Modulating the sEH/EETs Axis Restrains Specialized Proresolving Mediator Impairment and Regulates T Cell Imbalance in Experimental Periodontitis.

Epoxyeicosatrienoic acids (EETs) and other epoxy fatty acids are short-acting lipids involved in resolution of inflammation. Their short half-life, due to its metabolism by soluble epoxide hydrolase (sEH), limits their effects. Specialized proresolving mediators (SPMs) are endogenous regulatory lipids insufficiently synthesized in uncontrolled and chronic inflammation. Using an experimental periodontitis model, we pharmacologically inhibited sEH, examining its impact on T cell activation and systemic SPM production. In humans, we analyzed sEH in the gingival tissue of periodontitis patients. Mice were treated with sEH inhibitor (sEHi) and/or EETs before ligature placement and treated for 14 d. Bone parameters were assessed by microcomputed tomography and methylene blue staining. Blood plasma metabololipidomics were carried out to quantify SPM levels. We also determined T cell activation by reverse transcription-quantitative PCR and flow cytometry in cervical lymph nodes. Human gingival samples were collected to analyze sEH using ELISA and electrophoresis. Data reveal that pharmacological sEHi abrogated bone resorption and preserved bone architecture. Metabololipidomics revealed that sEHi enhances lipoxin A4, lipoxin B4, resolvin E2, and resolvin D6. An increased percentage of regulatory T cells over Th17 was noted in sEHi-treated mice. Lastly, inflamed human gingival tissues presented higher levels and expression of sEH than did healthy gingivae, being positively correlated with periodontitis severity. Our findings indicate that sEHi preserves bone architecture and stimulates SPM production, associated with regulatory actions on T cells favoring resolution of inflammation. Because sEH is enhanced in human gingivae from patients with periodontitis and connected with disease severity, inhibition may prove to be an attractive target for managing osteolytic inflammatory diseases.

Artificial-Cofactor-Mediated Hydrogen and Electron Transfer Endows AuFe/Polydopamine Superparticles with Enhanced Glucose Oxidase-Like Activity.

Various applications related to glucose catalysis have led to the development of functional nanozymes with glucose oxidase (GOX)-like activity. However, the unsatisfactory catalytic activity of nanozymes is a major challenge for their practical applications due to their inefficient hydrogen and electron transfer. Herein, we present the synthesis of AuFe/polydopamine (PDA) superparticles that exhibit photothermal-enhanced GOX-like activity. Experimental investigations and theoretical calculations reveal that the glucose oxidation process catalyzed by AuFe/PDA follows an artificial-cofactor-mediated hydrogen atom transfer mechanism, which facilitates the generation of carbon-centered radical intermediates. Rather than depending on charged Au surfaces for thermodynamically unstable hydride transfer, Fe(III)-coordinated PDA with abundant amino and phenolic hydroxyl groups serves as cofactor mimics, facilitating both hydrogen atom and electron transfer in the catalytic process. Finally, leveraging the photothermal-enhanced GOX-like and catalase-like activities of AuFe/PDA, we establish a highly sensitive and accurate point-of-care testing blood glucose determination with exceptional anti-jamming capabilities.

Indole alkaloids isolated from the Nicotiana tabacum-derived Aspergillus fumigatus 0338 as potential inhibitors for tobacco powdery mildew and their mode of actions.

To explore active natural products against tobacco powdery mildew caused by Golovinomyces cichoracearum, an extract from the fermentation of endophytic Aspergillus fumigatus 0338 was investigated. The mechanisms of action for active compounds were also studied in detail. As a result, 14 indole alkaloid derivatives were isolated, with seven being newly discovered (1-7) and the remaining seven previously described (8-14). Notably, compounds 1-3 are rare linearly fused 6/6/5 tricyclic prenylated indole alkaloids, with asperversiamide J being the only known natural product of this kind. The isopentenyl substitutions at the 5-position in compounds 4 and 5 are also rare, with only compounds 1-(5-prenyl-1H-indol-3-yl)-propan-2-one (8) and 1-(6-methoxy-5-prenyl-1H-indol3-yl)-propan-2-one currently available. In addition, compounds 6 and 7 are new framework indole alkaloid derivatives bearing a 6-methyl-1,7-dihydro-2H-azepin-2-one ring. The purified compounds were evaluated for their activity against G. cichoracearum, and the results revealed that compounds 7 and 9 demonstrated obvious anti-G. cichoracearum activities with an inhibition rate of 82.6% and 85.2%, respectively, at a concentration of 250 µg/mL, these rates were better than that of the positive control agent, carbendazim (78.6%). The protective and curative effects of compounds 7 and 9 were also better than that of positive control, at the same concentration. Moreover, the mechanistic study showed that treatment with compound 9 significantly increased the structural tightness of tobacco leaves and directly affect the conidiospores of G. cichoracearum, thereby enhancing resistance. Compounds 7 and 9 could also induce systemic acquired resistance (SAR), directly regulating the expression of defense enzymes, defense genes, and plant semaphorins, which may further contribute to increased plant resistance. Based on the activity experiments and molecular dockings, the indole core structure may be the foundation of these compounds' anti-G. cichoracearum activity. Among them, the indole derivative parent structures of compounds 6, 7, and 9 exhibit strong effects. Moreover, the methoxy substitution in compound 7 can enhance their activity. By isolating and structurally identifying the above indole alkaloids, new candidates for anti-powdery mildew chemical screening were discovered, which could enhance the utilization of N. tabacum-derived fungi in pesticide development.

