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The safety and efficacy of the lipid nanoparticle (LNP) delivery system are crucial for the successful development of messenger RNA vaccines. We designed and synthesized a series of ketal ester lipids (KELs), featuring a biodegradable ketal moiety in the linker and ester segments in the tail. Through iterative optimization of the head and tail groups of KELs, we tuned the pKa and molecular shapes, and identified (4S)‐KEL12 as a safe and efficient ionizable lipid for mRNA delivery. (4S)‐KEL12 LNP showed significantly higher delivery efficacy and lower toxicity than the DLin‐MC3‐DMA LNP. In comparison to SM‐102 LNP, (4S)‐KEL12 LNP exhibited better spleen tropism, reduced liver tropism, and hepatotoxicity. Additionally, (4S)‐KEL12 demonstrated good biodegradability following intramuscular or intravenous injection. Notably, (4S)‐KEL12 LNP encapsulated with a therapeutic mRNA cancer vaccine elicited robust cellular immune responses leading to substantial tumor regression along with prolonged survival in tumor‐bearing mice. Our results suggest that (4S)‐KEL12 LNP holds great promise for mRNA vaccine delivery. The comprehensive analysis of the structure‐activity relationship, toxicity, biodegradability, distribution, expression, efficacy, and stereochemistry of these LNPs will greatly contribute to the rational design and discovery of novel lipid‐based delivery systems. [ABSTRACT FROM AUTHOR]

This single‐center, randomized, open, two‐preparation, single‐dose, two‐period, self‐crossover trial aimed to assess the bioequivalence and safety of the test (T) preparation compared to the reference (R) preparation following intravenous injection in healthy subjects under fasting conditions. Twenty‐four healthy subjects were enrolled in the study and subjects were randomly divided into two groups at a 1:1 ratio and were administered once per period, with an 8‐day washout period. During each period, serum drug concentrations were detected for pharmacokinetic analysis and adverse events were recorded for safety analysis. The 90% confidence intervals for the geometric mean ratios (T:R) of maximum serum concentration, area under the serum concentration‐time curve from time zero to the last measurable concentration, and area under the serum concentration‐time curve from time zero to infinite time fell within the predefined bioequivalence range of 80%‐125%, indicating bioequivalence between the T and R preparation under fasting conditions. Additionally, four subjects (16.7%) experienced five instances of adverse events in the T group, while five subjects (21.7%) experienced five instances of adverse events in the R group. This trial indicated the potential bioequivalence between the T and R products under fasting conditions, based on pharmacokinetic and safety profile. [ABSTRACT FROM AUTHOR]

Prostate-specific membrane antigen (PSMA) positron emission tomography (PET) is used to select patients with biochemical recurrence for metastasis-directed radio-guided surgery (RGS). During RGS cancerous tissue can be identified after intravenous injection of the PSMA-targeted tracer [99mTc]Tc-PSMA-I&S. The aim was to study the correlation between the maximum standardized uptake value (SUVmax) on the preoperative PSMA PET/CT and the intraoperative numerical signal (counts/second) of the lesion measured by Drop-In gamma probe. Twenty-nine patients were included in this prospective TRACE-study (NCT03857113). Thirty-three lesions (29 nodal, 4 local recurrence) were preoperatively identified with a median SUVmax of 6.2 (interquartile range [IQR] 4.2–9.7). Median intraoperative signal was 134 counts/s (IQR 81–220) in vivo and 109 (IQR 72–219) ex vivo, showing strong correlation with SUVmax-values (ρs 0.728 and 0.763; p < 0.001, respectively). Our findings show a direct relation between SUVmax-values on PSMA PET/CT and numerical signal from the gamma probe, indicating SUVmax can be used to select patients for PSMA-RGS. [ABSTRACT FROM AUTHOR]

