[Emergency medicine: what's new in 2023]. / Médecine d'urgence: ce qui a changé en 2023.

Research in prehospital and in-hospital emergency medicine is essential to the development of this discipline. By calling certain practices into question (thrombolysis for minor strokes, use of coagulation factors for patients with severe polytrauma), providing access to new technologies (video-laryngoscopy, POCT troponins in pre-hospital care) or questioning new practices (double defibrillation, pulmonary US in pneumonia), research enables emergency physicians to adapt their day-to-day practice.

La recherche en médecine d'urgence, tant sur le plan préhospitalier qu'hospitalier, est nécessaire et même indispensable à la fois au développement de cette discipline, mais également à la reconnaissance de ses spécificités. Par la remise en question de certaines pratiques (thrombolyse pour les AVC mineurs, utilisation de facteurs de la coagulation pour le polytraumatisé sévère), l'accès à de nouvelles technologies (vidéo-laryngoscopie, troponines POCT en préhospitalier) ou le questionnement sur de nouvelles pratiques (double défibrillation, US pulmonaire dans la pneumonie), la recherche permet aux urgentistes d'adapter leur pratique quotidienne à l'état de l'art.

Direct Alkylative Amination Using 1-Allylsilatrane.

Homoallylic amines prepared via addition of allylsilanes often require preformed imine substrates, metal catalysts, fluoride activators, or use of protected amines. In this metal-free, air- and water-tolerant procedure, aromatic aldehyde and aniline substrates undergo direct alkylative amination using easily accessible 1-allylsilatrane.

Opportunities and Challenges for the Development of MRCK Kinases Inhibitors as Potential Cancer Chemotherapeutics.

Cytoskeleton organization and dynamics are rapidly regulated by post-translational modifications of key target proteins. Acting downstream of the Cdc42 GTPase, the myotonic dystrophy-related Cdc42-binding kinases MRCKα, MRCKß, and MRCKγ have recently emerged as important players in cytoskeleton regulation through the phosphorylation of proteins such as the regulatory myosin light chain proteins. Compared with the closely related Rho-associated coiled-coil kinases 1 and 2 (ROCK1 and ROCK2), the contributions of the MRCK kinases are less well characterized, one reason for this being that the discovery of potent and selective MRCK pharmacological inhibitors occurred many years after the discovery of ROCK inhibitors. The disclosure of inhibitors, such as BDP5290 and BDP9066, that have marked selectivity for MRCK over ROCK, as well as the dual ROCK + MRCK inhibitor DJ4, has expanded the repertoire of chemical biology tools to study MRCK function in normal and pathological conditions. Recent research has used these novel inhibitors to establish the role of MRCK signalling in epithelial polarization, phagocytosis, cytoskeleton organization, cell motility, and cancer cell invasiveness. Furthermore, pharmacological MRCK inhibition has been shown to elicit therapeutically beneficial effects in cell-based and in vivo studies of glioma, skin, and ovarian cancers.

Direct photochemical route to azoxybenzenes via nitroarene homocoupling.

We report on a direct photochemical method for the one-pot, catalyst- and additive-free synthesis of azoxybenzene and substituted azoxy derivatives from nitrobenzene building blocks. This reaction is conducted at room temperature and under air, and can be applied to substrates with a wide range of substituents. Yields of products derived from para- and meta-substituted nitrobenzenes are typically good, while sterically encumbered ortho-substituted substrates are not as fruitful. Photochemical Wallach rearrangement of generated azoxybenzenes to ortho-hydroxyazoxybenzenes was observed in some cases, most markedly in selected ortho-halogenated nitrobenzenes. Overall, this method provides an efficient, green pathway to highly value-added azoxybenzene products.

Dual antagonists of α5ß1/αvß1 integrin for airway hyperresponsiveness.

Inhibition of integrin α5ß1 emerges as a novel therapeutic option to block transmission of contractile forces during asthma attack. We designed and synthesized novel inhibitors of integrin α5ß1 by backbone replacement of known αvß1 integrin inhibitors. These integrin α5ß1 inhibitors also retain the nanomolar potency against αvß1 integrin, which shows promise for developing dual integrin α5ß1/αvß1 inhibitor. Introduction of hydrophobic adamantane group significantly boosted the potency as well as selectivity over integrin αvß3. We also demonstrated one of the inhibitors (11) reduced airway hyperresponsiveness in ex vivo mouse tracheal ring assay. Results from this study will help guide further development of integrin α5ß1 inhibitors as potential novel asthma therapeutics.