Accuracy of an autonomous dental implant robotic system in dental implant surgery.

STATEMENT OF PROBLEM: Autonomous dental implant robot systems (ADIRSs) have been marketed for dental implant surgery; however, research on their accuracy is limited. PURPOSE: The purpose of this clinical study was to examine the accuracy of an ADIRS. MATERIAL AND METHODS: Seventy-four participants with partial edentulism underwent implant surgery by using the ADIRS. Before surgery, a cone beam computed tomography (CBCT) scan was conducted, and its image data were fed into the ADIRS navigation and positioning system for iterative reconstruction and surgical path planning. After local anesthesia administration, area disinfection, and patient registration, the robot prepared the osteotomy and placed the implant under guidance of the navigation system. A postoperative CBCT scan was made to assess deviations between the planned and actual implant positions. The global coronal, apical, and angular deviations were measured and analyzed. A generalized linear mixed model (GLMM) was used to compare the differences in major outcome variables (α=.05). RESULTS: All implant procedures were successfully carried out without any complications during surgery. A total of 86 implants were placed in 74 participants. The mean ±standard deviation global coronal deviation, global apical deviation, and angular deviation was 0.61 ±0.20 mm (95% CI: 0.23 to 1.0 mm), 0.79 ±0.32 mm (95% CI: 0.17 to 1.41 mm), and 2.56 ±1.10 degrees (95% CI: 0.42 to 4.70 degrees), respectively. The findings from the GLMM revealed that the implant region (premolar, molar; maxilla, mandible; left, right), implant length, and surgeon did not significantly impact accuracy (P>.05). CONCLUSIONS: ADIRS showed high accuracy for implant placement because of the control of angular deviation and axial errors. The implant region, implant length, and surgeon had no significant influence on the accuracy of implant placement. Nevertheless, more clinical studies are required to support evidence-based clinical outcomes.

Experimental and modeling investigation of dual-source iron release in water-solid-gas interaction of abandoned coal mine drainage.

After mine closure and flooding, abandoned iron-prone devices and equipment (e.g., steel bolts and ground support meshes) and iron-bearing minerals (e.g., pyrite) form a dual-source iron pollution system in mine groundwater. Dual-source iron contributes to the water-solid-gas interaction in abandoned coal mines and the release of iron at different periods after mine closure, posing environmental risks in groundwater and discharging acid mine drainage, which contains large amounts of iron. In this study, a series of hydrochemical experiments were conducted to simulate the iron release process of the dual-source system, and electrochemical experiments were carried out to reveal the reaction mechanism, characterize the dual-source iron pollution release mode and quantify the release rate ratio. PHREEQC package was used to simulate the long-term hydrogeochemistry reactions of the water-solid-gas interaction to determine the key factors and suitable conditions that inhibit dual-source iron release. The results show that the dual-source system of iron-bearing minerals (pyrite) and steel bolts promote iron release from each other. The resulting calculated annual iron release indicated that the overall iron release rate ratio is: dual-source > bolt > pyrite, indicating that mine water would remain acidic for a long time due to the continuous release of iron from the system. Numerical modeling results show that maintaining the environment temperature below 25 °C and the pH above 3.5 is an effective way to reduce the iron release rate.

Metal-Organic Framework-Based Artificial Organelle Corrects Microenvironment Interference for Accurate Intratumoral Glucose Analysis.

Enzymatic catalysis with high efficiency allows them a great prospect in metabolite monitoring in living cells. However, complex tumor microenvironments, such as acidity, H2 O2 , and hypoxia, are bound to disturb catalytic reactions for misleading results. Here, we report a spatially compartmentalized artificial organelle to correct intratumoral glucose analysis, where the zeolitic imidazolate framework-8 immobilized glucose oxidase-horseradish peroxidase cascade core and catalase-directed shell act as signal transduction and guarding rooms respectively. The acid-digested core and stable shell provide appropriate spaces to boost biocatalytic efficiency with good tolerability. Notably, the endogenous H2 O2 is in situ decomposed to O2 by catalase, which not only overcomes the interference in signal output but also alleviates the hypoxic states to maximize glucose oxidation. The marked protective effect and biocompatibility render artificial organelles to correct the signal transduction for dynamic monitoring glucose in vitro and in vivo, achieving our goal of accurate intratumoral metabolite analysis.

