bluuebunny/crossref_metadata_2025 huggingface dataset:
Synthetic Routes to Approved Drugs Containing a Spirocycle
Authors: Moshnenko Nazar , Kazantsev Alexander , Chupakhin Evgeny , Bakulina Olga , Dar’in Dmitry
Published: May 2023

The use of spirocycles in drug discovery and medicinal chemistry has been booming in the last two decades. This has clearly translated into the landscape of approved drugs. Among two dozen clinically used medicines containing a spirocycle, 50% have been approved in the 21st century. The present review focuses on the notable synthetic routes to such drugs invented in industry and academia, and is intended to serve as a useful reference source of synthetic as well as general drug information for researchers engaging in the design of new spirocyclic scaffolds for medicinal use or embarking upon analog syntheses inspired by the existing approved drugs.
Development and Characterization of Novel Selective, Non-Basic Dopamine D2 Receptor Antagonists for the Treatment of Schizophrenia
Authors: Stępnicki Piotr , Wośko Sylwia , Bartyzel Agata , Zięba Agata , Bartuzi Damian , Szałaj Klaudia , Wróbel Tomasz M. , Fornal Emilia , Carlsson Jens , Kędzierska Ewa , Poleszak Ewa , Castro Marián , Kaczor Agnieszka A.
Published: May 2023

The dopamine D2 receptor, which belongs to the family of G protein-coupled receptors (GPCR), is an important and well-validated drug target in the field of medicinal chemistry due to its wide distribution, particularly in the central nervous system, and involvement in the pathomechanism of many disorders thereof. Schizophrenia is one of the most frequent diseases associated with disorders in dopaminergic neurotransmission, and in which the D2 receptor is the main target for the drugs used. In this work, we aimed at discovering new selective D2 receptor antagonists with potential antipsychotic activity. Twenty-three compounds were synthesized, based on the scaffold represented by the D2AAK2 compound, which was discovered by our group. This compound is an interesting example of a D2 receptor ligand because of its non-classical binding to this target. Radioligand binding assays and SAR analysis indicated structural modifications of D2AAK2 that are possible to maintain its activity. These findings were further rationalized using molecular modeling. Three active derivatives were identified as D2 receptor antagonists in cAMP signaling assays, and the selected most active compound 17 was subjected to X-ray studies to investigate its stable conformation in the solid state. Finally, effects of 17 assessed in animal models confirmed its antipsychotic activity in vivo.
Perspectives on the Lindman Hypothesis and Cellulose Interactions
Authors: Norgren Magnus , Costa Carolina , Alves Luís , Eivazi Alireza , Dahlström Christina , Svanedal Ida , Edlund Håkan , Medronho Bruno
Published: May 2023

In the history of cellulose chemistry, hydrogen bonding has been the predominant explanation when discussing intermolecular interactions between cellulose polymers. This is the general consensus in scholarly textbooks and in many research articles, and it applies to several other biomacromolecules’ interactions as well. This rather unbalanced description of cellulose has likely impacted the development of materials based on the processing of cellulose—for example, via dissolution in various solvent systems and regeneration into solid materials, such as films and fibers, and even traditional wood fiber handling and papermaking. In this review, we take as a starting point the questioning of the general description of the nature of cellulose and cellulose interactions initiated by Professor Björn Lindman, based on generic physicochemical reasoning about surfactants and polymers. This dispute, which became known as “the Lindman hypothesis”, highlights the importance of hydrophobic interactions in cellulose systems and that cellulose is an amphiphilic polymer. This paper elaborates on Björn Lindman’s contribution to the subject, which has caused the scientific community to revisit cellulose and reconsider certain phenomena from other perspectives.
Fluorine-Functionalized Polyphosphazene Immunoadjuvant: Synthesis, Solution Behavior and In Vivo Potency
Authors: Tagad Harichandra D. , Marin Alexander , Wang Ruixue , Yunus Abdul S. , Fuerst Thomas R. , Andrianov Alexander K.
Published: May 2023

The inclusion of fluorine motifs in drugs and drug delivery systems is an established tool for modulating their biological potency. Fluorination can improve drug specificity or boost the vehicle’s ability to cross cellular membranes. However, the approach has yet to be applied to vaccine adjuvants. Herein, the synthesis of fluorinated bioisostere of a clinical stage immunoadjuvant—poly[di(carboxylatophenoxy)phosphazene], PCPP—is reported. The structure of water-soluble fluoropolymer—PCPP-F, which contains two fluorine atoms per repeat unit—was confirmed using 1H, 31P and 19F NMR, and its molecular mass and molecular dimensions were determined using size-exclusion chromatography and dynamic light scattering. Insertion of fluorine atoms in the polymer side group resulted in an improved solubility in acidic solutions and faster hydrolytic degradation rate, while the ability to self-assemble with an antigenic protein, lysozyme—an important feature of polyphosphazene vaccine adjuvants—was preserved. In vivo assessment of PCPP-F demonstrated its greater ability to induce antibody responses to Hepatitis C virus antigen when compared to its non-fluorinated counterpart. Taken together, the superior immunoadjuvant activity of PCPP-F, along with its improved formulation characteristics, demonstrate advantages of the fluorination approach for the development of this family of macromolecular vaccine adjuvants.
Dynamic and Static Nature of XH-∗-π and YX-∗-π (X = F, Cl, Br, and I; Y = X and F) in the Distorted π-System of Corannulene Elucidated with QTAIM Dual Functional Analysis
Authors: Hayashi Satoko , Kato Takahiro , Sugibayashi Yuji , Nakanishi Waro
Published: May 2023

