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Here we will briefly describe the commissioning of the Double ElectroStatic Ion Ring ExpEriment (DESIREE) facility at Stockholm University, Sweden. This device uses purely electrostatic focussing and deflection elements and allows ion beams of opposite charge to be confined under extreme high vacuum and cryogenic conditions in separate “rings” and then merged over a common straight section. This apparatus allows for studies of interactions between cations and anions at very low and well-defined centre-of-mass energies (down to a few meV) and at very low internal temperatures (down to a few K).

We use a novel electrostatic ion storage ring to measure the radiative lifetime of the upper level in the 3p5 2P°1/2 → 3p5 2P°3/2 spontaneous radiative decay in 32S- to be 503 ± 54 sec. This is by orders of magnitude the longest lifetime ever measured in a negatively charged ion. Cryogenic cooling of the storage ring gives a residual-gas pressure of a few times 10-14 mbarat 13 Kand storage of 10 keV sulfur anions for more than an hour. Our experimental results differ by 13δ from the only available theoretical prediction [P. Andersson et al., Phys. Rev. A 73, 032705 (2006)]. [ABSTRACT FROM AUTHOR]

ABSTRACT Parity forbidden radiative transitions from metastable levels are observed in spectra of low-density astrophysical plasmas. These lines are used as probes of the physical conditions, made possible due to the long lifetime of their upper level. In a joint effort, the FERRUM project aims to obtain new and accurate atomic data for the iron-group elements, and part of this project concerns forbidden lines. The radiative lifetimes of the metastable energy levels 3 d4(a 3 D)4 s c4 D 5/2 and 3 d4(a 3 D)4 s c4 D 7/2 of singly ionized chromium have been measured. The experiment has been performed at the ion storage ring CRYRING. We employed a laser-probing technique developed for measuring long lifetimes. In this article, we present the lifetimes of these levels to be τ5/2= 1.28(16) s and τ7/2= 1.37(7) s, respectively. A comparison with previous theoretical work shows good agreement and the result is discussed in a theoretical context. [ABSTRACT FROM AUTHOR]

The role of inflammation in the pathogenesis of bronchopulmonary dysplasia (BPD) is not well understood. By using a transgenic mouse expressing the inflammatory cytokine interleukin (IL)-1beta in the lung, we have shown that perinatal expression of IL-1beta causes a BPD-like illness in infant mice. We have used this model to identify mechanisms by which inflammation causes neonatal lung injury. Increased matrix metalloproteinase (MMP)-9 activity is associated with BPD. MMP-9 deficiency worsens alveolar hypoplasia in IL-1beta-expressing newborn mice, suggesting that MMP-9 has a protective role in neonatal inflammatory lung injury. The beta6 integrin subunit, an activator of transforming growth factor-beta, is involved in adult lung disease. Absence of the beta6 integrin subunit improves alveolar development in IL-1beta-expressing mice, suggesting that the beta6 integrin subunit is a pathogenetic factor in inflammatory lung disease in the newborn. The authors of clinical studies who have examined maternal inflammation as a risk factor for BPD have found variable results. We have shown that maternal IL-1beta production preceding fetal IL-1beta production prevents lung inflammation, alveolar hypoplasia, and airway remodeling in newborn IL-1beta-expressing mice. Thus, maternal inflammation may protect the newborn lung against subsequent inflammatory injury. In contrast, when maternal and fetal production of IL-1beta are induced simultaneously, the development of IL-1beta-induced lung disease in the newborn is not prevented. © Elsevier Inc. All rights reserved. [ABSTRACT FROM AUTHOR]

Purpose: To retrospectively evaluate long-term outcomes after temporomandibular joint (TMJ) discectomy., Methods: Included patients (n = 64) had undergone discectomy during 1989-1998 at Umeå University Hospital. A questionnaire was used to evaluate pre- and postoperative symptoms, postoperative complications, general pain, and subjective opinion about the outcome of the surgery., Results: The results are based on responses from 47 patients (40 women/7 men), including 36 (30 women/6 men) who completed the questionnaire and 11 (10 women/1 man) who were contacted by telephone and answered selected questions. Seventeen patients were excluded because of death, a move abroad, declining to participate, or no available patient information. Among the respondents, 41 (87%) were satisfied with the results, five (11%) were unsatisfied, and one (2%) patient did not answer the question. The results showed a significant long-term improvement in locking, clicking/crepitation, and pain when chewing or opening the jaw (p = 0.001). The prevalence of headaches had decreased significantly at follow-up (p = 0.001). Reported impaired jaw-opening capacity showed no significant improvement (p = 0.08). Of the 47 respondents, 19 (40%) had asked for additional treatment after the discectomy, and six of the 19 patients (13%) had undergone more surgery of the joint., Conclusion: The results of this retrospective long-term follow-up study indicate that TMJ discectomy has a high success rate, as most patients were satisfied with the postoperative results. Discectomy is thus an effective surgical intervention for patients with disabling TMJ pain and dysfunction when conservative interventions have been unsuccessful., (© 2024. The Author(s).)