In vitro evaluation of platelet extracellular vesicles (PEVs) for corneal endothelial regeneration.

Corneal endothelial cells (CECs) slowly decrease in number with increasing age, which is a clinical issue as these cells have very limited regenerative ability. Therapeutic platelet biomaterials are increasingly used in regenerative medicine and cell therapy because of their safety, cost-effective manufacture, and global availability from collected platelet concentrates (PCs). Platelet extracellular vesicles (PEVs) are a complex mixture of potent bioactive vesicles rich in molecules believed to be instrumental in tissue repair and regeneration. In this study we investigated the feasibility of using a PEVs preparation as an innovative regenerative biotherapy for corneal endothelial dysfunction. The PEVs were isolated from clinical-grade human PC supernatants by 20,000 × g ultracentrifugation and resuspension. PEVs exhibited a regular, fairly rounded shape, with an average size of <200 nm and were present at a concentration of approximately 1011 /mL. PEVs expressed cluster of differentiation 41 (CD41) and CD61, characteristic platelets membrane markers, and CD9 and CD63. ELISA and LC-MS/MS proteomic analyses revealed that the PEVs contained mixtures of growth factors and multiple other trophic factors, as well as proteins related to extracellular exosomes with functional activities associated with cell cadherin and adherens pathways. CECs treated with PEVs showed increased viability, an enhanced wound-healing rate, stronger proliferation markers, and an improved adhesion rate. PEVs did not exert cellular toxicity as evidenced by the maintenance of cellular morphology and preservation of corneal endothelial proteins. These findings clearly support further investigations of PEV biomaterials in animal models for translation as a new CEC regeneration biotherapy.

First report of Dickeya dadantii causing bacterial soft rot of Thaumatophyllum bipinnatifidum in Taiwan.

Philodendrons are important foliage ornamentals planted worldwide (Chen et al. 2010). In November 2021, soft rot symptoms were observed on Philodendron selloum (now known as Thaumatophyllum bipinnatifidum; Sakuragui et al. 2018) grown in a nursery in Taichung, Taiwan. On symptomatic plants, the petioles were macerated; leaf lesions were also found on some plants (Figure S1). About 60% of the plants on site were symptomatic; these plants tended to cluster together. Four plants were sampled. Infected tissues were soaked and cut into pieces in 10 mM MgCl2 (using scalpels); undiluted samples were streak-plated onto nutrient agar (NA) and grown for 24 h at 28°C. Translucent, creamy-white colonies were isolated from all of the tissues examined, and 4 isolates, PHIL1 to PHIL4, were obtained (each from a different plant). All isolates exhibited typical phenotypes of bacteria belonging to Dickeya; they could cause maceration symptoms on potato slices, ferment glucose and produce phosphatase (Schaad et al. 2001); they could also produce indigoidine on NGM medium (NA added with glycerol and MnCl2; Lee and Yu. 2006). Polymerase chain reactions using Dickeya-specific primers 5A and 5B (Chao et al. 2006) amplified the expected amplicon in all 4 isolates. The 16S rDNA of PHIL1 to PHIL4 were amplified using primer pair 27f/1492r (Lane 1991) and the amplicons were sequenced; all 4 isolates shared the same 1,395-bp sequence (accession nos. ON203122, ON479664-ON479666). Among the strains belonging to known species (in GenBank), PHIL1 to PHIL4 shared the highest sequence identity (99.93%) with D. dadantii 3937; they also shared 98.78% sequence identity with D. dadantii CFBP 1269T. Multilocus sequence analysis (MLSA) targeting fragments of PHIL1 to PHIL4's dnaA (720 bp), dnaJ (672 bp), dnaX (450 bp), gyrB (822 bp), and recN (762 bp) genes (Marrero et al. 2013) were conducted. The five-gene concatenated sequences (3,426 bp) of the 4 isolates (accession nos. ON227444-ON227448, ON494509-ON494523) were identical. A maximum-likelihood phylogenetic analysis including these sequences and those of type strains of other known Dickeya species revealed that PHIL1 to PHIL4 clustered with strains belonging to D. dadantii (Figure S2). Koch's postulates were fulfilled with an inoculation test conducted on T. bipinnatifidum (17 cm in aboveground height; 7-months-old). Stab inoculation using sterile toothpicks was conducted on petioles. Three plants were tested for each isolate and 2 petioles were inoculated for each plant; all 4 isolates were included in the assay. The pathogen loads inoculated were quantified by the spread plate method and were 3.22 - 4.81 x 107 colony forming units. Three plants were stabbed with bacteria-free toothpicks, serving as controls. All plants were bagged post inoculation and kept in a growth chamber (28°C; 14 h light). After 72 h, all of the inoculated petioles exhibited symptoms resembling those observed in the nursery. Bacteria were re-isolated from the symptomatic tissues (one isolate from each treatment), and all of their five-gene concatenated sequences were the same as those of PHIL1 to PHIL4. This is the first formal report of the occurrence of D. dadantii infecting T. bipinnatifidum in Taiwan. Studies have shown that D. dadantii could affect other Araceae plants in Taiwan (Lee and Chen 2021). Since different Araceae ornamentals are often planted together in gardens and nurseries, growers should be aware of potential transmission of D. dadantii among them.

