Not all apparently gynandromorphic butterflies are gynandrous: The case of Polyommatus icarus and its relatives (Lepidoptera: Lycaenidae).

Beside the more than two thousand normal specimens of Polyommatus icarus (Rottemburg, 1775) yielded by rearing experiments, there was one perfectly bilateral dichromatic individual first considered to be gynandrous. On the basis of analysing genitalia traits, wing surface covering scale micromorphology, and the spectral characteristics of the blue colour generated by the cover scales, the gender of the specimen has been identified as female. This exemplar was investigated in comparison with gynandrous specimens from the collections of the Hungarian Natural History Museum exhibiting various degrees of intermixing of blue and brown coloration. Focus stacking microscopy for detailed scale morphology and UV-visible reflectance spectroscopy was used for the characterization of the optical properties. Inspecting literature references and the Lycaenidae collection of the museum, further examples have been found for female bilateral dichromatism in the closely related polyommatine lycaenid species Lysandra bellargus (Rottemburg, 1775) and Lysandra coridon (Poda, 1761) what suggests that polyommatine female dichromaticity may be displayed by the manner of bilaterality and mosaicism, phenomena hitherto solely connected to gynandromorphy.

Vinyl and Alkynyl Substituted Heterocycles as Privileged Scaffolds in Transition Metal Promoted Stereoselective Synthesis.

ConspectusBiologically active compounds and pharmaceutically relevant intermediates often feature sterically congested stereogenic centers, in particular, carbon stereocenters that are either tertiary tetrasubstituted ones or quaternary in nature. Synthons that comprise such bulky and often structurally complex core units are of high synthetic value and represent important incentives for communities connected to drug discovery and development. Streamlined approaches that give access to a diverse set of compounds incorporating acyclic bulky stereocenters are relatively limited, though vital. They enable further exploration of three-dimensional entities that can be designed and implemented in discovery programs, thereby extending the pool of molecular properties that is inaccessible for flat molecules. However, the lack of modular substrates in particular areas of chemical space inspired us to consider functionalized heterocycles known as cyclic carbonates and carbamates as a productive way to create sterically crowded alkenes and stereocenters.In this Account, we describe the major approximations we followed over the course of 8 years using transition metal (TM) catalysis as an instrument to control the stereochemical course of various allylic and propargylic substitution processes and related transformations. Allylic substitution reactions empowered by Pd-catalysis utilizing a variety of nucleophiles are discussed, with amination being the seed of all of this combined work. These procedures build on vinyl-substituted cyclic carbonates (VCCs) that are simple and easy-to-access precursors and highly modular in nature compared to synthetically limited vinyl oxiranes. Overall these decarboxylative conversions take place with either "linear" or "branched" regioselectivities that are ligand controlled and offer access to a wide scope of functional allylic scaffolds. Alternative approaches, including dual TM/photocatalyzed transformations, allowed us to expand the repertoire of challenging stereoselective conversions. This was achieved through key single-electron pathways and via formal umpolung of intermediates, resulting in new types of carbon-carbon bond formation reactions significantly expanding the scope of allylic substitution reactions.Heterocyclic substrate variants that have triple bond functional groups were also designed by us to enable difficult-to-promote stereoselective propargylic substitution reactions through TM catalysis. In these processes, inspired by the Nishibayashi laboratory and their seminal findings in the area, we discovered various new reactivity patterns. This provided access to a range of different stereodefined building blocks such as 1,2-diborylated 1,3-dienes and tetrasubstituted α-allenols under Cu- or Ni-catalysis. In this realm, the use of lactone-derived substrates gives access to elusive chiral γ-amino acids and lactams with high stereofidelity and good structural diversity.Apart from the synthetic efforts, we have elucidated some of the pertinent mechanistic manifolds operative in these transformations to better understand the limitations and opportunities with these specifically functionalized heterocycles that allowed us to create complex synthons. We combined both theoretical and experimental investigations that lead to several unexpected outcomes in terms of enantioinduction models, catalyst preactivation, and intermediates that are intimately connected to rationales for the observed selectivity profiles. The combined work we have communicated over the years offers insight into the unique reactivity of cyclic carbonates/carbamates acting as privileged precursors. It may inspire other members of the synthetic communities to widen the scope of precursors toward novel stereoselective transformations with added value in drug discovery and development in both academic and commercial settings.

Uncommon life history and winter spawning of common carp (Cyprinus carpio) in a natural thermal spring, under temperate climate.