The dynamic and static nature of the XH-∗-π and YX-∗-π (X = F, Cl, Br, and I; Y = X and F) interactions in the distorted π-system of corannulene (π(C20H10)) is elucidated with a QTAIM dual functional analysis (QTAIM-DFA), where asterisks emphasize the presence of bond critical points (BCPs) on the interactions. The static and dynamic nature originates from the data of the fully optimized and perturbed structures, respectively, in QTAIM-DFA. On the convex side, H in F–H-∗-π(C20H10) and each X in Y–X-∗-π(C20H10) join to C of the central five-membered ring in π(C20H10) through a bond path (BP), while each H in X–H-∗-π(C20H10) does so to the midpoint of C=C in the central five-membered ring for X = Cl, Br, or I. On the concave side, each X in F–X-∗-π(C20H10) also joins to C of the central five-membered ring with a BP for X = H, Cl, Br, and I; however, the interactions in other adducts are more complex than those on the convex side. Both H and X in X–H-∗-π(C20H10) (X = Cl and Br) and both Fs in F–F-∗-π(C20H10) connect to the three C atoms in each central five-membered ring (with three BPs). Two, three, and five BPs were detected for the Cl–Cl, I–H, Br–Br, and I–I adducts, where some BPs do not stay on the central five-membered ring in π(C20H10). The interactions are predicted to have a vdW to CT-MC nature. The interactions on the concave side seem weaker than those on the convex side for X–H-∗-π(C20H10), whereas the inverse trend is observed for Y–X-∗-π(C20H10) as a whole. The nature of the interactions in the π(C20H10) adducts of the convex and concave sides is examined in more detail, employing the adducts with X–H and F–X placed on their molecular axis together with the π(C24H12) and π(C6H6) adducts.
Design, Synthesis, and Antiproliferative Activity of Benzopyran-4-One-Isoxazole Hybrid Compounds
Authors: Gupta Shilpi , Park Shang Eun , Mozaffari Saghar , El-Aarag Bishoy , Parang Keykavous , Tiwari Rakesh Kumar
Published: May 2023

The biological significance of benzopyran-4-ones as cytotoxic agents against multi-drug resistant cancer cell lines and isoxazoles as anti-inflammatory agents in cellular assays prompted us to design and synthesize their hybrid compounds and explore their antiproliferative activity against a panel of six cancer cell lines and two normal cell lines. Compounds 5a–d displayed significant antiproliferative activities against all the cancer cell lines tested, and IC50 values were in the range of 5.2–22.2 μM against MDA-MB-231 cancer cells, while they were minimally cytotoxic to the HEK-293 and LLC-PK1 normal cell lines. The IC50 values of 5a–d against normal HEK-293 cells were in the range of 102.4–293.2 μM. Compound 5a was screened for kinase inhibitory activity, proteolytic human serum stability, and apoptotic activity. The compound was found inactive towards different kinases, while it completely degraded after 2 h of incubation with human serum. At 5 μM concentration, it induced apoptosis in MDA-MB-231 by 50.8%. Overall, these findings suggest that new benzopyran-4-one-isoxazole hybrid compounds, particularly 5a–d, are selective anticancer agents, potentially safe for human cells, and could be synthesized at low cost. Additionally, Compound 5a exhibits potential anticancer activity mediated via inhibition of cancer cell proliferation and induction of apoptosis.
Nonadiabatic Derivative Couplings Calculated Using Information of Potential Energy Surfaces without Wavefunctions: Ab Initio and Machine Learning Implementations
Authors: Chen Wen-Kai , Wang Sheng-Rui , Liu Xiang-Yang , Fang Wei-Hai , Cui Ganglong
Published: May 2023

In this work, we implemented an approximate algorithm for calculating nonadiabatic coupling matrix elements (NACMEs) of a polyatomic system with ab initio methods and machine learning (ML) models. Utilizing this algorithm, one can calculate NACMEs using only the information of potential energy surfaces (PESs), i.e., energies, and gradients as well as Hessian matrix elements. We used a realistic system, namely CH2NH, to compare NACMEs calculated by this approximate PES-based algorithm and the accurate wavefunction-based algorithm. Our results show that this approximate PES-based algorithm can give very accurate results comparable to the wavefunction-based algorithm except at energetically degenerate points, i.e., conical intersections. We also tested a machine learning (ML)-trained model with this approximate PES-based algorithm, which also supplied similarly accurate NACMEs but more efficiently. The advantage of this PES-based algorithm is its significant potential to combine with electronic structure methods that do not implement wavefunction-based algorithms, low-scaling energy-based fragment methods, etc., and in particular efficient ML models, to compute NACMEs. The present work could encourage further research on nonadiabatic processes of large systems simulated by ab initio nonadiabatic dynamics simulation methods in which NACMEs are always required.
Dental Bleaching with Phthalocyanine Photosensitizers: Effects on Dentin Color and Collagen Content
Authors: Wu Zhouyan , Wang Guodong , Li Zhiming , Li Zhengquan , Huang Dandan , Huang Mingdong , Lin Minkui
Published: May 2023

