A Field Study of Carbon Monoxide Levels in Snow Caves During Short-Term Stove Use.

INTRODUCTION: While the use of camping stoves in poorly ventilated areas is discouraged, the need to address dehydration challenges in harsh arctic conditions has led to their unconventional use inside snow caves for snow melting, subjecting occupants to unknown carbon monoxide (CO) levels. This study, located at sea level in northeastern Greenland, aimed to assess CO levels and dynamics during short cooking sessions in newly constructed emergency snow caves. METHODS: In 5 snow caves, constructed according to the same design principles by 4 different individuals, a single MSR Whisperlite multifuel burner, primed with ethanol and burning white gas, was used to melt snow. CO concentrations were monitored every minute until all the snow in a 5-L pot was converted to water and CO levels returned to below 10 ppm. RESULTS: A total of 16 experiments conducted showed that the priming phase generated the highest CO peaks, with a maximum of 120 ppm. Time-weighted averages ranged from 14 ppm to 67 ppm, with trial durations of 15 to 21 min. A single trial with a dirty burner resulted in up to a 10-fold increase in CO levels. CONCLUSIONS: While single, short cooking sessions of less than 10 min burn time in newly constructed snow caves may be tolerated under specific conditions, the study highlighted substantial variation between caves and the importance of using clean burners, emphasizing the need for further research to gain a comprehensive understanding of CO exposure dynamics in snow caves.

Development of an ex-vivo porcine lower urinary tract model to evaluate the performance of urinary catheters.

Intermittent catheterization is the gold standard method for bladder management in individuals with urinary retention and/or incontinence. It is therefore important to understand the performance of urinary catheters, especially on parameters associated to risks of developing urinary tract infections, and that may impact the quality of life for urinary catheter users. Examples of such parameters include, urine flowrate, occurrence of flow-stops, and residual urine left in the bladder after flow-stop. Reliable in-vitro and/or ex-vivo laboratory models represent a strong asset to assess the performance of urinary catheters, preceding and guiding in-vivo animal studies and/or human clinical studies. Existing laboratory models are generally simplified, covering only portions of the catheterization process, or poorly reflect clinical procedures. In this work, we developed an ex-vivo porcine lower urinary tract model that better reflects the catheterization procedure in humans and allows to investigate the performance of standard of care catheters. The performance of three standard of care catheters was investigated in the developed model showing significant differences in terms of flowrate. No differences were detected in terms of residual volume in the bladder at first flow-stop also when tuning the abdominal pressure to mimic a sitting down and standing up position. A newly discovered phenomenon named hammering was detected and measured. Lastly, mucosal suction was observed and measured in all standard of care catheters, raising the concern for microtrauma during catheterization and a need for new and improved urinary catheter designs. Results obtained with the ex-vivo model were compared to in-vivo studies, highlighting similar concerns.

Macrolide Inspired Macrocycles as Modulators of the IL-17A/IL-17RA Interaction.

Interleukin 17 (IL-17) cytokines promote inflammatory pathophysiology in many autoimmune diseases, including psoriasis, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease. Such broad involvement of IL-17 in various autoimmune diseases makes it an ideal target for drug discovery. Psoriasis is a chronic inflammatory disease characterized by numerous defective components of the immune system. Significantly higher levels of IL-17A have been noticed in lesions of psoriatic patients, if compared to non-lesion parts. Therefore, this paper is focused on the macrolide inspired macrocycles as potential IL-17A/IL-17RA modulators and covers the molecular design, synthesis, and in vitro profiling. Macrocycles are designed to diversify and enrich chemical space through different ring sizes and a variety of three-dimensional shapes. Inhibitors in the nM range were identified in both target-based and phenotypic assays. In vitro ADME as well as in vivo PK properties are reported.

Evaluating Dermal Pharmacokinetics and Pharmacodymanic Effect of Soft Topical PDE4 Inhibitors: Open Flow Microperfusion and Skin Biopsies.