Common carp female generally matures at age 4-5 years old and spawns between April and July under the temperate climate. Contrary to a range of 0-28 °C of temperate freshwaters, the water temperature of Lake Hévíz (Hungary, Central Europe), the largest natural bathable thermal lake in the world, varies between 26 and 35 °C seasonally. The specific environmental conditions (continuously warm water and its individual chemical composition, special nutrient base, lack of natural lakeside spawning substrate compared to usual spawning grounds, continuous high human disturbance, etc.) suggest that the carp population here may also differ in reproductive characteristics from their counterparts in surrounding waters. Our findings suggest that the self-sustaining dwarf common carp population of Lake Hévíz matures 2 to 4 years earlier (at the age of one) and spawns 1 to 3 months before (between February and April, at 27-30 °C water temperature) than carp typically do in the temperate zone (16-20 °C). Successful winter spawning was verified by rearing larvae from the collected eggs and in situ induced propagation.

Ni-Catalyzed Regio- and Enantioselective Homoallylic Coupling: Synthesis of Chiral Branched 1,5-Dienes Featuring a Quaternary Stereogenic Center and Mechanistic Analysis.

Asymmetric synthesis of small molecules comprising quaternary stereogenic carbon centers represents a challenging objective. Here regio- and enantioselective synthesis of chiral 1,5-dienes featuring quaternary stereocenters is reported via nickel-promoted by reductive homoallylic coupling. The developed methodology features an atypical preference for the formation of unusual branched regioisomers (rr >20 : 1) in a sterically challenging allylic substitution event and furnishes the products with enantiomeric ratios of up to 98 : 2 and with high chemo- and E-selectivity. A range of experimental evidences suggest that zinc plays a dual role to generate electrophilic and nucleophilic Ni(II)-allyl intermediates empowering a unique formal bimetallic cross-electrophile manifold in two separate kinetic regimes.

The dual role of cannabidiol on monocyte-derived dendritic cell differentiation and maturation.

Introduction: Extracts and compounds isolated from hemp (Cannabis sativa) are increasingly gaining popularity in the treatment of a number of diseases, with topical formulations for dermatological conditions leading the way. Phytocannabinoids such as ( )-cannabidiol, ( )-cannabinol and ( )-Δ9-tetrahydrocannabivarin (CBD, CBN, and THCV, respectively), are present in variable amounts in the plant, and have been shown to have mostly anti-inflammatory effects both in vitro and in vivo, albeit dominantly in murine models. The role of phytocannabinoids in regulating responses of dendritic cells (DCs) remains unclear. Methods: Our research aimed to investigate the effects of CBD, CBN, and THCV on human DCs differentiated from monocytes (moDCs). moDCs were treated with up to 10 µM of each phytocannabinoid, and their effects on viability, differentiation, and maturation were assessed both alone, and in conjunction with TLR agonists. The effects of CBD on cytokine production, T cell activation and polarization as well as the transcriptome of moDCs was also determined. Results: Phytocannabinoids did not influence the viability of moDCs up to 10 µM, and only CBD had effects on maturational markers of moDCs, and neither compound influenced LPS-induced activation at 10 µM. Since only CBD had measurable effects on moDCs, in our subsequent experiments we tested the effect only of that pCB. On moDCs differentiated in the presence of CBD subsequent activation by LPS induced a markedly different, much more tolerogenic response. CBD-treated moDCs also produced significantly more interleukin (IL)-6, TNFα and, importantly, IL-10 in response to LPS, which shows a shift toward anti-inflammatory signaling, as well as a more robust secretory response in general. To rule out the possibility that these effects of CBD are specific to TLR4 signaling, we determined the effect of CBD on TLR7/8-induced maturation as well, and saw similar, although less marked responses. CBD-treated moDCs were also less efficient at activating naïve T cells after LPS stimulation, further supporting the tolerogenic effect of this phytocannabinoid on moDCs. Reactome pathway analysis showed an inflammatory response to LPS in moDCs, and to a lesser extent to CBD as well. In contrast CBD-treated moDCs responded to LPS with a shift towards a more tolerogenic phenotype, as IL-10 signaling was the most prominently induced pathway in this group. Discussion: Our results show that CBD achieves an anti-inflammatory effect on adaptive immune responses only in the presence of an activating stimuli on moDCs by reprogramming cells during long-term treatment, and not through acute, short-term effects.

Randomized Phase II Study of the Safety and Efficacy of Semorinemab in Participants With Mild-to-Moderate Alzheimer Disease: Lauriet.