With the increasing demand for tooth bleaching in esthetic dentistry, its safety has been the focus of a comprehensive body of literature. In this context, the aim of the present study was to evaluate the application effects of pentalysine β-carbonylphthalocyanine zinc (ZnPc(Lys)5)-mediated photodynamic therapy in dentin bleaching and its effects on dentin collagen. We first established a new and reproducible tooth staining model using dentin blocks stained by Orange II and then bleached with ZnPc(Lys)5 (25 μM) and hydrogen peroxide (10% or 30%). Data were analyzed with one- and two-way ANOVA and a significance level of p < 0.05. ZnPc(Lys)5 effectively bleached the dentin samples to an extent comparable to hydrogen peroxide at either 10% or 30% concentrations. Further studies on the dentin morphology, chemical element distribution, and protein constituents, using an electron microscope, energy dispersive spectroscopy, X-ray photoelectron spectroscopy, and SDS-PAGE, demonstrated that treatment with the photosensitizer preserved the dentin structure and, at the same time, the major organic component, collagen type I. For comparison, hydrogen peroxide (10% or 30%) treatment significantly degraded the collagen protein. This work indicated that the photosensitizer exerts potent bleaching effects on dentin staining; importantly, does not damage dentin and its collagen content; and opens up a new strategy to further explore various photosensitizers for the bleaching of both tooth enamel and dentin.
Mössbauer and Structure-Magnetic Properties Analysis of AyB1−yCxFe2−xO4 (C=Ho,Gd,Al) Ferrite Nanoparticles Optimized by Doping
Authors: Lin Qing , Yang Fang , Zhang Qian , Su Kaimin , Xu Huiren , He Yun , Lin Jinpei
Published: May 2023

AyB1−yCxFe2−xO4 (C=Ho,Gd,Al) ferrite powders have been synthesized by the sol-gel combustion route. The X-ray diffraction of the CoHoxFe2−xO4 (x = 0~0.08) results indicated the compositions of single-phase cubic ferrites. The saturation magnetisation of CoHoxFe2−xO4 decreased by the Ho3+ ions, and the coercivity increased initially and then decreased with the increase of the calcination temperature. The Mössbauer spectra indicated that CoHoxFe2−xO4 displays a ferrimagnetic behaviour with two normal split Zeeman sextets. The magnetic hyperfine field tends to decrease by Ho3+ substitution owing to the decrease of the A–B super-exchange by the paramagnetic rare earth Ho3+ ions. The value of the quadrupole shift was very small in the CoHoxFe2−xO4 specimens, indicating that the symmetry of the electric field around the nucleus is good in the cobalt ferrites. The absorption area of the Mössbauer spectra changed with increasing Ho3+ substitution, indicating that the substitution influences the fraction of iron ions at tetrahedral A and octahedral B sites. The X-ray diffraction of Mg0.5Zn0.5CxFe2−xO4(C=Gd,Al) results confirmed the compositions of single-phase cubic ferrites. The variation of the average crystalline size and lattice constant are related to the doping of gadolinium ions and aluminum ions. With increasing gadolinium ions and aluminum ions, the coercivity increased and the saturation magnetization underwent a significant change. The saturation magnetization of AlMg0.5Zn0.5FeO4 ferrite reached a minimum value (MS= 1.94 mu/g). The sample exhibited ferrimagnetic and paramagnetic character with the replacement with Gd3+ ions, that sample exhibited paramagnetic character with the replacement with Al3+ ions, and the isomer shift values indicated that iron is in the form of Fe3+ ions.
Proteomic Signature of Extracellular Vesicles Associated with Colorectal Cancer
Authors: Soloveva Natalia , Novikova Svetlana , Farafonova Tatiana , Tikhonova Olga , Zgoda Victor
Published: May 2023

The proteins of extracellular vesicles (EVs) provide proteomic signatures that reflect molecular features of EV-producing cells, including cancer cells. Detection of cancer cell EV proteins is of great interest due to the development of novel predictive diagnostic approaches. Using targeted mass spectrometry with stable-isotope-labeled peptide standards (SIS), we measured in this study the levels of 34 EV-associated proteins in vesicles and whole lysate derived from the colorectal cancer (CRC) cell lines Caco-2, HT29 and HCT116. We also evaluated the abundance of 13 EV-associated proteins (FN1, TLN1, ITGB3, HSPA8, TUBA4A, CD9, CD63, HSPG2, ITGB1, GNAI2, TSG101, PACSIN2, and CDC42) in EVs isolated from blood plasma samples from 11 CRC patients and 20 healthy volunteers. Downregulation of TLN1, ITGB3, and TUBA4A with simultaneous upregulation of HSPG2 protein were observed in cancer samples compared to healthy controls. The proteomic cargo of the EVs associated with CRC represents a promising source of potential prognostic markers.
The History of Desulfovibrio gigas Aldehyde Oxidoreductase—A Personal View
Authors: Moura José J. G.
Published: May 2023

A story going back almost 40 years is presented in this manuscript. This is a different and more challenging way of reporting my research and I hope it will be useful to and target a wide-ranging audience. When preparing the manuscript and collecting references on the subject of this paper—aldehyde oxidoreductase from Desulfovibrio gigas—I felt like I was travelling back in time (and space), bringing together the people that have contributed most to this area of research. I sincerely hope that I can give my collaborators the credit they deserve. This study is not presented as a chronologic narrative but as a grouping of topics, the development of which occurred over many years.
Nanoimprint Mold Consisting of an Adhesive Lap Joint between a Nanopatterned Metal Sleeve and a Carbon Composite Roll
Authors: Khaliq Amin , Kamran Muhammad Ahmad , Jeong Myung Yung
Published: May 2023