We have previously demonstrated that messenger RNA (mRNA) lipoplexes composed of N-hexadecyl-N,N-dimethylhexadecan-1-aminium bromide (DC-1-16), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), and polyethylene glycol-cholesteryl ether (PEG-Chol) exhibited high protein expression in the lungs and spleen of mice after intravenous injection and induced high levels of antigen-specific IgG1 upon immunisation. In this study, we optimised PEG modification in mRNA lipoplexes to reduce mRNA accumulation in the lungs and evaluated the suppression of tumour growth in mice bearing mouse lymphoma E.G7-ovalbumin (OVA) tumours by immunising them with an intravenous injection of OVA mRNA lipoplexes. PEGylation of mRNA lipoplexes with 3 mol% PEG-Chol (LP-DC-1-16-3PCL) prevented agglutination of erythrocytes and reduced accumulation in the lungs. Intravenous injection of LP-DC-1-16-3PCL lipoplexes containing OVA mRNA into mice induced high levels of anti-OVA IgG1 (83,000 mU/mL) in serum, and exhibited a high cytotoxic activity (97%) against E.G7-OVA cells by the splenocytes of mice. Furthermore, immunisation with LP-DC-1-16-3PCL lipoplexes containing OVA mRNA suppressed E.G7-OVA tumour growth compared to control mRNA. Based on these results, LP-DC-1-16-3PCL lipoplexes may be an effective mRNA vaccine for inducing antibody- and cytotoxic cell-mediated immune responses to tumours through intravenous injection. [ABSTRACT FROM AUTHOR]

AbstractObjectiveMethodsResultsConclusionsAutoimmune hepatitis (AIH) is a chronic progressive autoimmune disease with unclear etiology. As a bioactive metabolite of Vitamin D, 1,25(OH)2D3 can stimulate the production of tolerogenic dendritic cells (DCs) that overexpress programmed cell death ligand 1 (PD-L1). Although these cells have been shown to play a part in autoimmune diseases, their role in AIH remains unclear.This study aimed to investigate the potential effect of 1,25(OH)2D3-modulated DCs (PD-L1high VD3-DCs) in a murine model of experimental autoimmune hepatitis (EAH).Our results showed that intravenous injection of PD-L1high VD3-DCs significantly attenuated liver injury and EAH severity in mice. In addition, PD-L1high VD3-DC infusion improved the imbalance between splenic regulatory T cells (TFR) and follicular helper T (TFH) cells in EAH mice by increasing the number of TFR cells and restoring TFR/TFH ratio. Also, PD-L1high VD3-DC infusion selectively promoted TFR expansion and inhibited TFH differentiation. Furthermore, PD-L1high VD3-DC infusion increased TGF-β and IL-10 production, inhibited IL-21 secretion, upregulated key TFH transcriptional factors, and reduced the levels of serum immunoglobulins in EAH mice.To sum up, PD-L1high VD3-DC infusion could control EAH progression in mice by regulating TFR/TFH imbalance, indicating PD-L1high VD3-DC infusion might be a promising therapeutic approach for AIH treatment. [ABSTRACT FROM AUTHOR]

Background: Recent years, exosomes have been increasing used to treat diseases, but there is little research on how exosomes affect the metabolism of the body after entering. Therefore, in this study, we discussed the changes of metabolic spectrum and determined the differentially expressed metabolites in the serum of cynomolgus monkeys after injecting exosomes. Six cynomolgus monkeys were divided into control group and exosomes group. After intravenous injection of exosomes, the peripheral blood serum of cynomolgus monkeys was collected at baseline, day 1, day 7 and day 14 respectively. An ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry-based non-targeted metabolomics platform was used to detect the metabolites. The metabolic spectra of two groups of cynomolgus monkeys were identified and compared, and the time series changes of metabolites in exosomes were described. Results: The results showed that there was significant difference in metabolic spectrum between the two groups. 45, 114, 49, 39 differentially expressed metabolites were identified in baseline, day 1, day 7, and day 14, respectively. 6-hydroxydopamine, a metabolite related to the regulation of nerve function, was also found. Tryptophan metabolism, choline metabolism in cancer, porphyrin and chlorophyll metabolism were involved in day 1. Sphingolipid metabolism and histidine metabolism were involved in day 7. Three pathways, including choline metabolism, sphingolipid metabolism and biotin metabolism in cancer were involved in day 14. Through time series analysis, it was found that the level of propionylcarnitine and biliverdin increased on day 1 after inoculation with exosomes, while the level of hippuric acid decreased. These changes of immune-related metabolites suggested that exosomes might participate in the immunoregulation reaction after entering the body of cynomolgus monkeys. Conclusions: In our current study, we found that exosomes injected intravenously affect the changes of metabolites and metabolic pathways in cynomolgus monkeys. Intravenous injection of exosomes may affect the metabolite 6-hydroxydopamine, sphingolipid metabolic pathway, and choline metabolic in cancer pathway, which is of some significance for the treatment of Parkinson's disease. In addition, exosomes may also affect the immune-related metabolites in vivo, such as propionylcarnitine, biliverdin, hippuric acid metabolites, as well as tryptophan metabolism pathway, sphingolipid metabolism pathway involved in immune regulation, which is of great significance for the future study of immune-regulatory mechanisms of exosomes. [ABSTRACT FROM AUTHOR]