BACKGROUND AND OBJECTIVES: Accumulation of tau pathology in Alzheimer disease (AD) correlates with cognitive decline. Anti-tau immunotherapies were proposed as potential interventions in AD. While antibodies targeting N-terminal tau failed to demonstrate clinical efficacy in prodromal-to-mild AD, their utility at other disease stages was not evaluated in prior studies. Lauriet is a phase 2 study of an anti-tau monoclonal antibody, semorinemab, in patients with mild-to-moderate AD. METHODS: The phase 2 Lauriet study included a randomized, placebo-controlled, double-blind period, during which participants with mild-to-moderate AD received 4,500 mg of IV semorinemab or placebo every 4 weeks for 48 or 60 weeks. Participants who chose to continue in the subsequent optional open-label extension received 4,500 mg of semorinemab every 4 weeks for up to 96 weeks. Coprimary efficacy endpoints were change from baseline to week 49 or 61 on the 11-item version of the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog11) and the Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale. Secondary efficacy endpoints included change from baseline on the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating-Sum of Boxes (CDR-SB). Safety, pharmacokinetics, and pharmacodynamic effects were also evaluated. RESULTS: Between December 3, 2018, and February 27, 2020, 624 individuals were screened, 272 participants were randomized, and 238 were included in the modified intent-to-treat population (received ≥1 dose(s) of study medication and underwent baseline and ≥1 postbaseline assessment(s)). Baseline characteristics were well balanced. At week 49, the semorinemab arm demonstrated a 42.2% reduction (-2.89 points, 95% CI -4.56 to -1.21, p = 0.0008) in decline on the ADAS-Cog11 (coprimary endpoint) relative to the placebo arm. However, no treatment effects were observed on the ADCS-ADL scale (coprimary endpoint; absolute difference between the 2 treatment arms in the ADCS-ADL score change from baseline of -0.83 points, 95% CI -3.39 to 1.72, p = 0.52) or on the MMSE or CDR-SB (secondary endpoints). Semorinemab was safe and well tolerated. DISCUSSION: Based on the results of the prespecified coprimary endpoints, this study was negative. While semorinemab had a significant effect on cognition measured by the ADAS-Cog11, this effect did not extend to improved functional or global outcomes. These results may warrant further exploration of semorinemab or other anti-tau therapies in mild-to-moderate AD. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that semorinemab does not slow functional decline in patients with mild-to-moderate AD. TRIAL REGISTRATION INFORMATION: The Lauriet study is registered on ClinicalTrials.gov, NCT03828747, and EudraCT 2018-003398-87.

Pruritogenic molecules in the skin of patients with dermatomyositis.

Introduction: Pruritus is a common excruciating symptom in systemic autoimmune diseases such as dermatomyositis (DM) but the pathogenesis is not fully understood. We intended to investigate the targeted expression analysis of candidate molecules involved in the development of pruritus in lesional vs. non-lesional skin samples of patients affected with active DM. We looked for correlations between the investigated pruriceptive signaling molecules, disease activity, and itching sensation of DM patients. Methods: Interleukins (IL-33 and IL-6), tumor necrosis factor α (TNF-α), peroxisome proliferator-activated receptor γ (PPAR-γ), and ion channels belonging to the transient receptor potential (TRP) family were analyzed. The expression of TNF-α, PPAR-γ, IL-33, IL-6, and TRP channels in lesional DM skin was evaluated by RT-qPCR and immunohistochemistry and was compared with non-lesional DM skin samples. Pruritus, disease activity, and damage of DM were evaluated by the 5-D itch scale and Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI), respectively. Statistical analysis was performed with IBM SPSS 28 software. Results: A total of 17 active DM patients participated in the study. We could show that the itching score was positively correlated with the CDASI activity score (Kendall's tau-b = 0.571; p = 0.003). TNF-α gene expression was significantly higher in lesional DM skin than in non-lesional DM skin (p = 0.009) and differed in the subgroups of patients with different itch intensities (p = 0.038). The mRNA expression of lesional IL-6 correlated positively with 5-D itch and CDASI activity score (Kendall's tau-b = 0.585; p = 0.008 and 0.45; p = 0.013, respectively). TRPV4 expressions were positively correlated with CDASI damage score (Kendall's tau-b = 0.626; p < 0.001), but the mRNA expressions of the TRP family, PPAR-γ, IL-6, and IL-33 were not different in lesional and non-lesional samples. Immunohistochemistry analysis did not find significant alterations in the expressions of TNF-α, PPAR-γ, IL-6, and IL-33 in lesional and non-lesional regions. Discussion: Our results argue that cutaneous disease activity, TNF-α, and IL-6 might play a central role in DM-associated itch, while TRPV4 plays a central role in tissue regeneration.