Roll-to-roll nanoimprinting is an emerging technology that has revolutionized the sectors of flexible electronics, thin films, and solar cells with its high throughput. However, there is still room for improvement. In this study, a FEM analysis (in ANSYS) was carried out on a large-area roll-to-roll nanoimprint system in which the master roller consists of a large nanopatterned nickel mold joined to a carbon fiber reinforced polymer (CFRP) base roller using epoxy adhesive. Deflections and pressure uniformity of the nano-mold assembly were analyzed under loadings of different magnitudes in a roll-to-roll nanoimprinting setup. Optimization of deflections was performed with applied loadings, and the lowest deflection value was 97.69 nm. The adhesive bond viability was assessed under a range of applied forces. Finally, potential strategies to reduce deflections were also discussed, which can be helpful in increasing pressure uniformity.
Exploring the Versatility of Microemulsions in Cutaneous Drug Delivery: Opportunities and Challenges
Authors: Ait-Touchente Zouhair , Zine Nadia , Jaffrezic-Renault Nicole , Errachid Abdelhamid , Lebaz Noureddine , Fessi Hatem , Elaissari Abdelhamid
Published: May 2023

Microemulsions are novel drug delivery systems that have garnered significant attention in the pharmaceutical research field. These systems possess several desirable characteristics, such as transparency and thermodynamic stability, which make them suitable for delivering both hydrophilic and hydrophobic drugs. In this comprehensive review, we aim to explore different aspects related to the formulation, characterization, and applications of microemulsions, with a particular emphasis on their potential for cutaneous drug delivery. Microemulsions have shown great promise in overcoming bioavailability concerns and enabling sustained drug delivery. Thus, it is crucial to have a thorough understanding of their formulation and characterization in order to optimize their effectiveness and safety. This review will delve into the different types of microemulsions, their composition, and the factors that affect their stability. Furthermore, the potential of microemulsions as drug delivery systems for skin applications will be discussed. Overall, this review will provide valuable insights into the advantages of microemulsions as drug delivery systems and their potential for improving cutaneous drug delivery.
The Nano4XX Nanotechnology Platform: The Triumph of Nanotechnology
Authors: Kordas George
Published: May 2023

If a person is diagnosed with cancer, doctors recommend surgery, chemotherapy, and radiotherapy [...]
In Vivo Toxicity Assessment of the Probiotic Bacillus amyloliquefaciens HTI-19 Isolated from Stingless Bee (Heterotrigona itama) Honey
Authors: Zulkhairi Amin Fatin Aina , Shafiq Cheng Mohamad Zulhafiz , Sabri Suriana , Ismail Norsharina , Chan Kim Wei , Mohd Esa Norhaizan , Mohd Lila Mohd Azmi , Nur-Fazila Saulol Hamid , Khalifa Shaden A. M. , El-Seedi Hesham R. , Zawawi Norhasnida
Published: May 2023

This study evaluated the acute and sub-acute toxicity of B. amyloliquefaciens HTI-19 (isolated from stingless bee honey) in female Sprague Dawley rats. In an acute toxicity study, the rats received a low dosage (1 × 109 CFU·mL−1), medium dosage (3 × 109 CFU·mL−1), or high dosage (1 × 1010 CFU·mL−1) of B. amyloliquefaciens HTI-19 daily orally by syringe-feeding for 14 days. For the subacute toxicity study, rats received a low dosage (1 × 109 CFU·mL−1) or a high dosage (1 × 1010 CFU·mL−1) for 28 days. The probiotic feeding in acute and sub-acute toxicity studies showed no mortality or significant abnormalities in rats throughout the experimental period. In week 2 of the acute study, the body weight of the rats showed a significant increase (p < 0.05) compared to the control. By gross and microscopic examination of organs, no evidently significant changes were observed in the morphology of organs. Serum biochemical tests and blood hematology tests also revealed no treatment-related changes. Overall, these data indicated that oral administration of B. amyloliquefaciens HTI-19 up to 1 × 109 CFU·mL−1 for 28 days can be considered safe.
Serum Acylcarnitines Profile in Critically Ill Survivors According to Illness Severity and ICU Length of Stay: An Observational Study
Authors: Rousseau Anne-Françoise , Dongier Alice , Colson Camille , Minguet Pauline , Defraigne Jean-Olivier , Minguet Grégory , Misset Benoit , Boemer François
Published: May 2023

The acylcarnitine (AC) profile has been shown to be altered in survivors of a prolonged stay in intensive care unit (ICU), with higher short-chain derivates compared to reference ranges. The present study aimed at describing the AC profile of patients surviving a short ICU stay versus patients surviving a >7-day multiple organ dysfunction. Patients discharged from ICU after an elective and non-complicated cardiac surgery (CS) were recruited. For each CS, one to two adults, matched for gender and age, were recruited among patients enrolled in our post-ICU follow-up program after an ICU stay ≥7 days (PS). In both groups, the AC profile was determined during the week following ICU discharge. A total of 50 CS patients (SAPS II 23 (18–27)) survived an ICU stay of 2 (2–3) days and were matched to 85 PS patients (SAPS II 36 (28–51), p < 0.001) who survived an ICU stay of 11 (8–15.5) days. No carnitine deficiency was observed in either group. Their total AC/C0 ratio was similar: 0.355 (0.268–0.415) and 0.358 (0.289–0.417), respectively (p = 0.391). A ratio >0.4 representing a disturbed mitochondrial metabolism was observed in 26/85 (30.6%) PS patients and in 15/50 (30%) CS patients (p > 0.999). The long-chain ACs were elevated in both groups, with a greater increase in the CS group. The short-chain ACs were higher in the PS group: 1.520 (1.178–1.974) vs. 1.185 (0.932–1.895) μmol/L (p < 0.001). The role of the AC profile as potential marker of catabolism and/or mitochondrial dysfunction during the critical illness trajectory should be further investigated.
Impact of Grape Seed Powder and Black Tea Brew on Lipid Digestion—An In Vitro Co-Digestion Study with Real Foods
Authors: Tormási Judit , Abrankó László
Published: May 2023