Purpose: To highlight the safety and efficacy of tocilizumab (TCZ) in Graves' ophthalmopathy (GO) combined with ocular myasthenia gravis (OMG) patients refractory to steroids and cholinesterase inhibitor (CEI). Methods: This was retrospective case series. We reviewed the health records of patients with GO combined with OMG, ten of whom were refractory to corticosteroids and CEI treatment and received intravenous injection of TCZ. Ten patients were treated with four injections of TCZ (intravenously, 8 mg per kilogram of body weight, once a month). We analyzed the efficacy and safety of TCZ treatment for this subset of patients with GO and OMG. Results: The main outcomes including quality of life questionnaire in Graves' orbitopathy (GO-QoL) score, Clinical Activity Score (CAS), Myasthenia Gravis Activities of Daily Living profile (MG-ADL) score, proptosis, diplopia and ptosis were assessed at 3 time points: "Baseline" (before the TCZ injection), "4th month" (after fourth time TCZ injection), "Follow up" (Last follow-up). Comparing parameters at 4th month vs. at baseline, all indicators improved at 4th month including GO-QoL score of visual functioning subscale (82.29 ± 13.71 vs. 35.98 ± 20.66, P < 0.001), GO-QoL score of the appearance subscale (80 ± 8.75 vs. 40.63 ± 17.95, P < 0.001), CAS (1.3 ± 0.46 vs. 4.5 ± 0.81, P < 0.001), MG-ADL (2.5 ± 1.56 vs. 5.11 ± 1.14, P < 0.001). Furthermore, proptosis decreased from 19.73 ± 2.84 to 17.93 ± 2.26 mm at 4th month (P < 0.0001). Diplopia and ptosis were also resolved at 4th month. After following up for a minimum of 11 months, the patients had no signs of relapse. In addition, we observed that all analyzed patients exhibited no significant drug reactions following the administration of TCZ. Conclusion: Tocilizumab maybe a useful therapeutic option in refractory GO coexisting with OMG. However, considering the limitation of a retrospective study, short follow up period and small sample size of this study, randomized controlled studies are needed to validate our results. [ABSTRACT FROM AUTHOR]

Background: Activation of endothelial cells and platelets in atherothrombosis is characterized by upregulation of P-selectin. As a consequence, P-selectin represents a potential target for molecular imaging to identify thrombosis at an early stage. Fucoidan is a polysaccharide ligand extracted from brown algae with nanomolar affinity for P-selectin. This first-in-human study evaluated in healthy volunteers the safety, whole-body biodistribution, and dosimetry of 99mTc-fucoidan (Good Manufacturing Practices grade). We also investigated whether we could observe binding of 99mTc-fucoidan to human thrombi ex vivo and in vivo. In ten healthy volunteers, conjugate whole-body scans were performed up to 24 h following intravenous injection of 99mTc-fucoidan (370 MBq). Moreover, 99mTc-fucoidan uptake in ex vivo human thrombi (n = 11) was measured by gamma counting. Additionally, three patients with a newly diagnosed deep vein thrombosis (DVT) were subjected to 99mTc-fucoidan SPECT/CT imaging. Results: 99mTc-fucoidan was well tolerated in all participants without any drug-related adverse events. The total-body absorbed dose in males was comparable to females (0.012 ± 0.004 vs. 0.011 ± 0.005 mSv/MBq; p = 0.97). Gamma counting experiments demonstrated binding of tracer to ex vivo human thrombi that was 16% lower after blocking with a natural P-selectin ligand, Sialyl Lewis X. 99mTc-fucoidan demonstrated specific uptake at the thrombus site in one out of three scanned patients with DVT. Conclusions: 99mTc-Fucoidan has a favorable biodistribution and safety profile. 99mTc-fucoidan exhibited specific binding to human thrombi in both in vivo and ex vivo settings. Nonetheless, the in vivo results do not support further clinical investigation of 99mTc-fucoidan as an imaging modality for DVT. Other clinical implementations of a technetium− 99m-labeled P-selectin tracer should be considered. Trial registration: Clinicaltrials,NCT03422055.Registered 01/15/2018. URL: https://clinicaltrials.gov/study/NCT03422055Landelijk Trial Register, NL7739. Registered 4/2/2019. https://onderzoekmetmensen.nl/en/trial/26785 [ABSTRACT FROM AUTHOR]