TRPV4 Activation Increases the Expression of CD207 (Langerin) of Monocyte-Derived Langerhans Cells without Affecting their Maturation.

Langerhans cells (LCs) are the sole professional antigen-presenting cell normally found in the human epidermal compartment. Research into their physiological role is hindered by the fact that they are invariably activated during isolation from the skin. To overcome this challenge, we turned to a monocyte-derived LC (moLC) model, which we characterized with RNA sequencing, and compared the transcriptome of moLCs with that of donor-matched immature dendritic cells. We found that moLCs express markers characteristic of LC2 cells as well as TRPV4. TRPV4 is especially important in the skin because it has been linked to the conservation of the skin barrier, immunological responses, as well as acute and chronic itch, but we know little about its function on LCs. Our results show that TRPV4 activation increased the expression of Langerin and led to increased intracellular calcium concentration in moLCs. Regarding the functionality of moLCs, we found that TRPV4 agonism had a mitigating effect on their inflammatory responses because it decreased their cytokine production and T-cell activating capability. Because TRPV4 has emerged as a potential therapeutic target in dermatological conditions, it is important to highlight LCs as, to our knowledge, a previously unreported target of these therapies.

Synthesis of a Heparinoid Pentasaccharide Containing l-Guluronic Acid Instead of l-Iduronic Acid with Preserved Anticoagulant Activity.

l-Iduronic acid is a key constituent of heparin and heparan sulfate polysaccharides due to its unique conformational plasticity, which facilitates the binding of polysaccharides to proteins. At the same time, this is the synthetically most challenging unit of heparinoid oligosaccharides; therefore, there is a high demand for its replacement with a more easily accessible sugar unit. In the case of idraparinux, an excellent anticoagulant heparinoid pentasaccharide, we demonstrated that l-iduronic acid can be replaced by an easier-to-produce l-sugar while maintaining its essential biological activity. From the inexpensive d-mannose, through a highly functionalized phenylthio mannoside, the l-gulose donor was prepared by C-5 epimerization in 10 steps with excellent yield. This unit was incorporated into the pentasaccharide by α-selective glycosylation and oxidized to l-guluronic acid. The complete synthesis required only 36 steps, with 21 steps for the longest linear route. The guluronate containing pentasaccharide inhibited coagulation factor Xa by 50% relative to the parent compound, representing an excellent anticoagulant activity. To the best of our knowledge, this is the first biologically active heparinoid anticoagulant which contains a different sugar unit instead of l-iduronic acid.

Direct C-H Allylation of Unactivated Alkanes by Cooperative W/Cu Photocatalysis.

Here we report a photocatalytic methodology that enables the direct allylation of strong aliphatic C-H bonds with simple allylic chlorides. The method relies on a cooperative interaction of two metal catalysts in which the decatungstate anion acts as a hydrogen-atom abstractor generating a nucleophilic carbon-centered radical that engages in an SH2' reaction with an activated allylic π-olefin-copper complex. Because of this dual catalysis, the protocol allows for the functionalization of a range of chemical feedstocks and natural products under mild conditions in short reaction times.

Evaluating the Safety and Efficacy of Crenezumab vs Placebo in Adults With Early Alzheimer Disease: Two Phase 3 Randomized Placebo-Controlled Trials.