Pharmacokinetics (PK) of antisense oligonucleotides (ASOs) is characterized by rapid distribution from plasma to tissue and slow terminal plasma elimination driven by re-distribution from tissue. Quantitative understanding of tissue PK and RNA knockdown for various ASO chemistries, conjugations, and administration routes is critical for successful drug discovery. Here, we report concentration-time and RNA knockdown profiles for a gapmer ASO with locked nucleic acid ribose chemistry in mouse liver, kidney, heart, and lung after subcutaneous and intratracheal administration. Additionally, the same ASO with liver targeting conjugation (galactosamine- N -acetyl) is evaluated for subcutaneous administration. Data indicate that exposure and knockdown differ between tissues and strongly depend on administration route and conjugation. In a second study, we show that tissue PK is similar between the three different ribose chemistries locked nucleic acid, constrained ethyl and 2'- O -methoxyethyl, both after subcutaneous and intratracheal administration. Further, we show that the half-life in mouse liver may vary with ASO sequence. Finally, we report less than dose-proportional increase in liver concentration in the dose range of 3-30 μmol/kg. Overall, our studies contribute pivotal data to support design and interpretation of ASO in vivo studies, thereby increasing the probability of delivering novel ASO therapies to patients., Competing Interests: This study was sponsored by AstraZeneca. All authors were employees of AstraZeneca at the time of this research. P.J. is associate editor at Molecular Therapy Nucleic Acids., (© 2024 The Author(s).)

Invited for this month's cover is the groups of Prof. Minna Hakkarainen, Prof. István Furó and Assoc. Prof. Per-Olof Syrén at KTH Royal Institute of Technology. The image shows how microwave irradiation is an efficient pre-treatment method of polyethylene terephthalate (PET) for subsequent biocatalytic depolymerization. The Research Article itself is available at 10.1002/cssc.202300742., (© 2023 Wiley-VCH GmbH.)

Selective hydrolysis of polyamide-6 (PA-6) and polyamide-66 (PA-66) from commercial multicomponent PA-6/PA-66/polypropylene (PP) carpet is demonstrated by a microwave-assisted acid catalyzed hydrothermal process, yielding monomeric products and solid polypropylene residue. First, an effective method is established to chemically recycle neat PA-6 and PA-66 granules using microwave irradiation. The optimized, hydrochloric acid (HCl) catalyzed process leads to selective production of monomers, 6-aminocaproic acid or adipic acid and hexamethylenediamine, after only 30 min. A piece of commercial carpet is then recycled using the same reaction conditions, but with the alteration of the reaction time from 1 to 6 h. The produced water-soluble products and the remaining solid residue are carefully characterized, proving that the polyamide-part of the carpet is selectively hydrolyzed into water-soluble monomers and the polypropylene-part remains as an unconverted solid that can be further used to produce recycled filaments containing the carpet residue and virgin polypropylene. The developed process opens the possibility to recycle multicomponent materials, such as carpets, through selective hydrolysis. It can also contribute to a circular economy, producing original monomers and materials ready for a new life-cycle., Competing Interests: The authors declare no conflict of interest., (© 2021 The Authors. Global Challenges published by Wiley‐VCH GmbH.)