Accuracy of Different Surgical Guide Designs for Static Computer-Assisted Implant Surgery: An In Vitro Study.

The aims of this study were to evaluate the effect of (1) the different surgical guide designs and (2) implant placement location on the accuracy of fully guided implant placement in single edentulous sites using an in vitro study model. Forty-five partially edentulous models were scanned and divided into 3 groups: group 1, tooth-supported full-arch surgical guide; group 2, 3 different tooth-supported shortened surgical guides (SSGs); and group 3, tooth-supported full-arch surgical guide with a crossbar. All surgical guides were printed and used for fully guided implant placement. A total of 180 implants (60 per group) were placed, and scan bodies were positioned on all models, and postoperative surface scan files (STL) files were obtained. Superimposition of preoperative and postoperative STL files was performed, and the accuracy of implant position was evaluated. The interaction between group and implant location was statistically significant for angle, 3D offset at the base, and at the tip (P < .001). The post-hoc tests showed a statistically significantly higher deviation for group 2 compared to group 3 for all outcomes for implants #4 (P < .05) and #7 (P < .05). There was also a statistically significant difference in all outcomes between groups 1 and 3 for implant #7 (P < .05). All surgical guide designs presented satisfactory performance with clinically acceptable levels of deviation. However, SSGs presented higher accuracy for guided implant placement in a single-edentulous site, whereas a full-arch surgical guide with a crossbar presented superior outcomes when 2 or more guided implants were placed simultaneously.

Human platelet lysates for human cell propagation.

A pathogen-free and standardized xeno-free supplement of growth media is required for the ex vivo propagation of human cells used as advanced therapeutic medicinal products and for clinical translation in regenerative medicine and cell therapies. Human platelet lysate (HPL) made from therapeutic-grade platelet concentrate (PC) is increasingly regarded as being an efficient xeno-free alternative growth medium supplement to fetal bovine serum (FBS) for clinical-grade isolation and/or propagation of human cells. Most experimental studies establishing the superiority of HPL over FBS were conducted using mesenchymal stromal cells (MSCs) from bone marrow or adipose tissues. Data almost unanimously concur that MSCs expanded in a media supplemented with HPL have improved proliferation, shorter doubling times, and preserved clonogenicity, immunophenotype, in vitro trilineage differentiation capacity, and T-cell immunosuppressive activity. HPL can also be substituted for FBS when propagating MSCs from various other tissue sources, including Wharton jelly, the umbilical cord, amniotic fluid, dental pulp, periodontal ligaments, and apical papillae. Interestingly, HPL xeno-free supplementation is also proving successful for expanding human-differentiated cells, including chondrocytes, corneal endothelium and corneal epithelium cells, and tenocytes, for transplantation and tissue-engineering applications. In addition, the most recent developments suggest the possibility of successfully expanding immune cells such as macrophages, dendritic cells, and chimeric antigen receptor-T cells in HPL, further broadening its use as a growth medium supplement. Therefore, strong scientific rationale supports the use of HPL as a universal growth medium supplement for isolating and propagating therapeutic human cells for transplantation and tissue engineering. Efforts are underway to ensure optimal standardization and pathogen safety of HPL to secure its reliability for clinical-grade cell-therapy and regenerative medicine products and tissue engineering.

Plaque-Type Variant of Acquired Rhabdomyomatous Mesenchymal Hamartoma on the Chin: A Case Series.

ABSTRACT: Rhabdomyomatous mesenchymal hamartoma (RMH) is a rare benign tumor composed of skeletal muscle fibers and other mesenchymal-derived cells. The lesions are generally solitary sessile papules or skin tag lesions that occur during childhood. We retrospectively reviewed patients diagnosed with RMH pathologically between January 2001 and June 2020 at a tertiary medical center. A literature review was conducted. Seven plaque-type RMHs on the chin were found, including 6 in adults and one in a 14-year-old boy. The average age was 45.7 years. The onset of the RMH appearance was between several months and years. Pathologically, all patients showed a scattered haphazard arrangement of skeletal muscle bundles in the dermis and/or subcutis. Subcutis replaced by fibrous tissue and skeletal muscle bundles was present in 2 cases. Some skeletal muscles had a periadnexal distribution. This case series demonstrated a distinct clinical presentation of acquired RMH specifically located on the chin.

Clinical Analysis of Primary Nephrotic Syndrome Complicated by Plastic Bronchitis in Children.