Importance: Alzheimer disease (AD), a neurodegenerative disease characterized by ß-amyloid plaques and τ tangles in the brain, represents an unmet medical need with no fully approved therapeutics to modify disease progression. Objective: To investigate the safety and efficacy of crenezumab, a humanized monoclonal immunoglobulin G4 antibody targeting ß-amyloid oligomers, in participants with prodromal to mild (early) AD. Design, Setting, and Participants: Two phase 3 multicenter randomized double-blind placebo-controlled parallel-group efficacy and safety studies of crenezumab in participants with early AD, CREAD and CREAD2, were initiated in 2016 and 2017, respectively, and were designed to evaluate the efficacy and safety of crenezumab in participants with early AD. CREAD (194 sites in 30 countries) and CREAD2 (209 sites in 27 countries) were global multicenter studies. A total of 3736 and 3664 participants were screened in CREAD and CREAD2, respectively. A total of 3736 and 3664 participants were screened in CREAD and CREAD2, respectively. Both trials enrolled individuals aged 50 to 85 years with early AD. Participants with some comorbidities and evidence of cerebral infarction or more than 4 microbleeds or areas of leptomeningeal hemosiderosis on magnetic resonance imaging were excluded. After 2923 and 2858 were excluded, respectively, 813 participants in CREAD and 806 in CREAD2 were randomly assigned in a 1:1 ratio to either placebo or crenezumab. In the final analysis, there were 409 participants in the placebo group and 404 in the crenezumab group in CREAD and 399 in the placebo group and 407 in the crenezumab group in CREAD2. Data were analyzed up until January 2019 and August 2019, respectively. Interventions: Participants received placebo or 60 mg/kg crenezumab intravenously every 4 weeks for up to 100 weeks. Main Outcomes and Measures: The primary outcome was change from baseline to week 105 in Clinical Dementia Rating-Sum of Boxes (CDR-SB) score. Results: There were 813 participants in CREAD (mean [SD] age, 70.7 [8.2] years; 483 female and 330 male) and 806 in CREAD2 (mean [SD] age, 70.9 [7.7] years; 456 female and 350 male). Baseline characteristics were balanced between both groups. The between-group difference in mean change from baseline in CDR-SB score (placebo minus crenezumab) was -0.17 (95% CI, -0.86 to 0.53; P = .63) at week 105 in the CREAD study (88 placebo; 86 crenezumab). Compared with previous trials, no new safety signals were identified, and amyloid-related imaging abnormalities with edema were rare, mild, and transient. No meaningful changes in AD biomarkers were observed. Both studies were discontinued following a preplanned interim analysis indicating that CREAD was unlikely to meet the primary end point. Conclusions and Relevance: Crenezumab was well tolerated but did not reduce clinical decline in participants with early AD. Trial Registration: ClinicalTrials.gov Identifiers: CREAD, NCT02670083; CREAD2, NCT03114657.

Synthesis of Hydrofluoroolefin-Based Iodonium Reagent via Dyotropic Rearrangement and Its Utilization in Fluoroalkylation.

[1,2]-shift of atoms in alkyl fragments belongs to the class of dyotropic rearrangements. Various atoms, including halogens can be involved in the migration, however participation of iodine is unprecedented. Herein, we report our experimental and DFT studies on the oxidation triggered dyotropic rearrangement of iodo and chloro functions via butterfly-type transition state to demonstrate the migrating ability of λ3 -iodane centre. With the exploitation of dyotropic rearrangement we designed and synthesized a novel fluoroalkyl iodonium reagent from industrial feedstock gas HFO-1234yf. We demonstrated that the hypervalent reagent serves as an excellent fluoroalkylation agent for various amines and nitrogen heterocycles.

Clinical risk assessment in decision making for hospital discharge of patients with pulmonary embolism / Klinikai kockázatbecslésen alapuló döntéshozatal a tüdoemboliás betegek kórházi elbocsátása során

Introduction: There are a vast number of studies that analyze the safest possible way of early at-home treatment of patients with pulmonary embolism after diagnosis. Objective: Our study aimed to find out how many patients could be discharged safely and without complications, if using the three validated score systems of the 2019 European Society of Cardiology guideline regarding pulmonary embolism. Method: Throughout our retrospective, quantitative study, we gathered data from the 2015-2018 period before the establishment of the new, 2019 guideline. We assessed patients who had a diagnosis of pulmonary embolism at the emergency room in the given period. With the help of the prognostic score systems, we retrospectively made a risk stratification using the main symptoms and vital parameters. We analyzed the categorical variables with chi-square test. For assessing two continuous variables, we used Pearson's correlation. We defined our level of significance at p<0,05. Results: 374 (199 female and 175 male) patients were enrolled in our study. Our retrospective calculation had the following results: based on the PESI score 151 patients, on the basis of the sPESI 101 patients and according to the Hestia criteria 50 patients could have been discharged, treated at home without complications and increasing the mortality. The negative predictive value (PESI: 98%, sPESI: 100%, Hestia: 100% with CI: 95%) and sensitivity (PESI: 91%, sPESI: 100%, Hestia: 100%) of the three prognostic scores showed applicable efficiency. Conclusion: We concluded that all three prognostic criteria can be used safely taking the local clinical experience and preference into consideration, aiming at early discharge. Adapting them nationally could decrease hospital load.