Compact cell type-specific promoters are important tools for basic and preclinical research and clinical delivery of gene therapy. In this work, we designed novel MiniPromoters to target D1 and D2 type dopaminoceptive medium spiny neurons in the striatum by manually identifying candidate regulatory regions or employing the OnTarget webserver. We then empirically tested the designs in rAAV-PHP.B for specificity and robustness in three systems: intravenous injection in mice, intracerebroventricular injection in mice, and intracerebroventricular injection in non-human primates. Twelve MiniPromoters were designed from eight genes: seven manually and five using OnTarget. When delivered intravenously in mice, three MiniPromoters demonstrated highly selective expression in the striatum, with Ple389 (ADORA2A) showing high levels of dopamine D2-receptor cell co-localization. The same three MiniPromoters also displayed enriched expression in the striatum when delivered intracerebroventricularly in mice with high levels of DARPP32 co-localization. Finally, Ple389 (ADORA2A) was intracerebroventricularly injected in non-human primates and showed enriched expression in the striatum as in the mouse. Ple389 (ADORA2A) demonstrated expression in the medium spiny neurons in all three systems tested and exhibited the highest level of D2-MSNs and DARPP32 co-labeling in mice, demonstrating its potential as a tool for gene therapy approaches for Parkinson and Huntington disease treatment. [ABSTRACT FROM AUTHOR]

Tumor immune modulation can be achieved using intratumoral injection of different immunomodulators during different phases of the cancer-immunity cycle. Intratumoral infusion catheters have been used in brain tumors, but these are not suitable outside the brain, where breathing motion results in catheter migration. Here, we use microstereolithography to manufacture a barbed sidehole catheter, modeled after the barbs in a bee stinger, where the barbs maintain the catheter position in the tumor, and sideholes within the barbs infuse drug into tumor tissue. In pig liver, we demonstrated 183-fold higher local drug concentration using the barbed sidehole catheter, compared to intravenous injection of water-soluble drug. High resistance sideholes and pulsatile injection both generate higher pressure in the catheter, which overcomes the tissue pressure, resulting in more drug delivery into tumor. A physical model of intratumoral infusion catheters accurately predicts the observed drug delivery results. Our catheter design is retained in the liver (and does not migrate out with breathing motion), and it preferentially infuses the drug into tumor tissue (not intratumoral vessels). [ABSTRACT FROM AUTHOR]

Introduction: Haemophilia is a rare bleeding disorder caused by a deficient or absent clotting factor, leading to frequent bleeding. Multiple intravenous (IV) infusions have been the standard prophylactic treatment; however, newer treatment options involve less frequent subcutaneous (SC) injections. To inform future health economic evaluations, this study applied the time trade-off (TTO) method for estimation of utilities associated with haemophilia treatment for both people with the disease and potential caregivers. Methods: Using the TTO method, utilities were estimated through two online surveys distributed in the UK, Canada and the US. In survey 1 (S1), adults from the general population aged 18 years and above evaluated health states as if they were living with haemophilia themselves and were receiving treatment for the condition. In survey 2 (S2), adults from the general population with a child under the age of 15 years evaluated health states as if they were treating their child for haemophilia. The surveys assessed the following treatment aspects: frequency of treatment, treatment device and injection site reactions. Results: In total, 812, 739 and 703 respondents completed S1 and 712, 594 and 527 completed S2 in the UK, Canada and the US, respectively. In both surveys, the treatment device was associated with the largest impact on utilities for both people with haemophilia and caregivers. Monthly SC injections with a prefilled pen-device were associated with a significant utility gain compared with SC injections with a syringe and IV infusions. In S1, a lower treatment frequency was preferred in all three countries, while in S2, a lower treatment frequency was preferred only in the UK. Avoiding injection site reactions was associated with a significant utility gain in both surveys, but only in the UK and Canada. Conclusions: The study suggests that the administration of haemophilia treatment in particular has an impact on utilities for both people and caregivers living with the disease. Thus, less complex and time-consuming treatment devices are expected to improve health-related quality of life. This can be further modified additively by less frequent administration. These results can inform future health economic analyses of haemophilia and haemophilia treatment. [ABSTRACT FROM AUTHOR]