OBJECTIVE: To summarize the clinical features of primary nephrotic syndrome (PNS) complicated by plastic bronchitis (PB) in children to provide guidance for treatment. METHODS: We conducted a retrospective review of the clinical data of 25 children hospitalized with NS complicated by PB in our Hospital between 10/2016 and 03/2019, and summarized the clinical manifestations, imaging and fiberoptic bronchoscopy (FOB) examinations, treatment course and outcome of them. RESULTS: 1). The 25 children, with a nephrotic syndrome (NS) course of one to 36 months, were all diagnosed with PB after FOB, among which 8 cases (32%) had respiratory failure and required ventilatory support. All of them started with respiratory symptoms such as fever and cough, and then suffered from dyspnea and progressive aggravation after 1-3 day(s) of onset, with rapid occurrence of bidirectional dyspnea and even respiratory failure in severe cases. 2). Laboratory test for pathogens: influenza A virus H1N1 (11 cases), influenza B virus (9 cases), adenovirus (3 cases) and mycoplasma pneumoniae (2 cases). There was no statistically significant difference (P>0.05) between children with common NS complicated by influenza virus (IV) infection (not accompanied by dyspnea) and those with kidney disease who developed PB in the white blood cell count, lymphocyte count, the inflammatory biomarkers C-reactive protein (CRP), procalcitonin (PCT) and humoral immunity (IgG level), yet the total IgG level was found significantly higher and the blood albumin level lower in the latter (P<0.05). 3). The 25 children were all examined with the FOB and treated with lavage, 15 of which had typical bronchial tree-like casts and 10 broken and stringy casts. Based on histopathological classification, all children were of Type I. 4). Twenty children (80%) with influenza were administered the antiviral drug Oseltamivir, 20 (80%) were treated with antibiotics, oral hormones were replaced with the same dosage of intravenous Methylprednisolone for 5 cases (20%), and 20 (80%) were intravenously administered gamma globulins (400-500 mg/kg x 3 days). These children showed a remarkable improvement after treatment and there were no deaths. CONCLUSION: NS children are at high risk of influenza virus infection. Children with a severe case of NS are more susceptible to PB. If symptoms like shortness of breath, wheezing and progressive bidirectional dyspnea occur, FOB examination and lavage treatment should be performed as early as possible. Hyper-IgE-emia and hypoproteinemia may be the high risk factors for PNS complicated by PB in children. ZIEL: Ziel der Studie war es, durch Zusammenfassung der klinischen Merkmale des primären nephrotischen Syndroms (PNS) mit komplizierender plastischer Bronchitis (PB) im Kindesalter eine Orientierungshilfe für die Therapie der Erkrankung zu geben. METHODIK: Wir führten eine retrospektive Prüfung der klinischen Daten von 25 Kindern durch, die zwischen Oktober 2016 und März 2019 in unser Krankhaus aufgenommen wurden, und erstellten eine Zusammenfassung der klinischen Symptome, Untersuchungen mit bildgebenden Verfahren und fiberoptischer Bronchoskopie (FOB), des Therapieverlaufs und des Outcomes der Patienten. ERGEBNISSE: 1). Bei den 25 Kindern bestand ein nephrotisches Syndrom (NS) über einen Zeitraum von einem bis 36 Monaten. Bei allen Patienten wurde die Diagnose PB nach FOB gestellt, wobei in 8 Fällen (32%) eine beatmungspflichtige respiratorische Insuffizienz vorlag. Alle Patienten zeigten anfänglich Symptome einer Atemwegserkrankung wie Fieber und Husten, gefolgt von Atemnot und progredienter Verschlechterung 1 bis 3 Tage nach Erkrankungsbeginn. Dabei kam es rasch zum Auftreten bidirektionaler Atemnot, in schweren Fällen bis hin zur respiratorischen Insuffizienz. 2). Laboruntersuchung auf Erreger: Influenza-A-Virus H1N1 (11 Fälle), Influenza-B-Virus (9 Fälle), Adenovirus (3 Fälle) und Mycoplasma pneumoniae (2 Fälle). Es fand sich kein statistisch signifikanter Unterschied (P>0,05) zwischen Kindern, die ein "gewöhnliches" NS mit komplizierender Influenza-Virus (IV)-Infektion (ohne begleitende Atemnot) aufwiesen, und Kindern mit Nierenerkrankung, die eine PB entwickelten, hinsichtlich der Leukozyten- und Lymphozytenwerte sowie der Entzündungsmarker C-reaktives Protein (CRP), Procalcitonin (PCT) und humorale Immunität (IgG-Wert). Allerdings wurde bei der letzteren Patientengruppe ein signifikant höherer Gesamt-IgG-Wert und ein signifikant niedriger Albumin-Spiegel im Blut nachgewiesen (P<0.05). 3). Bei allen 25 Kindern erfolgte eine FOB und Therapie mit Lavage, bei 15 Kinder fanden sich typische verzweigte Ausgüsse der Bronchialäste und bei 10 Patienten desintegrierte und zähe Ausgüsse. Gemäß der histopathologischen Klassifikation waren alle Kinder vom Typ I. 4). Zwanzig Kinder (80%) mit Influenza erhielten das Virostatikum Oseltamivir, 20 Kinder (80%) eine Antibiotikatherapie, in 5 Fällen (20%) wurden oral gegebene Hormone durch intravenös in derselben Dosis verabreichtes Methylprednisolon ersetzt und 20 Kinder (80%) erhielten intravenös verabreichte Gammaglobuline (400-500 mg/kg Körpergewicht x 3 Tage). Diese Kinder zeigten eine bemerkenswerte Verbesserung nach der Therapie und es traten keine Todesfälle auf. SCHLUSSFOLGERUNG: Bei Kindern mit NS besteht ein hohes Risiko für eine Influenza-Virus-Infektion. Kinder mit schwerem NS sind anfälliger für PB. Bei Auftreten von Symptomen wie Atemnot, Giemen und Brummern sowie progredienter bidirektionaler Dyspnoe sollte baldmöglichst eine FOB-Untersuchung und eine therapeutische Lavage durchgeführt werden. Erhöhte IgE-Werte im Blut und Hypoproteinämie stellen möglicherweise Risikofaktoren für PNS mit komplizierender PB im Kindesalter dar.

