Site preference and local structural stability of Bi(III) substitution in hydroxyapatite using first-principles simulations.

Bismuth (Bi(III)) substitution in hydroxyapatite (HAp) lattice confers unique properties such as antibacterial, catalytic, radiosensitization, and conductive properties while preserving the innate bioactivity. Understanding the local structural changes upon Bi3+ substitution is essential for controlling the stability and optimizing the properties of HAp. Despite numerous experimental studies, the precise substitution behaviors, such as site preference and structural stability, remain incompletely understood. In this study, the substitution behavior of Bi(III) into the HAp lattice with formula of Ca9Bi(PO4)6(O)(OH) was investigated via first-principles simulation by implementing density functional theory. Energy calculations showed that Bi3+ preferentially occupies the Ca(2) site with an energy difference of ∼0.02 eV per atom. Local structure analysis revealed higher bond population values and an oxygen coordination shift from 7 to 6 for the Ca(2) site, attributed to the greater covalent interactions and its flexible environment accommodating the bulky Bi3+ ion and its stereochemically active lone pair. This work provides the first comprehensive investigation on Bi3+ ion substitution site preference in HAp using first-principles simulations.

Folic acid-mediated enhancement of the diagnostic potential of luminescent europium-doped hydroxyapatite nanocrystals for cancer biomaging.

Early and accurate cancer diagnosis is crucial for improving patient survival rates. Luminescent nanoparticles have emerged as a promising tool in fluorescence bioimaging for cancer diagnosis. To enhance diagnostic accuracy, ligands promoting endocytosis into cancer cells are commonly incorporated onto nanoparticle surfaces. Folic acid (FA) is one such ligand, known to specifically bind to folate receptors (FR) overexpressed in various cancer cells such as cervical and ovarian carcinoma. Therefore, surface modification of luminescent nanoparticles with FA can enhance both luminescence efficiency and diagnostic accuracy. In this study, luminescent europium-doped hydroxyapatite (EuHAp) nanocrystals were prepared via hydrothermal method and subsequently modified with (3-Aminopropyl)triethoxysilane (APTES) followed by FA to target FR-positive human cervical adenocarcinoma cell line (HeLa) cells. The sequential grafting of APTES and then FA formed a robust covalent linkage between the nanocrystals and FA. Rod-shaped FA-modified EuHAp nanocrystals, approximately 100 nm in size, exhibited emission peaks at 589, 615, and 650 nm upon excitation at 397 nm. Despite a reduction in photoluminescence intensity following FA modification, fluorescence microscopy revealed a remarkable 120-fold increase in intensity compared to unmodified EuHAp, attributed to the enhanced uptake of FA-modified EuHAp. Additionally, confocal microscope observations confirmed the specificity and the internalization of FA-modified EuHAp nanocrystals in HeLa cells. In conclusion, the modification of EuHAp nanocrystals with FA presents a promising strategy to enhance the diagnostic potential of cancer bioimaging probes.

Ligand Installation to Polymeric Micelles for Pediatric Brain Tumor Targeting.

Medulloblastoma is a life-threatening disease with poor therapeutic outcomes. In chemotherapy, low drug accumulation has been a cause of these outcomes. Such inadequate response to treatments has been associated with low drug accumulation, particularly with a limited cellular uptake of drugs. Recently, the conjugation of drugs to ligand molecules with high affinity to tumor cells has attracted much attention for enhancing drug internalization into target cells. Moreover, combining tumor-targeting ligands with nano-scaled drug carriers can potentially improve drug loading capacity and the versatility of the delivery. Herein, we focused on the possibility of targeting CD276/B7-H3, which is highly expressed on the medulloblastoma cell membrane, as a strategy for enhancing the cellular uptake of ligand-installed nanocarriers. Thus, anti-CD276 antibodies were conjugated on the surface of model nanocarriers based on polyion complex micelles (PIC/m) via click chemistry. The results showed that the anti-CD276 antibody-installed PIC/m improved intracellular delivery into CD276-expressing medulloblastoma cells in a CD276-dependent manner. Moreover, increasing the number of antibodies on the surface of micelles improved the cellular uptake efficiency. These observations indicate the potential of anti-CD276 antibody-installed nanocarriers for promoting drug delivery in medulloblastoma.