Introduction: The lungs possess many xenobiotic metabolizing enzymes which influence the pharmacokinetics and safety of inhaled medicines. Anticipating metabolism in the lungs provides an opportunity to optimize new inhaled medicines and overcome challenges in their development., Areas Covered: This article summarizes current knowledge on xenobiotic metabolizing enzymes in the lungs. The impact of metabolism on inhaled medicines is considered with examples of how this impacts small molecules, biologics and macromolecular formulation excipients. Methods for measuring and predicting xenobiotic lung metabolism are critically reviewed and the potential for metabolism to influence inhalation toxicology is acknowledged., Expert Opinion: Drugs can be optimized by molecular modification to (i) reduce systemic exposure using a 'soft drug' approach, (ii) improve bioavailability by resisting metabolism, or (iii) use a prodrug approach to overcome pharmacokinetic limitations. Drugs that are very labile in the lungs may require a protective formulation. Some drug carriers being investigated for PK-modification rely on lung enzymes to trigger drug release or biodegrade. Lung enzyme activity varies with age, race, smoking status, diet, drug exposure and preexisting lung disease. New experimental technologies to study lung metabolism include tissue engineered models, improved analytical capability and in silico models.

Patients in Opioid Substitution Treatment (OST) have increased mortality and morbidity, with circulatory conditions suggested to be a contributing factor. Since OST patients tend to have unmet physical healthcare needs, a small-scale intervention providing on-site primary healthcare (PHC) in OST clinics was implemented in Malmö, Sweden in 2016. In this study, we assessed registered circulatory conditions and healthcare utilization in OST patients with and without use of on-site PHC. Patients from four OST clinics in Malmö, Sweden, were recruited to a survey study in 2017-2018. Medical records for the participants were retrieved for one year prior to study participation ( n = 192), and examined for circulatory diagnoses, examinations and follow-ups. Patients with and without on-site PHC were compared through descriptive statistics and univariate analyses. Eighteen percent ( n = 34) of the sample had 1≤ registered circulatory condition, and 6% ( n = 12) attended any clinical physiology examination or follow-up, respectively. Among patients utilizing on-site PHC ( n = 26), the numbers were 27% ( n = 7) for circulatory diagnosis, 15% ( n = 4) for examinations, and 12% ( n = 3) for follow-up. OST patients seem underdiagnosed in regard to their circulatory health. On-site PHC might be a way to diagnose and treat circulatory conditions among OST patients, although further research is needed.

Both initiation and suppression of inflammation are hallmarks of the immune response. If not balanced, the inflammation may cause extensive tissue damage, which is associated with common diseases, e.g., asthma and atherosclerosis. Anti-inflammatory drugs come with side effects that may be aggravated by high and fluctuating drug concentrations. To remedy this, an anti-inflammatory drug should have an appropriate pharmacokinetic half-life or better still, a sustained anti-inflammatory drug response. However, we still lack a quantitative mechanistic understanding of such sustained effects. Here, we study the anti-inflammatory response to a common glucocorticoid drug, dexamethasone. We find a sustained response 22 hours after drug removal. With hypothesis testing using mathematical modeling, we unravel the underlying mechanism-a slow release of dexamethasone from the receptor-drug complex. The developed model is in agreement with time-resolved training and testing data and is used to simulate hypothetical treatment schemes. This work opens up for a more knowledge-driven drug development to find sustained anti-inflammatory responses and fewer side effects., (© 2020 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Background: For the treatment of respiratory disease, inhaled drug delivery aims to provide direct access to pharmacological target sites while minimizing systemic exposure. Despite this long-held tenet of inhaled therapeutic advantage, there are limited data of regional drug localization in the lungs after inhalation. The aim of this study was to investigate the distribution and retention of different chemotypes typifying available inhaled drugs [slowly dissolving neutral fluticasone propionate (FP) and soluble bases salmeterol and salbutamol] using mass spectrometry imaging (MSI). Methods: Salmeterol, salbutamol, and FP were simultaneously delivered by inhaled nebulization to rats. In the same animals, salmeterol- d 3 , salbutamol- d 3 , and FP- d 3 were delivered by intravenous (IV) injection. Samples of lung tissue were obtained at 2- and 30-minute postdosing, and high-resolution MSI was used to study drug distribution and retention. Results: IV delivery resulted in homogeneous lung distribution for all molecules. In comparison, while inhalation also gave rise to drug presence in the entire lung, there were regional chemotype-dependent areas of higher abundance. At the 30-minute time point, inhaled salmeterol and salbutamol were preferentially retained in bronchiolar tissue, whereas FP was retained in all regions of the lungs. Conclusion: This study clearly demonstrates that inhaled small molecule chemotypes are differentially distributed in lung tissue after inhalation, and that high-resolution MSI can be applied to study these retention patterns.