The importance of clinical risk assessment in reducing the pathway of acute coronary syndrome / A klinikai kockázatbecslés jelentosége az akut coronaria szindróma betegút csökkentésében

Introduction: Early diagnosis of acute coronary syndrome is emergency providers' task. In the last decade, vast amounts of clinical risk stratification scores were developed to decrease the hospital load of patients by selecting them properly. Objective: Together with the diagnostic and therapeutic challenges, decreasing treatment duration is essential for the improvement of acute coronary syndrome prognosis. Our aim was to assess the HEART score's time-and therapy -related effects on acute coronary syndrome detection as a decision support system. Method: We conducted a retrospective, quantitative study at a county state emergency department amongst patients with the myocardial infarction ICD codes. We assessed their admission time, the way they were delivered to the hos-pital, their presenting symptoms, vital parameters, chronic medical conditions, laboratory and imaging results and the time of their admission to the percutan intervention center. We calculated the HEART score retrospectively from the collected data. Results: Our sample size consisted of 360 people. Coronary artery disease (80%) and hypertension (73.3%) were the most common risk factors, while chest pain (80%) and shortness of breath (48.6%) were the most common com-plaints. Coronary artery disease, hypertension and diabetes are not related to percutan coronary intervention admis-sion times (p = 0.110; p = 0.173; p = 0.507). We found a correlation between the presence of chest pain and mortal-ity (p = 0.009). The calculated HEART score had a correlation with the fact of coronary intervention admission (p = 0.005). Conclusion: We conclude that the retrospectively calculated HEART score correlates with percutan coronary inter-vention admission. Choosing the proper risk stratification can increase the lifespan of the patients and hospital cost-efficiency.

Opioidergic Signaling-A Neglected, Yet Potentially Important Player in Atopic Dermatitis.

Atopic dermatitis (AD) is one of the most common skin diseases, the prevalence of which is especially high among children. Although our understanding about its pathogenesis has substantially grown in recent years, and hence, several novel therapeutic targets have been successfully exploited in the management of the disease, we still lack curative treatments for it. Thus, there is an unmet societal demand to identify further details of its pathogenesis to thereby pave the way for novel therapeutic approaches with favorable side effect profiles. It is commonly accepted that dysfunction of the complex cutaneous barrier plays a central role in the development of AD; therefore, the signaling pathways involved in the regulation of this quite complex process are likely to be involved in the pathogenesis of the disease and can provide novel, promising, yet unexplored therapeutic targets. Thus, in the current review, we aim to summarize the available potentially AD-relevant data regarding one such signaling pathway, namely cutaneous opioidergic signaling.

Pruritus: A Sensory Symptom Generated in Cutaneous Immuno-Neuronal Crosstalk.

Pruritus or itch generated in the skin is one of the most widespread symptoms associated with various dermatological and systemic (immunological) conditions. Although many details about the molecular mechanisms of the development of both acute and chronic itch were uncovered in the last 2 decades, our understanding is still incomplete and the clinical management of pruritic conditions is one of the biggest challenges in daily dermatological practice. Recent research revealed molecular interactions between pruriceptive sensory neurons and surrounding cutaneous cell types including keratinocytes, as well as resident and transient cells of innate and adaptive immunity. Especially in inflammatory conditions, these cutaneous cells can produce various mediators, which can contribute to the excitation of pruriceptive sensory fibers resulting in itch sensation. There also exists significant communication in the opposite direction: sensory neurons can release mediators that maintain an inflamed, pruritic tissue-environment. In this review, we summarize the current knowledge about the sensory transduction of pruritus detailing the local intercellular interactions that generate itch. We especially emphasize the role of various pruritic mediators in the bidirectional crosstalk between cutaneous non-neuronal cells and sensory fibers. We also list various dermatoses and immunological conditions associated with itch, and discuss the potential immune-neuronal interactions promoting the development of pruritus in the particular diseases. These data may unveil putative new targets for antipruritic pharmacological interventions.

"Decide and run!" The role of prehospital care providers in reducing time loss for patients with stroke diagnosis / "Dönts és siess!" A prehospitális ellátók szerepe az idoveszteség csökkentésében stroke-iránydiagnózisú betegek esetén.