Multifunctional osthole liposomes and brain targeting functionality with potential applications in a mouse model of Alzheimer's disease.

Osthole (Ost) is a coumarin compound and a potential drug for Alzheimer's disease (AD). However, the effectiveness of Ost is limited by solubility, bioavailability, and low permeability of the blood-brain barrier. In this study, we constructed Ost liposomes with modified CXCR4 on the surface (CXCR4-Ost-Lips), and investigated the intracellular distribution of liposomes in APP-SH-SY5Y cells. In addition, the neuroprotective effect of CXCR4-Ost-Lips was examined in vitro and in vivo. The results showed that CXCR4-Ost-Lips increased intracellular uptake by APP-SH-SY5Y cells and exerted a cytoprotective effect in vitro. The results of Ost brain distribution showed that CXCR4-Ost-Lips prolonged the cycle time of mice and increased the accumulation of Ost in the brain. In addition, CXCR4-Ost-Lips enhanced the effect of Ost in relieving AD-related pathologies. These results indicate that CXCR4-modified liposomes are a potential Ost carrier to treat AD.

Application programming interface guided QA plan generation and analysis automation.

PURPOSE: Linear accelerator quality assurance (QA) in radiation therapy is a time consuming but fundamental part of ensuring the performance characteristics of radiation delivering machines. The goal of this work is to develop an automated and standardized QA plan generation and analysis system in the Oncology Information System (OIS) to streamline the QA process. METHODS: Automating the QA process includes two software components: the AutoQA Builder to generate daily, monthly, quarterly, and miscellaneous periodic linear accelerator QA plans within the Treatment Planning System (TPS) and the AutoQA Analysis to analyze images collected on the Electronic Portal Imaging Device (EPID) allowing for a rapid analysis of the acquired QA images. To verify the results of the automated QA analysis, results were compared to the current standard for QA assessment for the jaw junction, light-radiation coincidence, picket fence, and volumetric modulated arc therapy (VMAT) QA plans across three linacs and over a 6-month period. RESULTS: The AutoQA Builder application has been utilized clinically 322 times to create QA patients, construct phantom images, and deploy common periodic QA tests across multiple institutions, linear accelerators, and physicists. Comparing the AutoQA Analysis results with our current institutional QA standard the mean difference of the ratio of intensity values within the field-matched junction and ball-bearing position detection was 0.012 ± 0.053 (P = 0.159) and is 0.011 ± 0.224 mm (P = 0.355), respectively. Analysis of VMAT QA plans resulted in a maximum percentage difference of 0.3%. CONCLUSION: The automated creation and analysis of quality assurance plans using multiple APIs can be of immediate benefit to linear accelerator quality assurance efficiency and standardization. QA plan creation can be done without following tedious procedures through API assistance, and analysis can be performed inside of the clinical OIS in an automated fashion.

Anemia, hematinic deficiencies, and hyperhomocysteinemia in gastric parietal cell antibody-positive and -negative burning mouth syndrome patients.