Significant pulmonary metabolism of inhaled drugs could have drug safety implications or influence pharmacological effectiveness. To study this in vitro, lung microsomes or S9 are often employed. Here, we have determined if rat and human lung microsomes are fit for purpose or whether it is better to use specific cells where drug-metabolizing enzymes are concentrated, such as alveolar type II (ATII) cells. Activities for major hepatic and pulmonary human drug-metabolizing enzymes are assessed and the data contextualized towards an in vivo setting using an ex vivo isolated perfused rat lung model. Very low rates of metabolism are observed in incubations with human ATII cells when compared to isolated hepatocytes and fewer of the substrates are found to be metabolized when compared to human lung microsomal incubations. Reactions selective for flavin-containing monooxygenases (FMOs), CYP1B1, CYP2C9, CYP2J2, and CYP3A4 all show significant rates in human lung microsomal incubations, but all activities are higher when rat lung microsomes are used. The work also demonstrates that a lung microsomal intrinsic clearance value towards the lower limit of detection for this parameter (3 µL/min/mg protein) results in a very low level of pulmonary metabolic clearance during the absorption period, for a drug dosed into the lung in vivo.

Treatment of respiratory disease with a drug delivered via inhalation is generally held as being beneficial as it provides direct access to the lung target site with a minimum systemic exposure. There is however only limited information of the regional localization of drug retention following inhalation. The aim of this study was to investigate the regional and histological localization of salmeterol retention in the lungs after inhalation and to compare it to systemic administration. Lung distribution of salmeterol delivered to rats via nebulization or intravenous (IV) injection was analyzed with high-resolution mass spectrometry imaging (MSI). Salmeterol was widely distributed in the entire section at 5 min after inhalation, by 15 min it was preferentially retained in bronchial tissue. Via a novel dual-isotope study, where salmeterol was delivered via inhalation and d 3 -salmeterol via IV to the same rat, could the effective gain in drug concentration associated with inhaled delivery relative to IV, expressed as a site-specific lung targeting factor, was 5-, 31-, and 45-fold for the alveolar region, bronchial sub-epithelium and epithelium, respectively. We anticipate that this MSI-based framework for quantifying regional and histological lung targeting by inhalation will accelerate discovery and development of local and more precise treatments of respiratory disease.

To be fully embraced into mineral exploration, seismic data require to be acquired fast, cheaper and with minimum environmental impacts addressing also the often brown-field highly noisy environment where these surveys are employed. Since 2013 and through a number of case studies, we have been testing a newly developed for urban environment, digital-based 240 m long, seismic landstreamer for mine planning and mineral exploration purposes. Here, we present a pilot study examining the potential of the streamer for deep targeting a known, down to approximately 850 m depth, iron-oxide mineralization in the Bergslagen mineral district of central Sweden. Combined streamer (100-3C-MEMS (micro-electromechanical system), 2-4 m spacing) and 75 wireless recorders (mixed 10 Hz and MEMS, 10 m spacing) were used. A Bobcat-mounted drophammer, 500 kg, was used to generate the seismic signal. Within 4 days, approximately 3.5 km of seismic data using 2-10 m source and receiver spacing were acquired. Reflection data processing results clearly image the mineralization as a set of strong high-amplitude reflections and likely slightly extending beyond the known 850 m depth. This is encouraging and suggests such a cost-effective exploration method can be used in the area and elsewhere to delineate similar depth range iron-oxide deposits.

A fully starch-derived bioactive 3D porous scaffold is developed. The bioactivity is introduced through nanosized graphene oxide (nGO) derived from starch by microwave-assisted degradation to carbon spheres and further oxidation to GO nanodots. nGO is covalently attached to starch to prepare functionalized starch (SNGO) via an esterification reaction. nGO and SNGO exhibit no cytotoxicity to MG63 at least up to 1000 µg mL -1 under (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Porous scaffolds consisting of starch and SNGO (S/SNGO) or nGO (S/nGO) are prepared by freeze drying. The porosity and water uptake ability of the scaffolds depend on the concentration of nGO. Moreover, nGO, as a bioactive nanofiller, functions as an effective anchoring site for inducing CaP recrystallization in simulated body fluid. Among all modified starch-based scaffolds, the S/SNGO scaffold containing the highest concentration of covalently attached SNGO (50%) induces the largest amount of hydroxyapatite, a type of CaP crystal that is closest to bone. The prepared 3D porous nGO functionalized scaffold, thus, exhibits potential promise for bone/cartilage tissue engineering., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)