Összefoglaló. Bevezetés: A stroke-betegek ellátásában arra kell törekedni, hogy a tünetek jelentkezését követoen minél elobb a szakmai centrumba kerüljön a beteg. Célkituzés: Kutatásunkban a terápiás idoablak tarthatósága céljából vizsgáltuk, hogy mely tényezok bírnak hatással a prehospitális ellátás idotartamaira. Módszer: Keresztmetszeti, kvantitatív kutatásunkhoz az adatgyujtést két magyarországi város mentoállomásán, orvosi kompetenciával rendelkezo (eset-, rohamkocsi) és orvosi kompetenciával nem rendelkezo (mentogépkocsi) mentoegység szintjén végeztük 2017-es adatok feldolgozásával olyan betegek körében, akiknek a mentoegység általi iránydiagnózisa stroke volt (n = 220). Vizsgáltuk, hogy a mentoegységek által elvégzett vizsgálatok, a tapasztalt tünetek, a terápiás idoablakon belüliség miként befolyásolta a prehospitális idoket. Az adatfeldolgozást SPSS 26.0 statisztikai programmal végeztük. Az elemzéshez leíró statisztikát, χ2-próbát, F-próbát és T-próbát alkalmaztunk. Eredmények: Megállapítottuk, hogy az alkalmazott score-rendszer vizsgálati elemei közül, ha aphasia volt észlelheto a betegnél, úgy szignifikánsan meghosszabbodott a helyszínen töltött ido (p = 0,003). A gyors ABCDE-betegvizsgálat D-lépésében kötelezo a betegnél a vércukorszintmérés, ugyanakkor ez mintánk 25,45%-ában elmaradt. A helyszíni muszeres vércukorszintmérés hatással van a prehospitális késés alakulására az orvosi kompetencia nélküli egységek vonatkozásában (p<0,001). Következtetés: A helyszínen töltött ido az emelt szintu mentoegységek esetében hosszabb, mint az alacsonyabb szintu egységeknél. Következtetésként levonhatjuk, hogy a motoros vagy szenzoros aphasia nem befolyásolja a terápiát, pusztán a stroke-diagnózis valószínuségét növelo egyik tünet, így a helyszíni ido emiatti megnyúlása mindenképpen kerülendo, amire javasolt a továbbképzések alkalmával is felhívni az ellátók figyelmét. Az orvosi kompetencia nélküli egységek esetében beavatkozást igényel a muszeres vércukormérés idorabló hatásának csökkentése, hiszen látható, hogy az orvosi kompetenciával rendelkezo egységeknél ez a vizsgálat nem jelenik meg mint késést okozó tényezo. Orv Hetil. 2022; 163(7): 279-287. INTRODUCTION: When treating stroke patients, the aim should be to get the patient to a specialist stroke centre as soon as possible. OBJECTIVE: In our study, in order to be able to stay within the therapeutic window, we investigated which variables affect the time period of prehospital treatment. METHOD: For our cross-sectional quantitative study, we gathered data from two ambulance stations in Hungary, comparing the competence of physician and non-physician units. We processed information from 2017 regarding patients whose initial diagnosis was stroke (n = 220). We examined how investigations by the ambulance unit, symptoms experienced and therapeutic time window have affected prehospital times. As for the statistic software, we used SPSS 26.0. The analysis was conducted by performing χ2 test, F-test and T-test. RESULTS: We identified that if the aphasia component of the used score system was positive, the on-scene time increased significantly (p = 0.003). In the D section of the rapid ABCDE assessment, it is mandatory to measure the blood glucose level of the patient, however, in our sample it was omitted in 25.45% of the cases. We identified that on-site blood glucose measurement has an effect on prehospital delay for non-physician units (p<0.001). CONCLUSION: We found that the on-scene time is longer for physician units than for non-physician units. We concluded that motor or sensory aphasia does not affect the therapy, it is just one of the symptoms that can increase the likelihood of stroke diagnosis, therefore prolonging time for assessing aphasia in the field should be avoided. Moreover, it is recommended to make care providers aware of this during training sessions. Improvements are required in non-physician units to reduce the time consumed by blood glucose measurement, as it has been shown that within physician units this test does not appear to be a delay-causing factor. Orv Hetil. 2022; 163(7): 279-287.

Site-Specific Cerebrospinal Fluid Tau Hyperphosphorylation in Response to Alzheimer's Disease Brain Pathology: Not All Tau Phospho-Sites are Hyperphosphorylated.