Case report: Five patients with myocarditis after mRNA COVID-19 vaccination.

Objectives: To describe clinical features and laboratory data of myocarditis after the mRNA COVID-19 vaccine in children. Methods: We reviewed patients younger than 18 years of age, who visited our hospital because of myocarditis within 1 week after BNT162b2 from June 2021 to January 2022. Results: We identified five male patients aged 12-16 years who presented to our hospital with myocarditis within 2-3 days after the second dose of BNT162b2 COVID-19 vaccination between June 2021 and January 2022. All patients experienced chest pain, and fever, pain other than chest pain, and shortness of breath were present in two, three, and two patients, respectively. The serum troponin I level was increased in all patients except one, and electrocardiogram (ECG) showed ST elevation in all patients. Echocardiography revealed pericardial effusion and decreased ejection fraction in three and one patients, respectively. In accordance with the Japanese guidelines for myocarditis, the patients were treated with colchicine and aspirin. Chest pain improved within a few days with no hemodynamic instability. The patients were discharged with no sequelae. Conclusions: ST changes on ECG and elevated troponin I levels may aid the diagnosis of myocarditis after mRNA COVID-19 vaccination.

Immunological Changes of Basophil Hyperreactivity to Sweat in Patients With Well-Controlled Atopic Dermatitis.

Background: Sweat aggravates atopic dermatitis (AD). In patients with AD, type-I hypersensitivity to sweat may be shown by histamine release from patients' basophils in response to the semi-purified sweat antigen (QR), and the presence of specific immunoglobulin E (IgE) binding to MGL_1304, the component of QR. However, there has been no information on the immunological changes of type-I hypersensitivity to the sweat antigen in patients with well-controlled AD using topical corticosteroids (TCSs) and/or biologics as treatments. Method: Histamine-releasing tests using patients' basophils and QR and the detection of serum IgE against MGL_1304 and mite allergen Der f 1 were performed in patients with AD who were well controlled by topical TCS with/without dupilumab for 53-96 weeks. Results: In total, 14 patients were enrolled. Seven patients received TCS therapy alone (TCS group), and seven patients received TCS with dupilumab therapy (dupilumab group). In all participants, the level of specific IgE against MGL_1304 decreased after treatments, but histamine release from basophils in response to QR did not show a statistically significant reduction; rather, it increased. In the dupilumab group, all changes in histamine release induced by QR (increase), the IgE level against MGL_1304 (decrease), and that against Der f 1 (decrease) were statistically significant, whereas the TCS group showed no significant change in any of them. Conclusion: The well-controlled condition for 53-96 weeks resulted in no reduction of the hyperreactivity of basophils against in patients with AD, even with the treatment with dupilumab. This study suggests persistent basophil hyperreactivity to sweat antigen over a year or longer.

Effect of PEGylation on the Drug Release Performance and Hemocompatibility of Photoresponsive Drug-Loading Platform.

Coronary stenosis has been one of the most common heart diseases that drastically increases the risk of fatal disorders such as heart attack. Angioplasty using drug coated balloons (DCB) has been one of the most safe and promising treatments. To minimize the risk of thrombosis of such DCBs during intervention, a different approach that can secure high hemocompatibility under blood flow is necessary. Here we report a method of improving the photoresponsive platform's hemocompatibility by conjugating polyethylene glycol (PEG), onto the functional groups located at the balloon surface. In this study, latex microbeads were used as models for balloons to enable precise observation of its surface under microscopy. These beads were decorated with PEG polymers of a variety of lengths and grafting densities, along with the Cy5-Photoclevable (PC) linker conjugate to mimic drugs to be loaded onto the platform. Results showed that PEG length and grafting density are both critical factors that alter not only its hemocompatibility, but also the drug load and release efficiency of such platform. Thus, although further investigation is necessary to optimize the tradeoff between hemocompatibility, drug load, and release efficiency, it is safe to conclude that PEGylation of DCB surface is an effective method of enhancing and maintaining high hemocompatibility to minimize the risk of thrombosis during angioplasty.

