Imaging of atherosclerosis, targeting LFA-1 on inflammatory cells with 111In-DANBIRT

Background: 111In-DOTA-butylamino-NorBIRT (DANBIRT) is a novel radioligand which binds to Leukocyte Function-associated Antigen-1 (LFA-1), expressed on inflammatory cells. This study evaluated 111In-DANBIRT for the visualization of atherosclerotic plaque inflammation in mice. Methods and Results: ApoE−/− mice, fed an atherogenic diet up to 20 weeks (n = 10), were imaged by SPECT/CT 3 hours post injection of 111In-DANBIRT (~ 200 pmol, ~ 40 MBq). Focal spots of 111In-DANBIRT were visible in the aortic arch of all animals, with an average Target-to-Background Ratio (TBR) of 1.7 ± 0.5. In vivo imaging results were validated by ex vivo SPECT/CT imaging, with a TBR up to 11.5 (range 2.6 to 11.5). Plaques, identified by Oil Red O lipid-staining on excised arteries, co-localized with 111In-DANBIRT uptake as determined by ex vivo autoradiography. Subsequent histological processing and in vitro autoradiography confirmed 111In-DANBIRT uptake at plaque areas containing CD68 expressing macrophages and LFA-1 expressing inflammatory cells. Ex vivo incubation of a human carotid endarterectomy specimen with 111In-DANBIRT (~ 950 nmol, ~ 190 MBq) for 2 hours showed heterogeneous plaque uptake on SPECT/CT, after which immunohistochemical analysis demonstrated co-localization of 111In-DANBIRT uptake and CD68 and LFA-1 expressing cells. Conclusions: Our results indicate the potential of radiolabeled DANBIRT as a relevant imaging radioligand for non-invasive evaluation of atherosclerotic inflammation

Tool catalogue frame-based information tools

In the perception, knowledge production and policymaking on complex issues (‘wicked problems’), such as climate change, frames and framing play an important but often hidden role. Frames relate to one’s ‘schemas of interpretation’; the conceptual images, values, starting points, and mental models that one may have of an issue. This can include, for instance, one’s problem definition, perceptions of the cause-effect relationships in an issue, one’s primary goals, perception of one’s and others’ roles and responsibilities relating to the issue, and views on suitable strategies and interaction with (other) stakeholders (cf. Dewulf et al., 2005)

Phosporylation of androgen receptor isoforms

Phosphorylation of the human AR (androgen receptor) is directly correlated with the appearance of at least three AR isoforms on an SDS/polyacrylamide gel. However, it is still not clear to what extent phosphorylation is involved in the occurrence of isoforms, which sites are phosphorylated and what are the functions of these phosphosites. The human AR was expressed in COS-1 cells and AR phosphorylation was studied further by mutational analyses and by using reversed-phase HPLC and MS. The reversed-phase HPLC elution pattern of the three isoforms revealed that Ser-650 was phosphorylated constitutively. After de novo synthesis, only Ser-650 was phosphorylated in the smallest isoform of 110 kDa and both Ser-650 and Ser-94 were phosphorylated in the second isoform of 112 kDa. The hormone-induced 114 kDa isoform shows an overall increase in phosphorylation of all the isolated peptides. The activities of the Ser-Ala substitution mutant S650A (Ser-650-->Ala) was found to be identical with wild-type AR activation in four different cell lines and three different functional analyses, e.g. transactivation, N- and C-terminal-domain interaction and co-activation by transcriptional intermediary factor 2. This was also found for mutants S94A and S515A with respect to transactivation. However, the S515A mutation, which should eliminate phosphorylation of the potential mitogen-activated protein kinase site, Ser-515, resulted in an unphosphorylated form of the peptide containing Ser-650. This suggests that Ser-515 can modulate phosphorylation at another site. The present study shows that the AR isoform pattern from AR de novo synthesis is directly linked to differential phosphorylation of a distinct set of sites. After mutagenesis of these sites, no major change in functional activity of the AR was observed