Despite the widespread adoption of emergency coronary reperfusion therapy, reperfusion‐induced myocardial injury remains a challenging issue in clinical practice. Following myocardial reperfusion, S100A8/A9 molecules are considered pivotal in initiating and regulating tissue inflammatory damage. Effectively reducing the S100A8/A9 level in ischemic myocardial tissue holds significant therapeutic value in salvaging damaged myocardium. In this study, HA (hemagglutinin)‐ and RAGE (receptor for advanced glycation end products)‐ comodified macrophage membrane‐coated siRNA nanoparticles (MMM/RNA NPs) with siRNA targeting S100A9 (S100A9‐siRNA) are successfully prepared. This nanocarrier system is able to target effectively the injured myocardium in an inflammatory environment while evading digestive damage by lysosomes. In vivo, migration of MMM/RNA NPs to myocardial injury lesions is confirmed in a myocardial ischemia‐reperfusion injury (MIRI) mouse model. Intravenous injection of MMM/RNA NPs significantly reduced S100A9 levels in serum and myocardial tissues, further decreasing myocardial infarction area and improving cardiac function. Targeted reduction of S100A8/A9 by genetically modified macrophage membrane‐coated nanoparticles may represent a new therapeutic intervention for MIRI. [ABSTRACT FROM AUTHOR]

Background Purpose Methods Results Conclusion Total‐body positron emission tomography (PET), already well‐established in the pre‐clinical setting, makes it possible to study multi‐parameters in biological systems as a whole, rather than focusing on single tissues analysis. Simultaneous kinetic analysis of multiple organs poses some daunting new challenges.To explore quantifying the pharmacokinetics of Na[18F]F in multiple dissimilar murine organs simultaneously in vivo with total‐body PET imaging using different compartmental models for each organ and a shared cardiovascular system.Six mice underwent a 60‐min total‐body PET scan following intravenous bolus injection of Na[18F]F. Compartmental models were constructed for each organ (heart, lungs, liver, kidneys, and bone) using an image derived input function. Non‐linear least squares fitting of a model that connects the five organs to a shared cardiovascular system was used to analyze both the first 3 min of data and the full hour. Analysis was repeated 5000 times using different initial parameter values for each duration, permitting analysis of correlations between parameters.The models give a good qualitative account of the activity curves irrespective of the duration of the data; however, the quality of the fits to 3 min of data (average χν2$\chi _\nu ^2$ is 2.72) was generally better. Comparison of perfusion values to literature values was possible for the liver and lungs with the former (liver, 0.540 ± 0.177 mL/ml/min) being well‐above expectations and the latter (lungs, 0.184 ± 0.413 mL/ml/min) in rough agreement. Correlations between microparameter values (especially affecting k2) caused very noticeable problems for data modeling from both the kidneys and the femur.The present study demonstrates an approach to performing kinetic modeling for multiple organs simultaneously with Na[18F]F. The observed correlations between microparameter values remain a challenge. Nonetheless, many microparameters can be estimated reliably with a quantitative analysis of perfusion being possible for some organs. [ABSTRACT FROM AUTHOR]

Purpose: Intravenous injections are a common invasive procedure for delivering fluids or medications. Although patients experience pain from needle insertion, this discomfort is often overlooked due to its short duration and perceived insignificance. This study aimed to assess the effect of applying cryotherapy and thermotherapy using a flexible thermoelectric device on relieving the pain caused by intravenous injections. Methods: This randomized controlled trial utilized the modified thermoelectric element (M-TEE) tourniquet, which improves heat and cold transfer through a flexible TEE. Participants were hospitalized adults who had an 18-gauge angiocatheter inserted for surgery. The M-TEE tourniquet was applied 10-12 cm above the injection site, providing thermotherapy (40°C-45°C) or cryotherapy (0°C-10°C) to the respective groups. The control group received no temperature treatment. Pain, peripheral oxygen saturation, pulse rate, and regional blood flow were measured. Post- injection, satisfaction surveys were conducted with participants and practitioners. Results: There was a significant difference in pain perception among the three groups (F = 3.38, p = .041), with the cryotherapy group reporting less pain than the control group (p = .036). Regional venous blood flow significantly increased during thermotherapy (F = 5.99, p = .004), although regional arterial flow remained unchanged. Participant satisfaction differed across groups (F = 3.26, p = .046), with higher satisfaction in the cryotherapy group than in the control group (p = .040). Nurses’ satisfaction also varied significantly (F = 24.14, p < .001) across the groups. Conclusion: The M-TEE tourniquet effectively reduces intravenous injection pain and increases patient and practitioner satisfaction, particularly with cryotherapy. [ABSTRACT FROM AUTHOR]