PURPOSE: To investigate the difference in clinical efficacy in AD patients between two topical PDE4 inhibitors using dermal open flow microperfusion and cAMP as a pharmacodynamic read-out in fresh human skin explants. METHODS: Clinical formulations were applied to intact or barrier disrupted human skin explants and both skin biopsy samples and dermal interstitial fluid was sampled for measuring drug concentration. Furthermore, cAMP levels were determined in the skin biopsies as a measure of target engagement. RESULTS: Elevated cAMP levels were observed with LEO 29102 while no evidence of target engagement was obtained with LEO 39652. In barrier impaired skin the dISF concentration of LEO 29102 was 2100 nM while only 33 nM for LEO 39652. For both compounds the concentrations measured in skin punch biopsies were 7-33-fold higher than the dISF concentrations. CONCLUSIONS: Low unbound drug concentration in dISF in combination with minimal target engagement of LEO 39652 in barrier impaired human skin explants supports that lack of clinical efficacy of LEO 39652 in AD patients is likely due to insufficient drug availability at the target. We conclude that dOFM together with a pharmacodynamic target engagement biomarker are strong techniques for establishing skin PK/PD relations and that skin biopsies should be used with caution.

Discovery and Early Clinical Development of Isobutyl 1-[8-Methoxy-5-(1-oxo-3H-isobenzofuran-5-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxylate (LEO 39652), a Novel "Dual-Soft" PDE4 Inhibitor for Topical Treatment of Atopic Dermatitis.

We describe the design of a novel PDE4 scaffold and the exploration of the dual-soft concept to reduce systemic side effects via rapid elimination: introducing ester functionalities that can be inactivated in blood as well as by the liver (dual-soft) while being stable in human skin. Compound 40 was selected as a clinical candidate as it was potent and rapidly degraded by blood and liver to inactive metabolites and because in preclinical studies it showed high exposure at the target organ: the skin. Preclinical and clinical data are presented confirming the value of the dual-soft concept in reducing systemic exposure.

DNA flowerstructure co-localizes with human pathogens in infected macrophages.

Herein, we characterize the cellular uptake of a DNA structure generated by rolling circle DNA amplification. The structure, termed nanoflower, was fluorescently labeled by incorporation of ATTO488-dUTP allowing the intracellular localization to be followed. The nanoflower had a hydrodynamic diameter of approximately 300 nanometer and was non-toxic for all mammalian cell lines tested. It was internalized specifically by mammalian macrophages by phagocytosis within a few hours resulting in specific compartmentalization in phagolysosomes. Maximum uptake was observed after eight hours and the nanoflower remained stable in the phagolysosomes with a half-life of 12 h. Interestingly, the nanoflower co-localized with both Mycobacterium tuberculosis and Leishmania infantum within infected macrophages although these pathogens escape lysosomal degradation by affecting the phagocytotic pathway in very different manners. These results suggest an intriguing and overlooked potential application of DNA structures in targeted treatment of infectious diseases such as tuberculosis and leishmaniasis that are caused by pathogens that escape the human immune system by modifying macrophage biology.

Musculoskeletal pain is common in competitive gaming: a cross-sectional study among Danish esports athletes.

OBJECTIVES: The interest for competitive esports is growing. Little is known regarding musculoskeletal (MSK) pain among esports athletes. We aimed to investigate (1) the prevalence of MSK pain, (2) the association between MSK pain and esports-related training volume and (3) the association between MSK pain and physical activity levels. METHODS: Athletes aged 15-35 years who participated in structured esports through a computer-based game were eligible for inclusion. Participant demographics, hours/week spent on esports, self-report MSK pain sites, pain frequency, sleep, care-seeking behaviour and physical activity levels were collected through online questionnaires. The primary outcome was any MSK pain in the body during the previous week. RESULTS: Of 188 included athletes, 42.6% reported MSK pain. The most common pain site was the back (31.3%). Athletes with MSK pain participated in significantly less esports training compared with athletes without MSK pain (mean difference -5.6 hours/week; 95% CI -10.6 to -0.7, p=0.035). There was no significant difference in physical activity levels between groups (mean difference 81.1 metabolic equivalent of task-minutes/week; 95% CI -1266.9 to 1429.1, p=0.906). CONCLUSION: Back pain is common among esports athletes. Athletes with MSK pain participated in less esports training compared with those without pain, suggesting a potentially negative effect of pain on esports participation.

Using Polarized Spectroscopy to Investigate Order in Thin-Films of Ionic Self-Assembled Materials Based on Azo-Dyes.