Control of Porphyrin Planarity and Aggregation by Covalent Capping: Bissilyloxy Porphyrin Silanes.

Porphyrins are cornerstone functional materials that are useful in a wide variety of settings, ranging from molecular electronics to biology and medicine. Their applications are often hindered, however, by poor solubilities that result from their extended, solvophobic aromatic surfaces. Attempts to counteract this problem by functionalizing their peripheries have been met with only limited success. Here, we demonstrate a versatile strategy to tune the physical and electronic properties of porphyrins using an axial functionalization approach. Porphyrin silanes (PorSils) and bissilyloxy PorSils (SOPS) are prepared from porphyrins by operationally simple κ4N-silylation protocols, introducing bulky silyloxy "caps" that are central and perpendicular to the planar porphyrin. While porphyrins typically form either J- or H-aggregates, SOPS do not self-associate in the same manner: the silyloxy axial substituents dramatically improve the solubility by inhibiting aggregation. Moreover, axial porphyrin functionalization offers convenient handles through which optical, electronic, and structural properties of the porphyrin core can be modulated. We observe that the identity of the silyloxy substituent impacts the degree of planarity of the porphyrin in the solid state as well as the redox potentials.

Chiral Brønsted Acid-Catalyzed Metal-Free Asymmetric Direct Reductive Amination Using 1-Hydrosilatrane.

The asymmetric direct reductive amination of prochiral ketones with aryl amines using 1-hydrosilatrane with a chiral Brønsted acid catalyst is reported. This is the first known example of chiral Brønsted acid-catalyzed asymmetric reductive amination using a silane as the hydride source. The reaction features a highly practical reducing reagent and proceeds efficiently at room temperature without a specialized reaction setup or equipment to exclude air or moisture. This method provides high conversion and enantiomeric excess up to 84% of the desired chiral secondary amines with minimal side products.

Total Synthesis of Covalent Cysteine Protease Inhibitor N-Desmethyl Thalassospiramide C and Crystallographic Evidence for Its Mode of Action.

A total synthesis of N-desmethyl thalassospiramide C, a unique strained macrocyclic proteobacterial depsipeptide, enabled a detailed crystallographic study of its covalent complex with cathepsin K, a member of a medicinally important family of cysteine proteases. The study provides support for the mechanism of action, and the insight gained can be used for structure-based drug design targeting these calpain proteases.

Discovery of selective urokinase plasminogen activator (uPA) inhibitors as a potential treatment for multiple sclerosis.

We report here the design and synthesis of a novel series of benzylamines that are potent and selective inhibitors of uPA with promising oral availability in rat. Further evaluation of one representative (ZK824859) of the new structural class showed that this compound lowered clinical scores when dosed in either acute or chronic mouse EAE models, suggesting that uPA inhibitors of this type could be useful for the treatment of multiple sclerosis.

Differing structural properties of foods affect the development of mandibular control and muscle coordination in infants and young children.

The development of chewing is an essential motor skill that is continually refined throughout early childhood. From a motor control perspective, the advancement of textures is dependent upon the fit between a child's oral anatomic and motor system and food properties. The purpose of this exploratory study is to identify age-related changes in chewing motor coordination and control and to determine if these changes are associated with the differing structural properties of solid foods, as well as to explore the role of explanatory variables such as the emergence of teeth and bite force. The masticatory muscle coordination (i.e., coupling of synergistic and antagonistic muscle pairs) and control (i.e., speed, displacement, chewing rate, duration, and number of chews) of fifty children were assessed cross-sectionally at five ages: 9-, 12-, 18-, 24-, and 36-months using electromyography (EMG) and 3D optical motion capture while children ate three foods that had differing structural properties. The results of this study found that children made gains in their chewing motor control (decreased duration of chewing sequences and lateral jaw displacement) and coordination (improved jaw muscle coupling) throughout this period. The structural differences in foods also affected chewing performance at all ages. These preliminary findings suggest that some solid textures are better adapted for immature mandibular control than others and that the development of chewing is a protracted process that may be impacted by the emergence of teeth and changes to bite force.