Docetaxel has exhibited excellent therapeutic effects in cancer treatment; however, its hydrophobicity, short blood circulation time, and high blood toxicity restrict its clinical application. The use of mPEG-PLA micelles to deliver docetaxel into the body has been verified as an effective approach to enhance its therapeutic efficacy. However, mPEG-PLA micelles are easily disassembled in the bloodstream, which can easily lead to premature drug release. To broaden the application scenarios of mPEG PLA micelles, we utilized the π–π stacking effect as an intermolecular force to design a novel mPEG-PLA-Lys(Fmoc) micelle to enhance the blood stability and permeability of drug-loaded micelles. The result showed that drug-loaded micelles for injection did not alter the tissue selectivity of docetaxel. Intravenous injection of the micelles in nude mice showed better antitumor efficacy than docetaxel injection and tumor recurrence rate is 0%, which is significantly lower than that of docetaxel injection (100%). The micelles designed by this research institute are anticipated to improve the clinical therapeutic effect of docetaxel. [ABSTRACT FROM AUTHOR]

To investigate the protective effect of lanthanum chloride on kidney injury in chronic kidney disease and its mechanism. 1. Patients with CKD stage 2–5 were selected to analyze the effect of lanthanum-containing preparations on CKD. 2. Sixty healthy male Wistar rats were randomly divided into control group, model group, lanthanum chloride groups (0.03 ng/kg, 0.1 ng/kg, 0.3 ng/kg, q.3d., i.v.), and lanthanum carbonate group (0.3 g/kg, q.d., p.o.). The model group was given 2 % adenine suspension (200 mg/kg, q.d., p.o.) for the first two weeks, followed by adenine (200 mg/kg, b.i.d., p.o.) for 2 weeks, and all animals were sacrificed after eight weeks of administration. 3. The serum and kidneys of rats in each group were collected to detect the oxidative stress indicators and the expressions of LC3B-Ⅱ/Ⅰ, p62, Bcl-2, Bax, Caspase-3 and Cleaved Caspase-3. 4. Human renal tubular epithelial cells (HK-2 cells) were divided into control group, model group, lanthanum chloride group, pyrophosphate (PPI) group, chloroquine (CQ) group, rapamycin group, doxorubicin (DOX) group and N-acetyl-L-cysteine (NAC) group. The mitochondrial status, mitophagy and apoptosis levels were detected. 1.Lanthanum-containing preparations can significantly reduce the biochemical indexes of kidney injury in patients with CKD. 2. In the model group, the glomerular and renal tubular edema, the mitochondria were short and round, and the expression of LC3B-Ⅱ/Ⅰ and Bax increased, while the expression of P62, Bcl-2 and Caspase-3 decreased, and there was a significant improvement in the administration group, especially the 0.1 ng/kg group and lanthanum carbonate group. 3. In the HK-2 cell model group, mitochondrial membrane potential decreased, morphology changed and the results were reversed by lanthanum chloride. Lanthanum chloride may alter the morphology of nano-hydroxyapatite, thereby inhibiting its induced mitophagy and mitochondria-mediated apoptosis, and ultimately improve CKD renal injury effectively. [Display omitted] • Lanthanum chloride has a protective effect against kidney injury in CKD. • Nano-hydroxyapatite was found in both in vitro and in vivo CKD models, and it plays a major role in alleviating CKD. • Lanthanum chloride may change nano-hydroxyapatite morphology, inhibiting mitophagy and apoptosis, improving CKD renal injury. [ABSTRACT FROM AUTHOR]