Effects of two foods with bioactive constituents (black tea brew, BTB and grape seed powder, GSP) on lipid digestibility was studied. Lipolysis inhibitory effect of these foods was examined using two test foods (cream and baked beef) with highly different fatty acid (FA) composition. Digestion simulations were performed either using both gastric and pancreatic lipase, or only with pancreatic lipase according to the Infogest protocol. Lipid digestibility was assessed based on the bioaccessible FAs. Results showed the triacylglycerols containing short- and medium-chain FAs (SCFA and MCFA) are non-preferred substrates for pancreatic lipase; however, this is not characteristic for GL. Our findings suggest that both GSP and BTB primarily affect the lipolysis of SCFAs and MCFAs, because the dispreference of pancreatic lipase towards these substrates was further enhanced as a result of co-digestion. Interestingly, GSP and BTB similarly resulted in significant decrease in lipolysis for cream (containing milk fat having a diverse FA profile), whereas they were ineffective in influencing the digestion of beef fat, having simpler FA profile. It highlights that the characteristics of the dietary fat source of a meal can be a key determinant on the observed extent of lipolysis when co-digested with foods with bioactive constituents.
Leucine and Glutamic Acid as a Biomarker of Sarcopenic Risk in Japanese People with Type 2 Diabetes
Authors: Nakajima Hanako , Okada Hiroshi , Kobayashi Ayaka , Takahashi Fuyuko , Okamura Takuro , Hashimoto Yoshitaka , Nakanishi Naoko , Senmaru Takafumi , Ushigome Emi , Hamaguchi Masahide , Fukui Michiaki
Published: May 2023

This study aimed to identify the serum metabolites associated with sarcopenic risk in Japanese patients with type 2 diabetes, determine the effect of dietary protein intake on the serum metabolic profile, and examine its association with sarcopenia. Ninety-nine Japanese patients with type 2 diabetes were included, and sarcopenic risk was defined as low muscle mass or strength. Seventeen serum metabolites were quantified after gas chromatography–mass spectrometry analysis. The relationship between dietary protein intake and the metabolites concerning sarcopenia was analyzed, and the factors affecting sarcopenic risk were clarified. Twenty-seven patients were classified as being at risk of sarcopenia, the same as the general risk, which was associated with older age, a longer duration of the disease, and a lower body mass index. Low levels of leucine and glutamic acid were significantly associated with low muscle strength (p = 0.002 and p < 0.001, respectively), and leucine was also associated with muscle mass (p = 0.001). Lower levels of glutamic acid had higher odds of sarcopenic risk after being adjusted for age and HbA1c (adjusted OR 4.27, 95% CI 1.07–17.11, p = 0.041), but not for leucine. Leucine and glutamic acid can serve as useful biomarkers for sarcopenia, highlighting potential targets for its prevention.
Milk Allergen Micro-Array (MAMA) for Refined Detection of Cow’s-Milk-Specific IgE Sensitization
Authors: Garib Victoria , Trifonova Daria , Freidl Raphaela , Linhart Birgit , Schlederer Thomas , Douladiris Nikolaos , Pampura Alexander , Dolotova Daria , Lepeshkova Tatiana , Gotua Maia , Varlamov Evgeniy , Beltyukov Evgeny , Naumova Veronika , Taka Styliani , Kiyamova Alina , Katsamaki Stefani , Karaulov Alexander , Valenta Rudolf
Published: May 2023

Background: Immunoglobulin-E(IgE)-mediated hypersensitivity to cow’s milk allergens is a frequent cause of severe and life-threatening anaphylactic reactions. Besides case histories and controlled food challenges, the detection of the IgE antibodies specific to cow’s milk allergens is important for the diagnosis of cow-milk-specific IgE sensitization. Cow´s milk allergen molecules provide useful information for the refined detection of cow-milk-specific IgE sensitization. Methods: A micro-array based on ImmunoCAP ISAC technology was developed and designated milk allergen micro-array (MAMA), containing a complete panel of purified natural and recombinant cow’s milk allergens (caseins, α-lactalbumin, β-lactoglobulin, bovine serum albumin-BSA and lactoferrin), recombinant BSA fragments, and α-casein-, α-lactalbumin- and β-lactoglobulin-derived synthetic peptides. Sera from 80 children with confirmed symptoms related to cow’s milk intake (without anaphylaxis: n = 39; anaphylaxis with a Sampson grade of 1–3: n = 21; and anaphylaxis with a Sampson grade of 4–5: n = 20) were studied. The alterations in the specific IgE levels were analyzed in a subgroup of eleven patients, i.e., five who did not and six who did acquire natural tolerance. Results: The use of MAMA allowed a component-resolved diagnosis of IgE sensitization in each of the children suffering from cow’s-milk-related anaphylaxis according to Sampson grades 1–5 requiring only 20–30 microliters of serum. IgE sensitization to caseins and casein-derived peptides was found in each of the children with Sampson grades of 4–5. Among the grade 1–3 patients, nine patients showed negative reactivity to caseins but showed IgE reactivity to alpha-lactalbumin (n = 7) or beta-lactoglobulin (n = 2). For certain children, an IgE sensitization to cryptic peptide epitopes without detectable allergen-specific IgE was found. Twenty-four children with cow-milk-specific anaphylaxis showed additional IgE sensitizations to BSA, but they were all sensitized to either caseins, alpha-lactalbumin, or beta-lactoglobulin. A total of 17 of the 39 children without anaphylaxis lacked specific IgE reactivity to any of the tested components. The children developing tolerance showed a reduction in allergen and/or peptide-specific IgE levels, whereas those remaining sensitive did not. Conclusions: The use of MAMA allows for the detection, using only a few microliters of serum, of IgE sensitization to multiple cow’s milk allergens and allergen-derived peptides in cow-milk-allergic children with cow-milk-related anaphylaxis.
Association between the Japanese Diet and Coronary Artery Disease in Patients Undergoing Coronary Angiography
Authors: Momiyama Yukihiko , Kishimoto Yoshimi , Saita Emi , Aoyama Masayuki , Ohmori Reiko , Kondo Kazuo
Published: May 2023

