Lung inflammation does not affect the clearance kinetics of lipid nanocapsules following pulmonary administration

Lipid nanocapsules (LNCs) are semi-rigid spherical capsules with a triglyceride core that present a promising formulation option for the pulmonary delivery of drugs with poor aqueous solubility. Whilst the biodistribution of LNCs of different size has been studied following intravenous administration, the fate of LNCs following pulmonary delivery has not been reported. We investigated quantitatively whether lung inflammation affects the clearance of 50nm lipid nanocapsules, or is exacerbated by their pulmonary administration. Studies were conducted in mice with lipopolysaccharide-induced lung inflammation compared to healthy controls. Particle deposition and nanocapsule clearance kinetics were measured by single photon emission computed tomography/computed tomography (SPECT/CT) imaging over 48 h. A significantly lower lung dose of (111)In-LNC50 was achieved in the lipopolysaccharide (LPS)-treated animals compared with healthy controls (p<0.001). When normalised to the delivered lung dose, the clearance kinetics of (111)In-LNC50 from the lungs fit a first order model with an elimination half-life of 10.5±0.9h (R(2)=0.995) and 10.6±0.3h (R(2)=1.000) for healthy and inflamed lungs respectively (n=3). In contrast, (111)In-diethylene triamine pentaacetic acid (DTPA), a small hydrophilic molecule, was cleared rapidly from the lungs with the majority of the dose absorbed within 20min of administration. Biodistribution to lungs, stomach-intestine, liver, trachea-throat and blood at the end of the imaging period was unaltered by lung inflammation. This study demonstrated that lung clearance and whole body distribution of lipid nanocapsules were unaffected by the presence of acute lung inflammation

Images across Europe: The sending and receiving of sexual images and associations with interpersonal violence in young people's relationships

This article explores young people's experiences of sending and receiving sexual images and text messages (sexting) within their interpersonal relationships and the contexts in which this occurs. The article uses data from a recent Daphne funded project ‘Safeguarding teenagers' intimate relationships’ (STIR) involving a survey with 4564 young people aged between 14 and 17 in a number of schools across five countries in Europe. Findings reveal that experiences of sexting vary by country and gender. The study also found that young people who reported victimisation in their relationships were more likely to have sent a sext message than those who had not. The article points to the need for a more nuanced understanding of the varied contexts and experiences around sexting in order to better develop policy, practice and education in this area

Comparing two artificial intelligence software packages for normative brain volumetry in memory clinic imaging

Purpose: To compare two artificial intelligence software packages performing normative brain volumetry and explore whether they could differently impact dementia diagnostics in a clinical context. Methods: Sixty patients (20 Alzheimer’s disease, 20 frontotemporal dementia, 20 mild cognitive impairment) and 20 controls were included retrospectively. One MRI per subject was processed by software packages from two proprietary manufacturers, producing two quantitative reports per subject. Two neuroradiologists assigned forced-choice diagnoses using only the normative volumetry data in these reports. They classified the volumetric profile as “normal,” or “abnormal”, and if “abnormal,” they specified the most likely dementia subtype. Differences between the packages’ clinical impact were assessed by comparing (1) agreement between diagnoses based on software output; (2) diagnostic accuracy, sensitivity, and specificity; and (3) diagnostic confidence. Quantitative outputs were also compared to provide context to any diagnostic differences. Results: Diagnostic agreement between packages was moderate, for distinguishing normal and abnormal volumetry (K =.41–.43) and for specific diagnoses (K =.36–.38). However, each package yielded high inter-observer agreement when distinguishing normal and abnormal profiles (K =.73–.82). Accuracy, sensitivity, and specificity were not different between packages. Diagnostic confidence was different between packages for one rater. Whole brain intracranial volume output differed between software packages (10.73%, p <.001), and normative regional data interpreted for diagnosis correlated weakly to moderately (rs =.12–.80). Conclusion: Different artificial intelligence software packages for quantitative normative assessment of brain MRI can produce distinct effects at the level of clinical interpretation. Clinics should not assume that different packages are interchangeable, thus recommending internal evaluation of packages before adoption