BACKGROUND/PURPOSE: Our previous study found the serum gastric parietal cell antibody (GPCA) positivity in 12.3% of burning mouth syndrome (BMS) patients. This study assessed whether GPCA-positive BMS (GPCA+BMS) patients had significantly higher frequencies of macrocytosis, anemia, hematinic deficiencies, and hyperhomocysteinemia than healthy control subjects or GPCA-negative BMS (GPCA-BMS) patients. METHODS: The mean corpuscular volume, blood hemoglobin (Hb), and serum iron, vitamin B12, folic acid, homocysteine, and GPCA levels were measured and compared between any two of three groups of 109 GPCA+BMS patients, 775 GPCA-BMS patients, and 442 healthy control subjects. RESULTS: We found that 109 GPCA+BMS patients had significantly higher frequencies of macrocytosis, blood Hb and serum iron and vitamin B12 deficiencies, and hyperhomocysteinemia than 442 healthy control subjects (all P-values < 0.001) and significantly higher frequencies of macrocytosis, blood Hb and serum vitamin B12 deficiencies, and hyperhomocysteinemia than 775 GPCA-BMS patients (all P-values < 0.01). Moreover, 775 GPCA-BMS patients had significantly higher frequencies of macrocytosis, blood Hb and serum iron, vitamin B12, and folic acid deficiencies, and hyperhomocysteinemia than 442 healthy control subjects (all P-values < 0.005). Pernicious anemia (45.5%) and normocytic anemia (24.2%) were the two most common types of anemia in 33 anemic GPCA+BMS patients. Moreover, normocytic anemia (61.3%), thalassemia trait-induced anemia (15.5%), and iron deficiency anemia (14.1%) were the three most common types of anemia in 142 anemic GPCA-BMS patients. CONCLUSION: GPCA+BMS patients have significantly higher frequencies of macrocytosis, blood Hb and serum vitamin B12 deficiencies, and hyperhomocysteinemia than healthy control subjects or GPCA-BMS patients.

Real-world experience with Ropeginterferon-alpha 2b (Besremi) in Philadelphia-negative myeloproliferative neoplasms.

BACKGROUND/PURPOSE: Ropeginterferon alpha-2b (Ropeg) is a novel pegylated interferon-alpha recently approved for the treatment of polycythemia vera (PV) in Europe. However, other than data from clinical trials, little is known about this agent in real world practice. METHODS: A compassionate use program employing Ropeg for treating patients with unmet medical need was initiated in Taiwan in 2017. Herein, we collected clinical data and assessed the safety as well as efficacy of Ropeg in nine patients treated in this program. RESULTS: Collectively, among evaluable patients, both the molecular response and complete blood count remission rates were 62.5%. Most therapy-related side effects were mild, and there was no treatment discontinuation attributable to intolerable adverse events. The agent also showed efficacy in symptom amelioration and spleen size reduction. Although no specific patterns of cytokine level alteration could be identified, significantly attenuated plasma levels of inflammation markers were observed in one particular patient who happened to have normalized spleen size and most remarkable reduction in JAK2 mutant allele burden, indicating all-around improvement in every aspect of this case. Furthermore, plasma hepcidin levels increased in two-thirds of PV patients, illustrating the potential of Ropeg to restore normal regulation of erythropoiesis. Using RNA sequencing on pre- and post-treatment samples from one patient, we demonstrated altered expression of genes participating in IFN response, inflammation, apoptosis, and cellular differentiation. CONCLUSION: Conclusively, observed signs of efficacy and safety in our real-world experience prove Ropeg as a promising option for the treatment of MPN.

Farnesol-Loaded Liposomes Protect the Epidermis and Dermis from PM2.5-Induced Cutaneous Injury.

Particulate matter with aerodynamic diameter ≤2.5 µm (PM2.5) increases oxidative stress through free radical generation and incomplete volatilization. In addition to affecting the respiratory system, PM2.5 causes aging- and inflammation-related damage to skin. Farnesol (Farn), a natural benzyl semiterpene, possesses anti-inflammatory, antioxidative, and antibacterial properties. However, because of its poor water solubility and cytotoxicity at high concentrations, the biomedical applications of Farn have been limited. This study examined the deleterious effects of PM2.5 on the epidermis and dermis. In addition, Farn-encapsulated liposomes (Lipo-Farn) and gelatin/HA/xanthan gel containing Lipo-Farn were prepared and applied in vivo to repair and alleviate PM2.5-induced damage and inflammation in skin. The prepared Lipo-Farn was 342 ± 90 nm in diameter with an encapsulation rate of 69%; the encapsulation significantly reduced the cytotoxicity of Farn. Lipo-Farn exhibited a slow-release rate of 35% after 192 h of incubation. The half-maximal inhibitory concentration of PM2.5 was approximately 850 µg/mL, and ≥400 µg/mL PM2.5 significantly increased IL-6 production in skin fibroblasts. Severe impairment in the epidermis and hair follicles and moderate impairment in the dermis were found in the groups treated with post-PM2.5 and continuous subcutaneous injection of PM2.5. Acute and chronic inflammation was observed in the skin in both experimental categories in vivo. Treatment with 4 mM Lipo-Farn largely repaired PM2.5-induced injury in the epidermis and dermis, restored injured hair follicles, and alleviated acute and chronic inflammation induced by PM2.5 in rat skin. In addition, treatment with 4 mM pure Farn and 2 mM Lipo-Farn exerted moderate reparative and anti-inflammatory effects on impaired skin. The findings of the current study indicate the therapeutic and protective effects of Lipo-Farn against various injuries caused by PM2.5 in the pilosebaceous units, epidermis, and dermis of skin.