Computational Study of Ways by Which exo-Silatranes Might Be Prepared.

exo-Silatranes involve cage structures where the nitrogen lone pair points away from the cage rather than into it. This distinguishes them from the well-established endo-silatranes. exo-Silatranes have not been observed experimentally, consistent with a significant benefit to silicon-nitrogen interactions inside the cages as suggested for endo-silatranes. Identifying examples of exo-silatranes would prove useful in understanding Si-N interactions, as they would represent the "no interaction" extreme of the spectrum. We have found four means by which exo-silatranes might be synthesized: (1) employing smaller cages; (2) employing constrained rings to stiffen the cage backbones; (3) employing steric interactions to enhance preference for the less crowded exo-geometry around nitrogen; (4) modifying the Lewis acidity and basicity of the silicon and nitrogen so significantly as to remove their desire to interact. The preference for exo geometries is established using the parameter Δ, representing the distance between the nitrogen atom and the least-squares plane containing the adjacent carbon atoms. In some cases, Δ values for exo-silatranes are greater than 0.3 Å. In others, they are near zero, indicating a nearly planar nitrogen atom. There are no obvious structural markers besides Δ that distinguish between exo- and endo-silatranes.

Extended Aromatic and Heteroaromatic Ring Systems in the Chalcone-Flavanone Molecular Switch Scaffold.

Previous work on the o-hydroxychalcone/flavanone molecular switching scaffold showed that simple substitutions alter the pH range in which rapid interconversion occurs. Herein, more impactful structural modifications were performed via alteration of the characteristic phenyl rings to alternative aromatic systems. It was determined that the scaffold was still viable after these changes and that the range of accessible midpoint pH values was markedly increased. To further explore the switch's scope, scaffolds able to have multiple switching events were also investigated.

A major pain in the Back and epigastrium: an unusual case of spontaneous celiac artery dissection.

A 60-year-old woman with mitral valve prolapse, chronic low back pain, and a 30-pack year smoking history presented for a second admission of poorly controlled mid-back pain 10 days after her first admission. She had concomitant epigastric pain, sharp/burning in quality, radiating to the right side and to the mid-back, not associated with food nor improving with pain medications. She denied nausea, vomiting, diarrhea, constipation, dark stools, or blood per rectum. Our purpose was to determine the cause of the patient's epigastric pain. Physical examination revealed epigastric and mid-back tenderness on palpation. Labs were normal except for a hemoglobin drop from 14 to 12.1 g/dL over 2 days. Abdominal ultrasound and subsequent esophagogastroduodenoscopy were normal. Contrast-enhanced abdominal computed tomographic (CT) scan revealed the development of a spontaneous celiac artery dissection as the cause of the epigastric pain. The patient was observed without stenting and subsequent CT angiography 4 days later did not reveal worsening of the dissection. She was discharged on aspirin and clopidogrel with outpatient follow-up. Thus far, less than 100 cases of isolated spontaneous celiac artery dissections have been reported. The advent of CT scans and magnetic resonance imaging has increasingly enabled its detection. Risk factors may include hypertension, arteriosclerosis, smoking, and cystic medial necrosis. There is a 5:1 male to female ratio with an average presenting age of 55. Management of dissections may include surgical repair, endovascular stenting, and selective embolization. Limited dissections can be managed conservatively with anti-platelet and/or anticoagulation agents and strict blood pressure control, as done in our patient.

Impact of mono- and disubstitution on the colorimetric dynamic covalent switching chalcone/flavanone scaffold.

The effect of aryl substitution on various aspects of the interconversion of ortho-hydroxychalcones and flavanones has been studied using multiple spectroscopic techniques. Derivatization of the core scaffold predictably alters the midpoint pH of this equilibration process suggesting its viability for application as a functional colorimetric molecular switch.

Design and synthesis of hydroxyethylamine (HEA) BACE-1 inhibitors: prime side chromane-containing inhibitors.