Three series of ionic self-assembled materials based on anionic azo-dyes and cationic benzalkonium surfactants were synthesized and thin films were prepared by spin-casting. These thin films appear isotropic when investigated with polarized optical microscopy, although they are highly anisotropic. Here, three series of homologous materials were studied to rationalize this observation. Investigating thin films of ordered molecular materials relies to a large extent on advanced experimental methods and large research infrastructure. A statement that in particular is true for thin films with nanoscopic order, where X-ray reflectometry, X-ray and neutron scattering, electron microscopy and atom force microscopy (AFM) has to be used to elucidate film morphology and the underlying molecular structure. Here, the thin films were investigated using AFM, optical microscopy and polarized absorption spectroscopy. It was shown that by using numerical method for treating the polarized absorption spectroscopy data, the molecular structure can be elucidated. Further, it was shown that polarized optical spectroscopy is a general tool that allows determination of the molecular order in thin films. Finally, it was found that full control of thermal history and rigorous control of the ionic self-assembly conditions are required to reproducibly make these materials of high nanoscopic order. Similarly, the conditions for spin-casting are shown to be determining for the overall thin film morphology, while molecular order is maintained.

Synthesis and Characterisation of Substrate-Based Peptides as Inhibitors of Histone Demethylase KDM4C.

The design and synthesis of modified pentapeptides based on a truncated version of the substrate for KDM4C, a histone lysine demethylase (KDM), and investigation of their inhibitory activity at KDM4C is reported. By modifying the lysine residue corresponding to lysine 9 at histone 3 (H3K9), three different series of peptides were designed and synthesized. One series contained N-acylated H3K9 and two series introduced triazoles in this position via click chemistry to enable facile variation of headgroups. The click reaction is compatible with free amino acids and this was performed on an azido containing deprotected pentapeptide demonstrating a highly facile and convergent synthetic strategy for making substrate-based inhibitors. One of the 14 peptides showed inhibitory activity at KDM4C demonstrating the need for an iron chelator in the pentapeptide series.

Differential role of AMPA receptors in mouse tests of antidepressant and anxiolytic action.

Depression and anxiety often co-occur, and conventional monoamine-facilitating antidepressants show efficacy against symptoms in both disorders. Rodent studies indicate that antidepressant effects of monoamine-based antidepressants involve increased α-amino-3-hydroxy-5- methyl-4-isoxazolepropionic acid glutamate receptor (AMPAR) neurotransmission, and positive allosteric modulators (PAMs) at AMPARs produced antidepressant-like effects in rodents. While this suggests that increased AMPAR-mediated neurotransmission is beneficial in depression management, preclinical studies addressing AMPARs in relation to anxiety have given ambiguous results with both anxiolytic-like and anxiogenic-like effects observed after AMPAR blockade. This study systematically compared the effects of the AMPAR potentiator LY451646 and the AMPAR antagonist GYKI-53655 on depression-related behaviour using the mouse forced swim (FST) and tail suspension tests (TST), and anxiety-related behaviour using the elevated zero maze (EZM), marble burying (MB) and novelty-induced hypophagia (NIH) tests. The serotonin-selective antidepressant citalopram was included for comparison. Due to the importance of AMPARs in learning and memory we also tested if GYKI-53655 disrupted performance in the V-maze test for attention-dependent behaviour, and the social transmission of food preference (STFP) test of long-term memory. LY451646 (3 mg/kg) showed an antidepressant-like profile in the FST and TST, and GYKI-53655 (≥ 5 mg/kg) had a depressogenic-like effect in the TST but no effect in the FST. Conversely, GYKI-53655 produced marked anxiolytic-like effects in the EZM (≥ 2.5 mg/kg), MBT (≥ 2.5 mg/kg), and NIH tests (≥ 5 mg/kg), while LY451646 (≥ 3 mg/kg) increased anxiety-like behaviour in the EZM. Citalopram showed an antidepressant-like effect in the FST (≥ 10 mg/kg), but not TST, an anxiolytic-like effect in the EZM (≥ 3 mg/kg) and MB test (≥ 2.5 mg/kg), and an anxiogenic-like effect in the NIH test (≥ 30 mg/kg). GYKI-53655 did not affect cognitive performance in the V-maze or STFP tests. Collectively, these findings suggest a differential role of AMPARs in depression and anxiety, with AMPAR activation promoting antidepressant responses and AMPAR inhibition promoting anxiolytic responses. The potential of AMPARs as a novel target in depression and anxiety pharmacotherapy is discussed.

Normative perceptual estimates for 91 healthy subjects age 60-75: impact of age, education, employment, physical exercise, alcohol, and video gaming.