Predictors of outcome for severely emotionally disturbed children in treatment

Despite general agreement that severely emotionally disturbed children and adolescents are an "at risk" group, and that ongoing evaluation and research into the effectiveness of services provided for them is important, very little outcome evaluation actually takes place. The absence of well-conducted and appropriately interpreted studies is particularly notable for day or residential treatment programs, which cater for the most severely emotionally disturbed youths. This thesis outlines the main areas of conceptual, pragmatic and methodological confusion and neglect which impede progress in research in this area. It argues for plurality of data analytic strategies and research designs. It then critically reviews the reported findings about the effectiveness of day and residential treatment in specialist facilities, and the predictors of good outcomes for this treatment type. This review confirms that there is very little to guide practice. Having argued for the legitimacy of its methods and the necessity to address basic questions, the thesis reports the results of a naturalistic study based on data accumulated during a decade-long evaluative research program taking place at Arndell Child and Adolescent Unit, Sydney. The study addresses the question of what child, family and treatment variables predict outcome for 159 children and adolescents treated at this facility from 1990 to 1999. Statistically significant results with large effect size were obtained. Among the most disturbed subgroup of forty three children, (a) psychodynamic milieu-based treatment was shown to be more effective than the “empirically-validated” cognitive-behavioural treatment which superseded it in 1996, and (b) children from step-families showed better outcome than those from other family structures. Furthermore, it was found for the study sample as a whole that severe school-based problem behaviours were associated with a limited trajectory of improvement in home-based problem behaviour. These results are discussed with regard to implications for treatment, research methodology, policy and further studies

Current noise in long diffusive SNS junctions in the incoherent MAR regime

Spectral density of current fluctuations at zero frequency is calculated for a long diffusive SNS junction with low-resistive interfaces. At low temperature, T << Delta, the subgap shot noise approaches linear voltage dependence, S=(2/ 3R)(eV + 2Delta), which is the sum of the shot noise of the normal conductor and voltage independent excess noise. This result can also be interpreted as the 1/3-suppressed Poisson noise for the effective charge q = e(1+2Delta/eV) transferred by incoherent multiple Andreev reflections (MAR). At higher temperatures, anomalies of the current noise develop at the gap subharmonics, eV = 2Delta/n. The crossover to the hot electron regime from the MAR regime is analyzed in the limit of small applied voltages.Comment: improved version, to be published in Phys. Rev.

Relativistic Random-Phase Approximation with density-dependent meson-nucleon couplings

The matrix equations of the relativistic random-phase approximation (RRPA) are derived for an effective Lagrangian characterized by density-dependent meson-nucleon vertex functions. The explicit density dependence of the meson-nucleon couplings introduces rearrangement terms in the residual two-body interaction, that are essential for a quantitative description of excited states. Illustrative calculations of the isoscalar monopole, isovector dipole and isoscalar quadrupole response of $^{208}$Pb, are performed in the fully self-consistent RRPA framework, based on effective interactions with a phenomenological density dependence adjusted to nuclear matter and ground-state properties of spherical nuclei. The comparison of the RRPA results on multipole giant resonances with experimental data constrains the parameters that characterize the isoscalar and isovector channel of the density-dependent effective interactions.Comment: RevTeX, 8 eps figures, submitted to Phys. Rev.

A microscopic estimate of the nuclear matter compressibility and symmetry energy in relativistic mean-field models

The relativistic mean-field plus RPA calculations, based on effective Lagrangians with density-dependent meson-nucleon vertex functions, are employed in a microscopic analysis of the nuclear matter compressibility and symmetry energy. We compute the isoscalar monopole and the isovector dipole response of $^{208}$Pb, as well as the differences between the neutron and proton radii for $^{208}$Pb and several Sn isotopes. The comparison of the calculated excitation energies with the experimental data on the giant monopole resonance in $^{208}$Pb, restricts the nuclear matter compression modulus of structure models based on the relativistic mean-field approximation to $K_{\rm nm}\approx 250 - 270$ MeV. The isovector giant dipole resonance in $^{208}$Pb, and the available data on differences between neutron and proton radii, limit the range of the nuclear matter symmetry energy at saturation (volume asymmetry) to 32 MeV $\leq a_4 \leq$ 36 MeV.Comment: 16 pages, 6 figure