Several cohort studies have reported that the Japanese diet is associated with reduced cardiovascular disease mortality. However, the results were not always consistent, and most of those studies conducted dietary surveys around 1990. We investigated the association between the Japanese diet and coronary artery disease (CAD) in 802 patients undergoing coronary angiography. The Japanese diet score was defined as the sum of scores of the intakes of fish, soy products, vegetables, seaweed, fruits, and green tea. CAD was found in 511 patients, of whom 173 had myocardial infarction (MI). Intakes of fish, soy products, vegetables, seaweed, fruits, and green tea were lower in patients with CAD, especially in those with MI, than in those without CAD. As a result, the Japanese diet score was significantly lower in patients with CAD than in those without CAD (p < 0.001). To clarify the association between the Japanese diet and CAD, the 802 study patients were divided into three tertiles by the Japanese diet score. The proportion of CAD decreased with the Japanese diet score, reaching 72% in patients at T1 (lowest score), 63% at T2, and 55% at T3 (highest) (p < 0.05). The proportion of MI also decreased with the Japanese diet score, reaching 25% at T1, 24% at T2, and 15% at T3 (p < 0.05). In a multivariate analysis, compared with T1, the adjusted odds ratios for CAD and MI were 0.41 (95% confidence interval [CI]: 0.26–0.63) and 0.61 (95% CI: 0.38–0.99) for T3, respectively. Thus, the Japanese diet was found to be inversely associated with CAD in Japanese patients undergoing coronary angiography.
Factors Associated with Turnover Intentions of Nurses Working in Japanese Hospitals Admitting COVID-19 Patients
Authors: Kitamura Yoshiko , Nakai Hisao
Published: May 2023

Three years after the outbreak of the coronavirus disease (COVID-19) pandemic, turnover among frontline nurses has increased. The participants of this study were nurses at two general hospitals in Ishikawa, Japan, receiving COVID-19 patients. An original self-report questionnaire was created based on previous research. The questionnaire was distributed to 400 nurses, and responses were received from 227 nurses (response rate: 56.8%). The factors influencing turnover intention at the facilities were having less time to relax (odds ratio [OR]: 2.88, 95% confidence interval [CI]: 1.12–7.41) and wanting to receive counseling (OR: 5.21, 95% CI: 1.30–20.91). As a strategy to prevent turnover, nurse managers should provide opportunities for nurses to receive counseling during normal working hours and pay particular attention to changes in nurses’ daily lives, such as changes in the time available for relaxation.
Impacts of Varying Blood Flow Restriction Cuff Size and Material on Arterial, Venous and Calf Muscle Pump-Mediated Blood Flow
Authors: Machek Steven B. , Harris Dillon R. , Heileson Jeffery L. , Wilburn Dylan T. , Forsse Jeffrey S. , Willoughby Darryn S.
Published: May 2023

Blood flow restriction (BFR) may become ineffective or potentially dangerous without sufficient standardization. The purpose of this investigation was therefore to (1) assess the viability of multiple sizes of a novel BFR cuff to determine arterial occlusion pressure (AOP) and (2) compare resting arterial, venous and calf muscle pump (cMP)-mediated blood flow between the aforementioned conditions and a commonly employed wide-rigid, tourniquet-style cuff. In randomized, counter-balanced, and crossover fashion, 20 apparently healthy males (18–40 years) donned a widely employed wide-rigid (WR) cuff, along with the largest (NE) and manufacturer-recommended sizes (NER) of a novel narrow-elastic cuff. Participants subsequently assessed AOP, as well as (at 80%AOP) arterial, venous, and venous cMP flow relative to baseline values via ultrasound. All analyses were performed at a significance level of p < 0.05. Analyses revealed a significant condition effect for AOP (p < 0.001; ηp2 = 0.907) whereby WR was significantly lower than both NE and NER; in addition, the latter two did not differ. Compared with baseline, there were no statistically significant differences between cuffs for either arterial or cMP-mediated blood flow. Unsurprisingly, no participants demonstrated venous blood flow at 80% AOP. These findings support the viability of a novel narrow-elastic BFR product, evidenced by consistent AOP acquisition and equivocal blood flow parameters.
The Involvement of Neutrophil in the Immune Dysfunction Associated with BVDV Infection
Authors: Abdelsalam Karim , Kaushik Radhey S , Chase Christopher
Published: May 2023

Bovine viral diarrhea virus (BVDV) induces immune dysfunction that often results in a secondary bacterial infection in the infected animals. The underlying mechanism of BVDV-induced immune dysfunction is not well understood. The role of BVDV-infected macrophage-secreted factors was investigated. BVDV-infected monocyte-derived macrophage (MDM) supernatants down-regulated the expression of neutrophil L-selectin and CD18. Regardless of the biotype, phagocytic activity and oxidative burst were downregulated by BVDV-infected MDM supernatants. However, only supernatants from cytopathic (cp) BVDV down-regulated nitric oxide production and neutrophil extracellular traps (NET) induction. Our data suggested that BVDV-induced macrophage-secreted factors caused immune dysfunction in neutrophils. Unlike lymphocyte depletion, the negative impact on neutrophils seems to be specific to cp BVDV biotype. Interestingly the majority of modified live BVDV vaccines are based on cp strain of BVDV.
Contrast-Associated Acute Kidney Injury Requiring Continuous Renal Replacement Therapy in A Neonate with Aortic Stenosis—A Case Report
Authors: Cirstoveanu Catalin , Georgescu Carmina , Ruxandra Nicolae , Bizubac Mihaela , Cinteza Eliza , Vasile Corina Maria , Filip Cristina , Margarint Irina
Published: May 2023