Discovery of enzymes for toluene synthesis from anoxic microbial communities.

Microbial toluene biosynthesis was reported in anoxic lake sediments more than three decades ago, but the enzyme catalyzing this biochemically challenging reaction has never been identified. Here we report the toluene-producing enzyme PhdB, a glycyl radical enzyme of bacterial origin that catalyzes phenylacetate decarboxylation, and its cognate activating enzyme PhdA, a radical S-adenosylmethionine enzyme, discovered in two distinct anoxic microbial communities that produce toluene. The unconventional process of enzyme discovery from a complex microbial community (>300,000 genes), rather than from a microbial isolate, involved metagenomics- and metaproteomics-enabled biochemistry, as well as in vitro confirmation of activity with recombinant enzymes. This work expands the known catalytic range of glycyl radical enzymes (only seven reaction types had been characterized previously) and aromatic-hydrocarbon-producing enzymes, and will enable first-time biochemical synthesis of an aromatic fuel hydrocarbon from renewable resources, such as lignocellulosic biomass, rather than from petroleum.

Adjunctive Reboxetine for Schizophrenia: Meta-analysis of Randomized Double-blind, Placebo-controlled Trials.

BACKGROUND: Results of previous studies on the safety and efficacy of adjunctive reboxetine for schizophrenia have been inconsistent. AIM: The aim of this study was to examine the efficacy and tolerability of reboxetine as an adjunct medication to antipsychotic treatment in a meta-analysis of randomized controlled trials (RCTs). METHODS: Two independent investigators extracted data for a random effects meta-analysis and assessed the quality of studies using risk of bias and the Jadad scale. Weighted and standardized mean differences (WMDs/SMDs) and risk ratio (RR)±95% confidence intervals (CIs) were calculated. RESULTS: Nine RCTs (n=630) with double-blind design were identified. Reboxetine outperformed placebo in improving negative (9 RCTs, n=602, SMD: -0.47 [95% CI: -0.87, -0.07], p=0.02; I2=82%), but not the overall, positive, and general psychopathology scores. The significant therapeutic effect on negative symptoms disappeared in the sensitivity analysis after removing an outlying study and in 50% (6/12) of the subgroup analyses. Reboxetine outperformed placebo in reducing weight (3 RCTs, n=186, WMD: -3.83 kg, p=0.04; I2=92%) and body mass index (WMD: -2.23 kg/m2, p=0.04; I2=95%). Reboxetine caused dry mouth but was associated with less weight gain overall and weight gain of ≥7% of the initial weight. All-cause discontinuation and other adverse events were similar between reboxetine and placebo. CONCLUSION: Adjunctive reboxetine could be useful for attenuating antipsychotic-induced weight gain, but it was not effective in treating psychopathology including negative symptoms in schizophrenia.

Anemia, hematinic deficiencies, hyperhomocysteinemia, and serum gastric parietal cell antibody positivity in 884 patients with burning mouth syndrome.

BACKGROUND/PURPOSE: Burning mouth syndrome (BMS) is characterized by burning sensation of the oral mucosa in the absence of clinically apparent oral mucosal alterations. This study evaluated the anemia, hematinic deficiencies, hyperhomocysteinemia, and serum gastric parietal cell antibody (GPCA) positivity in 884 BMS patients. METHODS: The blood hemoglobin (Hb) and serum iron, vitamin B12, folic acid, homocysteine, GPCA levels in 884 BMS patients were measured and compared with the corresponding levels in 442 age- and sex-matched healthy control subjects. RESULTS: We found that 175 (19.8%), 143 (16.2%), 42 (4.8%), 20 (2.3%), 170 (19.2%), and 109 (12.3%) BMS patients had blood Hb, serum iron, vitamin B12, and folic acid deficiencies, hyperhomocysteinemia, and serum GPCA positivity, respectively. Moreover, 884 BMS patients had significantly higher frequencies of blood Hb and serum iron, vitamin B12, and folic acid deficiencies, hyperhomocysteinemia, and serum GPCA positivity than 442 healthy control subjects (all P-values < 0.005). Of 175 anemic BMS patients, 95 had normocytic anemia, 27 had thalassemia trait-induced anemia, 21 had iron deficiency anemia, 15 had pernicious anemia, 15 had macrocytic anemia other than pernicious anemia, and 2 had microcytic anemia other than iron deficiency anemia and thalassemia trait-induced anemia. Burning sensation of oral mucosa (100.0%), dry mouth (48.1%), numbness of oral mucosa (30.7%), and dysfunction of taste (16.7%) were the four common symptoms in 884 BMS patients. CONCLUSION: BMS patients have significantly higher frequencies of blood Hb and serum iron, vitamin B12, and folic acid deficiencies, hyperhomocysteinemia, and serum GPCA positivity than healthy control subjects.