Clinical and histological characterization of transient dermal pain triggered by sweating stimuli.

BACKGROUND: Tingling dermal pain triggered by sweating impairs the lives of patients with cholinergic urticaria and generalized anhidrosis. However, dermal pain evoked by sweating stimuli has been under investigated. METHODS: To clarify characteristics of tingling dermal pain on sweating, we retrospectively evaluated clinical and histopathological manifestations in 30 patients having the main problem of dermal pain on sweating, and the efficacy of treatments. RESULTS: Dermal pain upon sweating affected mostly young males. It accompanied eruptions upon sweating and/or hypohidrosis in 24 patients, while 6 patients had dermal pain independently of hypohidrosis or eruptions. Dermal pain appeared immediately upon exposure to sweating stimuli, and disappeared within mostly 30 or 10 min. Hypohidrosis was not necessarily generalized but localized or absent. Histological analysis revealed that dermal pain could occur even without morphological changes and inflammation of sweat glands. Hypersensitivity to sweat contents was found only in 26% of patients. Sweat histamine and increase of plasma histamine after thermal induction in patients were significantly higher than those in healthy subjects. Effectiveness of steroid pulse therapy was demonstrated for dermal pain with hypohidrosis. Medications acting on nervous systems and regular sweat-inducing activities for promoting perspiration were also effective. CONCLUSIONS: Short-lasting tingling dermal pain appears immediately upon exposure to sweating stimuli, regardless of developing eruptions and/or presence of hypohidrosis, but possibly in association with sweat and plasma histamine.

Calculation of practical skin donor area for meshed skin grafting in real-world surgery.

Meshed skin grafting is a common technique in operations to minimize surgery on the donor site area. However, the donor site area is empirically determined by surgeons due to the lack of a reliable formula to calculate the donor area required to cover a skin defect. To determine the minimal size for donor skin, the expansion rates of 1.5:1, 3:1, and 6:1 meshed skin graft and the area actually covered by them were investigated in real-world operations. About 51 patients who received 57 operations with meshed skin grafts were enrolled in this study. The average clinical coverage rates of area in cases in which 1.5:1, 3:1, or 6:1 meshed skin grafting was performed were 1.02, 1.29, or 2.18, respectively. Those rates were notably low when recipient sites were concave. The average expansion rates of 1.5:1, 3:1, and 6:1 meshed skin grafts were about 1.16, 1.61, and 2.32, respectively. These results indicate that the size of donor skin should be about 85%, 60%, and 45% size of the recipient site to achieve the target 1.5:1, 3:1, and 6:1 meshed skin graft, respectively. In addition, the donor area should be adjusted in consideration of the shape of the recipient sites.

Relationship between Bulk Physicochemical Properties and Surface Wettability of Hydrogels with Homogeneous Network Structure.

Controlling hydrogel surface wettability is of great importance in the viewpoint of engineering biomaterials that are in contact with cells and tissues. However, studies reporting how the hydrogel bulk properties would affect the surface is scarce, and thus it has been difficult to fabricate hydrogels with the desired properties. Also, there has been no effective method to elucidate this, due to the inhomogeneity introduced in the network structure of conventional hydrogels. Here we report our approach in elucidating the relationship between hydrogel physicochemical parameters and surface wettability by using Tetra-PEG gels, which are known to have homogeneous network structure. Specifically, the polymer volume fraction (φ) and the molecular weight (MW) between the cross-links were controlled. The number of anions, cations, and ionic pairs introduced within the hydrogel, were also individually controlled. The surface wettability of the resulting hydrogels was then evaluated. Results showed that surface wettability is largely dependent on the concentration of charged groups that are introduced in the hydrogel bulk, especially those that are not paired and ionically stabilized. Our findings strongly support the fact that with conventional hydrogels, the correlation between surface wettability and its physicochemical properties had not been evaluated appropriately, and thus our insights will contribute significantly to accumulating further knowledge on controlling hydrogel surface wettability.