Is a chest radiograph indicated after chest tube removal in trauma patients? A systematic review

PURPOSE The aim of this systematic review was to assess the necessity of routine chest radiographs after chest tube removal in ventilated and nonventilated trauma patients. METHODS A systematic literature search was conducted in MEDLINE, Embase, CENTRAL, and CINAHL on May 15, 2020. Quality assessment was performed using the Methodological Index for Nonrandomized Studies criteria. Primary outcome measures were abnormalities on postremoval chest radiograph (e.g., recurrence of a pneumothorax, hemothorax, pleural effusion) and reintervention after chest tube removal. Secondary outcome measures were emergence of new clinical symptoms or vital signs after chest tube removal. RESULTS Fourteen studies were included, consisting of seven studies on nonventilated patients and seven studies on combined cohorts of ventilated and nonventilated patients, all together containing 1,855 patients. Nonventilated patients had abnormalities on postremoval chest radiograph in 10% (range across studies, 0-38%) of all chest tubes and 24% (range, 0-78%) of those underwent reintervention. In the studies that reported on clinical symptoms after chest tube removal, all patients who underwent reintervention also had symptoms of recurrent pathology. Combined cohorts of ventilated and nonventilated patients had abnormalities on postremoval chest radiograph in 20% (range, 6-49%) of all chest tubes and 45% (range, 8-63%) of those underwent reintervention. CONCLUSION In nonventilated patients, one in ten developed recurrent pathology after chest tube removal and almost a quarter of them underwent reintervention. In two studies that reported on clinical symptoms, all reinterventions were performed in patients with symptoms of recurrent pathology. In these two studies, omission of routine postremoval chest radiograph seemed safe. However, current literature remains insufficient to draw definitive conclusions on this matter, and future studies are needed. LEVEL OF EVIDENCE Systematic review study, level IV

Effects of timing and extent of smoking, type of cigarettes, and concomitant risk factors on the association between smoking and subclinical atherosclerosis

Background and Purpose \u2014 The purpose of this study was to evaluate the effects of timing and extent of smoking, type of cigarettes, and concomitant vascular risk factors (VRFs) on the association between smoking and carotid intima-media thickness (C-IMT) in a lipid clinic population. Methods \u2014 1804 patients (869 men, age 21 to 85 year) participated in the study. Smoking habits were recorded and C-IMTs were measured by B-mode ultrasound. The associations of C-IMT with smoking status (never, former, and current) and with the cigarettes\u2019 content of tar, nicotine, and carbon monoxide (alone or combined to define \u201clight\u201d or \u201cregular\u201d cigarettes) as well as the interactions between smoking status, gender, and VRFs were evaluated before and after adjustment for confounders. Results \u2014 C-IMT was highest in current smokers, lower in former, and lowest in never smokers. C-IMT of former and current smokers differed only after data adjustment for variables describing the extent and timing of smoking exposure. C-IMT was positively related to the number of pack-years (number of cigarettes smoked per day [cigarettes/d] multiplied by number of years smoked/20) in both former and current smokers. There were no differences in C-IMT between smokers of cigarettes with high or low nicotine, tar, or carbon monoxide content. Both diabetes and hypertension interacted positively with smoking in determining C-IMTs. Conclusions \u2014 In the present cross-sectional observational investigation, carried out in a cohort of patients attending a lipid clinic, consumption of light cigarettes does not reduce the atherogenic effect of smoking on C-IMT. The number of pack-years, cigarettes/d, and years of smoking are relevant covariates in evaluating the effects of smoking on vascular health. The presence of diabetes or hypertension strengthens the association between smoking and cardiovascular risk