Visual perception serves as the basis for much of the higher level cognitive processing as well as human activity in general. Here we present normative estimates for the following components of visual perception: the visual perceptual threshold, the visual short-term memory (VSTM) capacity and the visual perceptual encoding/decoding speed (processing speed) of VSTM based on an assessment of 91 healthy subjects aged 60-75. The estimates were modeled from input from a whole-report assessment based on a theory of visual attention. In addition to the estimates themselves, we present correlational data, and multiple regression analyses between the estimates and self-reported demographic data and lifestyle variables. The regression statistics suggest that education level, video gaming activity, and employment status may significantly impact the encoding/decoding speed of VTSM but not the capacity of VSTM nor the visual perceptual threshold. The estimates will be useful for future studies into the effects of various types of intervention and training on cognition in general and visual attention in particular.

Discovery and early clinical development of 2-{6-[2-(3,5-dichloro-4-pyridyl)acetyl]-2,3-dimethoxyphenoxy}-N-propylacetamide (LEO 29102), a soft-drug inhibitor of phosphodiesterase 4 for topical treatment of atopic dermatitis.

Development of orally available phosphodiesterase 4 (PDE4) inhibitors as anti-inflammatory drugs has been going on for decades. However, only roflumilast has received FDA approval. One key challenge has been the low therapeutic window observed in the clinic for PDE4 inhibitors, primarily due to PDE4 mediated side effects. Here we describe our approach to circumvent this issue by applying a soft-drug concept in the design of a topically acting PDE4 inhibitor for treatment of dermatological diseases. We used a fast follower approach, starting from piclamilast. In particular, simultaneous introduction of 2'-alkoxy substituents and changing an amide to a keto linker proved to be beneficial when designing potential soft-drug candidates. This effort culminated in identification of LEO 29102 (20), a potent, selective, and soft-drug PDE4 inhibitor with properties suitable for patient-friendly formulations giving efficient drug delivery to the skin. Compound 20 has reached phase 2 and demonstrated clinically relevant efficacy in the treatment of atopic dermatitis.

Cognitive aging on latent constructs for visual processing capacity: a novel structural equation modeling framework with causal assumptions based on a theory of visual attention.

We examined the effects of normal aging on visual cognition in a sample of 112 healthy adults aged 60-75. A testbattery was designed to capture high-level measures of visual working memory and low-level measures of visuospatial attention and memory. To answer questions of how cognitive aging affects specific aspects of visual processing capacity, we used confirmatory factor analyses in Structural Equation Modeling (SEM; Model 2), informed by functional structures that were modeled with path analyses in SEM (Model 1). The results show that aging effects were selective to measures of visual processing speed compared to visual short-term memory (VSTM) capacity (Model 2). These results are consistent with some studies reporting selective aging effects on processing speed, and inconsistent with other studies reporting aging effects on both processing speed and VSTM capacity. In the discussion we argue that this discrepancy may be mediated by differences in age ranges, and variables of demography. The study demonstrates that SEM is a sensitive method to detect cognitive aging effects even within a narrow age-range, and a useful approach to structure the relationships between measured variables, and the cognitive functional foundation they supposedly represent.

How low can you go: spatial frequency sensitivity in a patient with pure alexia.

Pure alexia is a selective deficit in reading, following lesions to the posterior left hemisphere. Writing and other language functions remain intact in these patients. Whether pure alexia is caused by a primary problem in visual perception is highly debated. A recent hypothesis suggests that a low level deficit - reduced sensitivity to particular spatial frequencies - is the underlying cause. We tested this hypothesis in a pure alexic patient (LK), using a sensitive psychophysical paradigm to examine her performance with simple patterns of different spatial frequency. We find that both in a detection and a classification task, LK's contrast sensitivity is comparable to normal controls for all spatial frequencies. Thus, reduced spatial frequency sensitivity does not constitute a general explanation for pure alexia, suggesting that the core deficit in this disorder is at a higher level in the visual processing stream.

Does increasing the ratio of AMPA-to-NMDA receptor mediated neurotransmission engender antidepressant action? Studies in the mouse forced swim and tail suspension tests.