Background: Acute kidney injury occurs commonly in the Neonatal Intensive Care Unit and is associated with increased mortality and morbidity. We report a case of a neonate with congenital heart disease who developed acute kidney injury after cardiac surgery, administration of iodinated contrast media for cardiac catheterization, and a combination of nephrotoxic drugs. Case report: A term neonate without a prenatal diagnosis of congenital heart disease and with a good postnatal transition was transferred at 13 days of life to the MS Curie Emergency Hospital for Children, Newborn Intensive Care Unit, from a regional hospital where he was admitted at 10 days of life with severe general status, respiratory distress, cyanosis, and arterial hypotension. The cardiac ultrasound detected critical aortic valve stenosis, hypoplastic descending aorta, acute heart failure, and pulmonary hypertension. The patient was intubated and mechanically ventilated and received antibiotherapy (meropenem, vancomycin, and colistin), inotropic and vasoactive support (epinephrine, norepinephrine, dopamine, and milrinone), and diuretic support (furosemide, aminophylline, and ethacrynic acid). A balloon aortic valvuloplasty was performed several hours after admission, but after two days the patient required reintervention by open heart surgery due to relapsing severe aortic stenosis. He developed oligo-anuria, generalized edema, and altered renal function tests on the second postoperative and fourth day post-contrast media administration. Continuous renal replacement therapy was initiated for 75 h, leading to almost instant improvement in blood pressure, then diuresis and creatinine levels. The patient required long-term treatment for heart, respiratory, and liver failure. He was discharged at almost four months of age with normal renal function tests, blood pressure, and good urine output without diuretic support. The literature review indicates that contrast-associated acute kidney injury (CA-AKI) requiring continuous renal replacement therapy is rare. Conclusions: Our current case proves that iodinated contrast media administration in a neonate with concomitant insults, such as cardiac surgery for a specific pathology, aortic stenosis, coarctation, arch stenosis, arterial hypotension, and administration of nephrotoxic drugs, may lead to severe kidney injury.
Monoclonal Antibodies in Pregnancy and Breastfeeding in Patients with Multiple Sclerosis: A Review and an Updated Clinical Guide
Authors: Gklinos Panagiotis , Dobson Ruth
Published: May 2023

The use of high-efficacy disease-modifying therapies (DMTs) early in the course of multiple sclerosis (MS) has been shown to improve clinical outcomes and is becoming an increasingly popular treatment strategy. As a result, monoclonal antibodies, including natalizumab, alemtuzumab, ocrelizumab, ofatumumab, and ublituximab, are frequently used for the treatment of MS in women of childbearing age. To date, only limited evidence is available on the use of these DMTs in pregnancy. We aim to provide an updated overview of the mechanisms of action, risks of exposure and treatment withdrawal, and pre-conception counseling and management during pregnancy and post-partum of monoclonal antibodies in women with MS. Discussing treatment options and family planning with women of childbearing age is essential before commencing a DMT in order to make the most suitable choice for each individual patient.
Using Natural Deep Eutectic Systems as Alternative Media for Ocular Applications
Authors: Sarmento Célia , Monteiro Hugo , Paiva Alexandre , Duarte Ana Rita C. , Jesus Ana Rita
Published: May 2023

The major goal of this work was to study the potential of natural deep eutectic systems (NADES) as new media for ocular formulations. In formulating eye drops, it is important to increase the retention time of the drug on the surface of eye; hence, due to their high viscosity, NADES may be interesting candidates for formulation. Different systems composed of combinations of sugars, polyols, amino acids, and choline derivatives were prepared and then characterized in terms of rheological and physicochemical properties. Our results showed that 5–10% (w/v) aqueous solutions of NADES have a good profile in terms of viscosity (0.8 to 1.2 mPa.s), osmolarity (412 to 1883 mOsmol), and pH (7.4) for their incorporation of ocular drops. Additionally, contact angle and refractive index were determined. Acetazolamide (ACZ), a highly insoluble drug used to treat glaucoma, was used as proof-of-concept. Herein, we show that NADES can increase the solubility of ACZ in aqueous solutions by at least up to 3 times, making it useful for the formulation of ACZ into ocular drops and thereby enabling more efficient treatment. The cytotoxicity assays demonstrated that NADES are biocompatible up to 5% (w/v) in aqueous media, promoting cell viability (above 80%) when compared to the control after 24 h incubation in ARPE-19 cells. Furthermore, when ACZ is dissolved in aqueous solutions of NADES, the cytotoxicity is not affected in this range of concentrations. Although further studies are necessary to design an optimal formulation incorporating NADES, this study shows that these eutectics can be powerful tools in the formulation of ocular drugs.
Pre-Clinical Assessment of Roflumilast Therapy in a Thoracic Model of Spinal Cord Injury
Authors: Sousa Carla S. , Lima Rui , Cibrão Jorge R. , Gomes Eduardo D. , Fernandes Luís S. , Pinho Tiffany S. , Silva Deolinda , Campos Jonas , Salgado António J. , Silva Nuno A.
Published: May 2023