The structure activity relationship of the prime region of conformationally restricted hydroxyethylamine (HEA) BACE inhibitors is described. Variation of the P1' region provided selectivity over Cat-D with a series of 2,2-dioxo-isothiochromanes and optimization of the P2' substituent of chromane-HEA(s) with polar substituents provided improvements in the compound's in vitro permeability. Significant potency gains were observed with small aliphatic substituents such as methyl, n-propyl, and cyclopropyl when placed at the C-2 position of the chromane.

Improved ligand binding energies derived from molecular dynamics: replicate sampling enhances the search of conformational space.

Does a single molecular trajectory provide an adequate sample conformational space? Our calculations indicate that for Molecular Mechanics--Poisson-Boltzmann Surface Area (MM-PBSA) measurement of protein ligand binding, a single molecular dynamics trajectory does not provide a representative sampling of phase space. For a single trajectory, the binding energy obtained by averaging over a number of molecular dynamics frames in an equilibrated system will converge after an adequate simulation time. A separate trajectory with nearly identical starting coordinates (1% randomly perturbed by 0.001 Å), however, can lead to a significantly different calculated binding energy. Thus, even though the calculated energy converges for a single molecular dynamics run, the variation across separate runs implies that a single run inadequately samples the system. The divergence in the trajectories is reflected in the individual energy components, such as the van der Waals and the electrostatics terms. These results indicate that the trajectories sample different conformations that are not in rapid exchange. Extending the length of the dynamics simulation does not resolve the energy differences observed between different trajectories. By averaging over multiple simulations, each with a nearly equivalent starting structure, we find the standard deviation in the calculated binding energy to be ∼1.3 kcal/mol. The work presented here indicates that combining MM-PBSA with multiple samples of the initial starting coordinates will produce more precise and accurate estimates of protein/ligand affinity.

Selective and brain-permeable polo-like kinase-2 (Plk-2) inhibitors that reduce α-synuclein phosphorylation in rat brain.

Polo-like kinase-2 (Plk-2) has been implicated as the dominant kinase involved in the phosphorylation of α-synuclein in Lewy bodies, which are one of the hallmarks of Parkinson's disease neuropathology. Potent, selective, brain-penetrant inhibitors of Plk-2 were obtained from a structure-guided drug discovery approach driven by the first reported Plk-2-inhibitor complexes. The best of these compounds showed excellent isoform and kinome-wide selectivity, with physicochemical properties sufficient to interrogate the role of Plk-2 inhibition in vivo. One such compound significantly decreased phosphorylation of α-synuclein in rat brain upon oral administration and represents a useful probe for future studies of this therapeutic avenue toward the potential treatment of Parkinson's disease.

Triazolopyridazine LRRK2 kinase inhibitors.

Leucine-rich repeat kinase 2 (LRRK2) has been implicated in the pathogenesis of Parkinson's disease (PD). Inhibition of LRRK2 kinase activity is a therapeutic approach that may lead to new treatments for PD. Herein we report the discovery of a series of [1,2,4]triazolo[4,3-b]pyridazines that are potent against both wild-type and mutant LRRK2 kinase activity in biochemical assays and show an unprecedented selectivity towards the G2019S mutant. A structural rational for the observed selectivity is proposed.

Discovery of 4-alkylamino-7-aryl-3-cyanoquinoline LRRK2 kinase inhibitors.

Mutations in leucine-rich repeat kinase 2 (LRRK2) are associated with familial Parkinson's disease (PD). The kinase activity of this complex protein is increased by pathogenic mutations. Inhibition of LRRK2 kinase activity has therefore emerged as a promising approach for the treatment of PD. Herein we report our findings on a series of 4-alkylamino-7-aryl-3-cyanoquinolines that exhibit kinase inhibitory activity against both wild type and G2019S mutant LRRK2. Activity was determined in both biochemical and cellular assays. Compound 14 was further evaluated in an in vivo pharmacodynamic study and found to significantly inhibit Ser935 phosphorylation after oral dosing.

Towards a dynamic covalent molecular switch: substituent effects in chalcone/flavanone isomerism.

Chalcone/flavanone interconversion occurs facilely under aqueous alkaline conditions making it a promising scaffold for the development of a covalent molecular switch. In this study, a single methoxy substituent is shown to have a significant impact on the equilibrium dynamics of this reaction; this impact is dependent on the site of substitution.