Monoamine-based antidepressant drugs increase α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) function and decrease N-methyl-d-aspartate receptor (NMDAR) function. The NMDAR antagonist ketamine shows potent antidepressant action in humans and the antidepressant-like effects of ketamine and monoamine-based antidepressants in rodents depend on increased AMPAR throughput. Further, the antidepressant-like effects of monoamine-based antidepressants are enhanced by AMPAR potentiation and by NMDAR antagonism. This has led to a hypothesis that antidepressant efficacy involves an increases ratio of AMPAR-to-NMDAR-mediated neurotransmission. To further elucidate the interaction of AMPAR, NMDAR and monoamine transmission we tested combinations of the AMPAR positive allosteric modulator (AMPA potentiator), (R,R)-N,N-(2,20-[biphenyl-4-40-diyl]bis[propane-2,1-diyl])dimethanesulfonamide (PIMSD), with: the uncompetitive NMDAR antagonist MK-801; nicotine, which has potent glutamate-releasing properties; and the selective serotonin reuptake inhibitor escitalopram using the mouse forced swim (mFST) and tail suspension tests (mTST). MK-801, nicotine or escitalopram did not induce antidepressant-like effects in either of the two tests. PIMSD enhanced the effect of MK-801 in the mFST, supporting the hypothesis that increasing AMPAR-to-NMDAR-mediated neurotransmission conveys antidepressant action. Nicotine-induced glutamate release simultaneously activates NMDARs and AMPARs and showed no net effect in the mFST when given alone. However, increasing the ratio of AMPAR-to-NMDA-R transmission by favouring AMPAR throughput with PIMSD revealed an antidepressant-like action of nicotine in the mFST. PIMSD also enhanced the effect of escitalopram treatment in the mFST and mTST, supporting existing evidence and suggesting a synergistic effect of simultaneously facilitating monoamine transmission and increasing the ratio of AMPAR-to-NMDAR throughput. No synergistic effects of the PIMSD+MK-801 or PIMSD+nicotine were found in the mTST, indicating a differential sensitivity of mFST and mTST when investigating glutamate-based antidepressant mechanisms. This study corroborates existing evidence that there may be an unexploited therapeutic potential in treating depression by directly increasing the ratio of AMPAR-to-NMDAR neurotransmission, possibly in combination with monoamine-based mechanisms.

Development of 2'-substituted (2S,1'R,2'S)-2-(carboxycyclopropyl)glycine analogues as potent N-methyl-d-aspartic acid receptor agonists.

A series of 2'-substituted analogues of the selective NMDA receptor ligand (2S,1'R,2'S)-2-(carboxycyclopropyl)glycine ((S)-CCG-IV) have been designed, synthesized, and pharmacologically characterized. The design was based on a docking study hypothesizing that substituents in the 2'-position would protrude into a region where differences among the NMDA receptor GluN2 subunits exist. Various synthetic routes were explored, and two different routes provided a series of alkyl-substituted analogues. Pharmacological characterization revealed that these compounds are NMDA receptor agonists and that potency decreases with increasing size of the alkyl groups. Variations in agonist activity are observed at the different recombinant NMDA receptor subtypes. This study demonstrates that it is possible to introduce substituents in the 2'-position of (S)-CCG-IV while maintaining agonist activity and that variation among NMDA receptor subtypes may be achieved by probing this region of the receptor.

[Venovenous hemodiafiltration for patient with baclofen intoxication]. / Venovenøs hæmodiafiltrering til baclofenforgiftet patient.

Twice a young man was admitted to hospital upon having taken baclofen overdoses by intention. The ingested dose was 1,850 mg at the first episode and up to 2,500 mg at the second. In both cases the patient had severe overdose symptoms and scored 4-5 on the Glascow Coma Scale and was admitted to intensive care. Continuous venovenous hemodiafiltration (CVVHDF) was initiated. The elimination pharmacokinetics and toxicokinetics for baclofen is not fully known. During the second submission a shorter elimination half-life time was observed and it might be due to either compartmental distribution of baclofen, or more likely caused by an advantageous effect of the CVVHDF.

Ingestion of six cylindrical and four button batteries.

We report a suicidal ingestion of six cylindrical and four button batteries, in combination with overdosed prescription medicine and smoking of cannabis.

Synthesis and application of a new fluorous-tagged ammonia equivalent.

A novel fluorous-tagged ammonia equivalent has been developed. It is based on a nitrogen-oxygen bond, which can be cleaved in a traceless manner by a molybdenum complex or samarium diiodide. The application in the synthesis of ureas, amides, sulfonamides, and carbamates is described. The scope of the fluorous N-O linker is exemplified by the synthesis of itopride, a drug used for the treatment of functional dyspepsia. Itopride was synthesized with the aid of fluorous purification methods and the product was isolated in good overall yield, with high purity.