The failure of axons to regenerate after a spinal cord injury (SCI) remains one of the greatest challenges in neuroscience. The initial mechanical trauma is followed by a secondary injury cascade, creating a hostile microenvironment, which not only is not permissive to regeneration but also leads to further damage. One of the most promising approaches for promoting axonal regeneration is to maintain the levels of cyclic adenosine monophosphate (cAMP), specifically by a phosphodiesterase-4 (PDE4) inhibitor expressed in neural tissues. Therefore, in our study, we evaluated the therapeutic effect of an FDA-approved PDE4 inhibitor, Roflumilast (Rof), in a thoracic contusion rat model. Results indicate that the treatment was effective in promoting functional recovery. Rof-treated animals showed improvements in both gross and fine motor function. Eight weeks post-injury, the animals significantly recovered by achieving occasional weight-supported plantar steps. Histological assessment revealed a significant decrease in cavity size, less reactive microglia, as well as higher axonal regeneration in treated animals. Molecular analysis revealed that IL-10 and IL-13 levels, as well as VEGF, were increased in the serum of Rof-treated animals. Overall, Roflumilast promotes functional recovery and supports neuroregeneration in a severe thoracic contusion injury model and may be important in SCI treatment.
Transforming Wound Management: Nanomaterials and Their Clinical Impact
Authors: T Ashwini , Prabhu Ashlesh , Baliga Vishal , Bhat Shreesha , Thenkondar Siddarth T. , Nayak Yogendra , Nayak Usha Y.
Published: May 2023

Wound healing is a complex process that can be further complicated in chronic wounds, leading to prolonged healing times, high healthcare costs, and potential patient morbidity. Nanotechnology has shown great promise in developing advanced wound dressings that promote wound healing and prevent infection. The review article presents a comprehensive search strategy that was applied to four databases, namely Scopus, Web of Science, PubMed, and Google Scholar, using specific keywords and inclusion/exclusion criteria to select a representative sample of 164 research articles published between 2001 and 2023. This review article provides an updated overview of the different types of nanomaterials used in wound dressings, including nanofibers, nanocomposites, silver-based nanoparticles, lipid nanoparticles, and polymeric nanoparticles. Several recent studies have shown the potential benefits of using nanomaterials in wound care, including the use of hydrogel/nano silver-based dressings in treating diabetic foot wounds, the use of copper oxide-infused dressings in difficult-to-treat wounds, and the use of chitosan nanofiber mats in burn dressings. Overall, developing nanomaterials in wound care has complemented nanotechnology in drug delivery systems, providing biocompatible and biodegradable nanomaterials that enhance wound healing and provide sustained drug release. Wound dressings are an effective and convenient method of wound care that can prevent wound contamination, support the injured area, control hemorrhaging, and reduce pain and inflammation. This review article provides valuable insights into the potential role of individual nanoformulations used in wound dressings in promoting wound healing and preventing infections, and serves as an excellent resource for clinicians, researchers, and patients seeking improved healing outcomes.
Medication-Related Problems Identified and Addressed by Pharmacists Dispensing COVID-19 Antivirals at a Community Pharmacy
Authors: Kieck Danielle , Mahalick Leeann , Vo Thanh Truc
Published: May 2023

Safe dispensing of coronavirus disease 2019 (COVID-19) oral antivirals requires comprehensive patient assessment to identify and address significant medication-related problems (MRPs). Given the fast-paced environment of community pharmacies and limited access to outside patient records, there are challenges with pharmacists ensuring the safe and appropriate dispensing of these medications. An independent community pharmacy in Pennsylvania developed and implemented a COVID-19 oral antiviral assessment protocol to systematically review all prescriptions dispensed for nirmatrelvir/ritonavir (Paxlovid™) and molnupiravir (Lagevrio™) to identify and address MRPs. A retrospective review was conducted to assess documented MRPs, including significant drug–drug interactions and inappropriate dosing requiring intervention, for prescriptions dispensed from 9 February 2022 to 29 April 2022. Pharmacists identified one or more significant MRPs requiring intervention on 42 of the 54 nirmatrelvir/ritonavir prescriptions (78%) and 0 of the 7 molnupiravir prescriptions. Most pharmacist interventions involved drug–drug interactions between nirmatrelvir/ritonavir and HMG-CoA reductase inhibitors and calcium channel blockers, along with four renal dose adjustments for nirmatrelvir/ritonavir. This study highlights the ability of community pharmacists to identify and address MRPs and promotes the use of a protocol to encourage safe dispensing practices for medications prone to MRPs.
Impact of Insect-Resistant Transgenic Maize 2A-7 on Diversity and Dynamics of Bacterial Communities in Rhizosphere Soil
Authors: Xu Xiaohui , Liu Xin , Li Fan , Hao Chaofeng , Sun Hongwei , Yang Shuke , Jiao Yue , Lu Xingbo
Published: May 2023

Artificial modification of Bacillus thuringiensis (Bt) proteins can effectively improve their resistance to target pests, but the effect of such modification on the diversity of rhizosphere microorganisms remains unclear. Transgenic maize 2A-7 contains two artificially modified Bt proteins, mCry1Ab and mCry2Ab. These proteins can enter soil and pose a potential threat to soil microbial diversity. To assess their impacts on rhizosphere bacteria communities, the contents of the two Bt proteins and changes in bacterial community diversity in the rhizosphere soils of transgenic maize 2A-7 and its control variety were analyzed at different growth stages in 2020. The results showed that the two Bt proteins were detected at low levels in the rhizosphere soils of 2A-7 plants. No significant differences in soil bacterial diversity were detected between 2A-7 and its control variety at any of the growth stages. Bioinformatics analysis indicated that the growth stage, rather than the cultivar, was the main factor causing changes in bacterial communities. This research provides valuable data for understanding the impact of Bt crops on the soil microbiome, and establishes a theoretical basis for evaluation of their safety.