mechanism by which the adenoviral (Ad) E1A oncogene induces cellular susceptibility to lysis by killer lymphocytes involves interactions between its first exon and different second-exon accessory regions. Mutational analysis showed that two first-exon regions--one in the N terminus and one in the conserved region 1 (CR1) domain--are necessary for this activity. E1A complex formation with cellular p300 protein through these first-exon-encoded regions correlated with induction of the cytolytic susceptible phenotype but was only effective in the context of E1A second-exon expression. An E1A first-exon deletion that prevented p300 binding eliminated both oncoprotein-induced cytolytic susceptibility and rejection of transfected sarcoma cells by immunocompetent animals. These results suggest that the E1A oncogene induces cytolytic susceptibility and tumor rejection by interactions with cellular proteins of the p300 family that affect transcription of genes involved in the cellular response to injury inflicted by host killer cells.

E1A second exon requirements for induction of target cell susceptibility to lysis by natural killer cells: implications for the mechanism of action.

The E1A oncogene of adenovirus type 5 induces susceptibility of mammalian cells to lysis by natural killer lymphocytes (NK cells). It is unknown whether sensitization to NK killing is mediated directly by targeting effects of interactions between E1A peptides and cell surface MHC molecules or indirectly by an E1A activity that requires structural integrity of the oncoprotein. To discriminate between these hypotheses, rat and hamster cells expressing wild type E1A were contrasted with those expressing truncated products resulting from E1A termination or deletion mutations. Transfected rat cells, expressing truncated proteins from the E1A first exon that encodes MHC-binding peptides, remained resistant to lysis by NK cells, whereas cells expressing full-length E1A protein were highly susceptible to lysis. Studies of infected hamster cells showed that addition of either of two, nonoverlapping, second exon regions reconstituted cytolytic susceptibility induction by E1A. The results do not support the E1A-peptide-MHC hypothesis, since no single E1A peptide coding region was sufficient to convey cytolytic susceptibility to expresser cells. The data indicate that coordinate functions of the E1A first exon and redundant accessory regions in the second exon are required for E1A-induced susceptibility to NK killing.

Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin on the hepatic storage of retinol in rats with different dietary supplies of vitamin A (retinol).

The effect of various dietary sources of vitamin A on liver storage of retinol has been investigated in Sprague-Dawley rats treated with single oral doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD): 0,0.1,1.0, or 10 microgram.kg-1. Each dose group consisted of 3 subgroups, each comprising 10 rats which received a diet with normal, low or high retinol content. The animals were killed 4 weeks after TCDD administration. Analyses of retinol were performed by high pressure liquid chromatography and glucuronosyltransferase activities were determined spectrophotometrically. A dose-dependent decrease in hepatic storage of retinol was evident. The high retinol diet did not fully compensate for the reduction caused by the highest TCDD-dose. Glucuronosyltransferase activity increased directly in relation to the TCDD-dose but in inverse proportion to the retinol content of the diet.