Mechanistic Insights into the Alternating Copolymerization of Epoxides and Cyclic Anhydrides Using a (Salph)AlCl and Iminium Salt Catalytic System

Mechanistic studies involving synergistic experiment and theory were performed on the perfectly alternating copolymerization of 1-butene oxide and carbic anhydride using a (salph)­AlCl/[PPN]Cl catalytic pair. These studies showed a first-order dependence of the polymerization rate on the epoxide, a zero-order dependence on the cyclic anhydride, and a first-order dependence on the catalyst only if the two members of the catalytic pair are treated as a single unit. Studies of model complexes showed that a mixed alkoxide/carboxylate aluminum intermediate preferentially opens cyclic anhydride over epoxide. In addition, ring-opening of epoxide by an intermediate comprising multiple carboxylates was found to be rate-determining. On the basis of the experimental results and analysis by DFT calculations, a mechanism involving two catalytic cycles is proposed wherein the alternating copolymerization proceeds via intermediates that have carboxylate ligation in common, and a secondary cycle involving a bis-alkoxide species is avoided, thus explaining the lack of side reactions until the polymerization is complete

Cellular and molecular defects in a patient with Hermansky-Pudlak syndrome type 5

<div><p>Hermansky-Pudlak syndrome (HPS) is a heterogeneous group of genetic disorders typically manifesting with tyrosinase-positive oculocutaneous albinism, bleeding diathesis, and pulmonary fibrosis, in some subtypes. Most HPS subtypes are associated with defects in Biogenesis of Lysosome-related Organelle Complexes (BLOCs), which are groups of proteins that function together in the formation and/or trafficking of lysosomal-related endosomal compartments. BLOC-2, for example, consists of the proteins HPS3, HPS5, and HPS6. Here we present an HPS patient with defective BLOC-2 due to a novel intronic mutation in <i>HPS5</i> that activates a cryptic acceptor splice site. This mutation leads to the insertion of nine nucleotides in-frame and results in a reduced amount of HPS5 at the transcript and protein level. In studies using skin fibroblasts derived from the proband and two other individuals with HPS-5, we found a perinuclear distribution of acidified organelles in patient cells compared to controls. Our results suggest the role of HPS5 in the endo-lysosomal dynamics of skin fibroblasts.</p></div

Mechanistic Studies of ε‑Caprolactone Polymerization by (salen)AlOR Complexes and a Predictive Model for Cyclic Ester Polymerizations

Aluminum alkoxide complexes (<b>2</b>) of salen ligands with a three-carbon linker and para substituents having variable electron-withdrawing capabilities (X = NO₂, Br, OMe) were prepared, and the kinetics of their ring-opening polymerization (ROP) of ε-caprolactone (CL) were investigated as a function of temperature, with the aim of drawing comparisons to similar systems with two-carbon linkers investigated previously (<b>1</b>). While <b>1</b> and <b>2</b> exhibit saturation kinetics and similar dependences of their ROP rates on substituents X (invariant <i>K</i>_eq, similar Hammett ρ = +1.4(1) and 1.2(1) for <i>k</i>₂, respectively), ROP by <b>2</b> was significantly faster than for <b>1</b>. Theoretical calculations confirm that, while the reactant structures differ, the transition state geometries are quite similar, and by analyzing the energetics of the involved distortions accompanying the structural changes, a significant contribution to the basis for the rate differences was identified. Using this knowledge, a simplified computational method for evaluating ligand structural influences on cyclic ester ROP rates is proposed that may have utility for future catalyst design

Molecular and expression analysis.

<p>(A) Chromatogram showing intronic mutation (c.285-10A>G) in genomic level (upper panel) and cDNA level (middle panel) of the patient. Lower panel shows normal cDNA sequence from control for comparison with patient. (B) Relative quantification of mRNA expression (three different isoforms) in patient derived dermal fibroblasts, compared to control. Error bar represents standard deviation from triplicates (*: p<0.05, **: p<0.01). (C) Western blotting results showing the expression of HPS5 in patients compared to control. Two different controls (Control-1 and Control-2), two additional patients with HPS5 (HPS5-1 and HPS5-2), and our proband were included. The level of protein expression was normalized with β-actin.</p