BACKGROUND: Understanding patterns of association between CSF phosphorylated tau (p-tau) species and clinical disease severity will aid Alzheimer's disease (AD) diagnosis and treatment. OBJECTIVE: To evaluate changes in tau phosphorylation ratios to brain imaging (amyloid PET, [18F]GTP1 PET, and MRI) and cognition across clinical stages of AD in two different cohorts. METHODS: A mass spectrometry (MS)-based method was used to evaluate the relationship between p-tau/tau phosphorylation ratios on 11 sites in CSF and AD pathology measured by tau PET ([18F]GTP1) and amyloid PET ([18F]florbetapir or [18F]florbetaben). Cohort A included cognitively normal amyloid negative (n = 6) and positive (n = 5) individuals, and amyloid positive prodromal (n = 13), mild (n = 12), and moderate AD patients (n = 10); and Cohort B included amyloid positive prodromal (n = 24) and mild (n = 40) AD patients. RESULTS: In this cross-sectional analysis, we identified clusters of phosphosites with different profiles of phosphorylation ratios across stages of disease. Eight of 11 investigated sites were hyperphosphorylated and associated with SUVR measures from [18F]GTP1 and amyloid PET. Novel sites 111, 153, and 208 may be relevant biomarkers for AD diagnosis to complement tau hyperphosphorylation measures on previously established sites 181, 205, 217, and 231. Hypophosphorylation was detected on residues 175, 199, and 202, and was inversely associated with [18F]GTP1 and amyloid PET. CONCLUSION: Hyperphosphorylated and hypophosphorylated forms of tau are associated with AD pathologies, and due to their different site-specific profiles, they may be used in combination to assist with staging of disease.

Anandamide Concentration-Dependently Modulates Toll-Like Receptor 3 Agonism or UVB-Induced Inflammatory Response of Human Corneal Epithelial Cells.

Photodamage-induced and viral keratitis could benefit from treatment with novel nonsteroid anti-inflammatory agents. Therefore, we determined whether human corneal epithelial cells (HCECs) express members of the endocannabinoid system (ECS), and examined how the endocannabinoid anandamide (AEA, N-arachidonoyl ethanolamine) influences the Toll-like receptor 3 (TLR3) agonism- or UVB irradiation-induced inflammatory response of these cells. Other than confirming the presence of cannabinoid receptors, we show that endocannabinoid synthesizing and catabolizing enzymes are also expressed in HCECs in vitro, as well as in the epithelial layer of the human cornea in situ, proving that they are one possible source of endocannabinoids. p(I:C) and UVB irradiation was effective in promoting the transcription and secretion of inflammatory cytokines. Surprisingly, when applied alone in 100 nM and 10 µM, AEA also resulted in increased pro-inflammatory cytokine production. Importantly, AEA further increased levels of these cytokines in the UVB model, whereas its lower concentration partially prevented the transcriptional effect of p(I:C), while not decreasing the p(I:C)-induced cytokine release. HCECs express the enzymatic machinery required to produce endocannabinoids both in vitro and in situ. Moreover, our data show that, despite earlier reports about the anti-inflammatory potential of AEA in murine cornea, its effects on the immune phenotype of human corneal epithelium may be more complex and context dependent.

TRPM4 links calcium signaling to membrane potential in pancreatic acinar cells.

Transient receptor potential cation channel subfamily M member 4 (TRPM4) is a Ca2+-activated nonselective cation channel that mediates membrane depolarization. Although, a current with the hallmarks of a TRPM4-mediated current has been previously reported in pancreatic acinar cells (PACs), the role of TRPM4 in the regulation of acinar cell function has not yet been explored. In the present study, we identify this TRPM4 current and describe its role in context of Ca2+ signaling of PACs using pharmacological tools and TRPM4-deficient mice. We found a significant Ca2+-activated cation current in PACs that was sensitive to the TRPM4 inhibitors 9-phenanthrol and 4-chloro-2-[[2-(2-chlorophenoxy)acetyl]amino]benzoic acid (CBA). We demonstrated that the CBA-sensitive current was responsible for a Ca2+-dependent depolarization of PACs from a resting membrane potential of -44.4 ± 2.9 to -27.7 ± 3 mV. Furthermore, we showed that Ca2+ influx was higher in the TRPM4 KO- and CBA-treated PACs than in control cells. As hormone-induced repetitive Ca2+ transients partially rely on Ca2+ influx in PACs, the role of TRPM4 was also assessed on Ca2+ oscillations elicited by physiologically relevant concentrations of the cholecystokinin analog cerulein. These data show that the amplitude of Ca2+ signals was significantly higher in TRPM4 KO than in control PACs. Our results suggest that PACs are depolarized by TRPM4 currents to an extent that results in a significant reduction of the inward driving force for Ca2+. In conclusion, TRPM4 links intracellular Ca2+ signaling to membrane potential as a negative feedback regulator of Ca2+ entry in PACs.