Mitochondrial DNA (mtDNA) mutations are frequent in cancer, yet their precise role in cancer progression remains debated. To functionally evaluate the impact of mtDNA variants on tumor growth and metastasis, we developed an enhanced cytoplasmic hybrid (cybrid) generation protocol and established isogenic human melanoma cybrid lines with wild-type mtDNA or pathogenic mtDNA mutations with partial or complete loss of mitochondrial oxidative function. Cybrids with homoplasmic levels of pathogenic mtDNA reliably established tumors despite dysfunctional oxidative phosphorylation. However, these mtDNA variants disrupted spontaneous metastasis from primary tumors and reduced the abundance of circulating tumor cells. Migration and invasion of tumor cells were reduced, indicating that entry into circulation is a bottleneck for metastasis amid mtDNA dysfunction. Pathogenic mtDNA did not inhibit organ colonization following intravenous injection. In heteroplasmic cybrid tumors, single-cell analyses revealed selection against pathogenic mtDNA during melanoma growth. Collectively, these findings experimentally demonstrate that functional mtDNA is favored during melanoma growth and supports metastatic entry into the blood. [ABSTRACT FROM AUTHOR]

This study evaluated the safety, tolerability, pharmacodynamics, and pharmacokinetics of recombinant neorudin (EPR‐hirudin [EH]) in patients with acute coronary syndrome (ACS), providing a basis for further therapeutic research. This open‐label, single‐center, nonrandomized, nonblinded, and noncontrolled trial categorized 24 patients with nonprogressive ACS who met the screening criteria into 3 groups. They received an intravenous injection of neorudin (0.4 mg/kg), followed by an intravenous drip at doses of 0.15, 0.30, and 0.45 mg/kg/h for 3 days in the low‐, medium‐, and high‐dose groups, respectively. The safety, tolerability, pharmacodynamics, and pharmacokinetics of EH were assessed after treatment, indicating that neorudin was safe and well tolerated in nonprogressive ACS. No serious adverse events or clinical composite end points were observed. The activated partial thromboplastin time and thrombin time increased significantly and dose dependently following EH administration across all groups compared to pretreatment values. Conversely, thrombin activity significantly decreased after drug administration but returned to baseline levels shortly after drug withdrawal. Within the administered dose range, neorudin exposure increased with the dose, and its half‐life was approximately 2 hours. Neorudin was found to be safe and tolerable for treating patients with nonprogressive ACS, demonstrating therapeutic efficacy at doses up to 0.45 mg/kg/h over a 3‐day period. [ABSTRACT FROM AUTHOR]

Introduction: Vitamin c can relieve the pain after other diseases, but there are no studies on whether vitamin C can relieve the pain after hip replacement. The purpose of this paper is to study whether vitamin C can relieve the pain after total hip replacement. Purpose: In this prospective, double-blind, placebo-controlled, randomized trial, 100 patients receiving THA at our hospital were randomly assigned to vitamin c or control groups. During the operation, the vitamin C group will receive intravenous injection of 3 g vitamin C, and the control group will receive 3 g placebo. If the patient has postoperative pain, 10 ml subcutaneous injection of morphine will be required as a rescue analgesic. The primary outcome was the amount of postoperative injection of morphine as a rescue analgesic and expression of inflammatory factors, and the secondary outcome was postoperative pain and hip recovery as assessed by visual analog scale (VAS). Results: The dosage of subcutaneous injection of morphine was significantly reduced in vitamin C group. VAS pain scores at rest and exercise were lower in the vitamin C group 24 h after surgery, and hip motion was better 24 h after surgery, but there was no significant difference between the two groups 24 h after surgery.Nonetheless, the overall changes in morphine usage and VAS scores did not surpass the established minimal clinically important differences (10 mg for morphine consumption; 1.5 at rest and 1.8 during movement for VAS scores). Conclusion: Adding intravenous vitamin c to multimodal analgesia significantly improved morphine consumption, VAS pain score, and functional recovery. However, it is recommended that single intravenous administration of vitamin C during the perioperative period may achieve better pain relief for patients after THA. [ABSTRACT FROM AUTHOR]

To determine the pharmacokinetic profile of methadone after intravenous (IV) and subcutaneous (SC) administration in domestic ferrets (Mustela putorius furo). Crossover experimental study. A group of eight healthy adult ferrets weighing 1.01 ± 0.23 kg (mean ± standard deviation). Methadone hydrochloride (0.3 mg kg–1) was injected IV or SC to each ferret with a 3 week washout period. Blood samples were collected via a jugular catheter before and 5, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240, 360 and 480 minutes after drug administration. Liquid chromatography–tandem mass spectrometry was used to determine plasma methadone concentrations. A nonlinear mixed effects model was used to analyze the data. After IV injection, systemic clearance (Cl ss) and volume of distribution (Vd ss) were 78.9 mL min–1 kg–1 and 9.8 L kg–1, respectively. Elimination half-life was 2.0 hours and SC bioavailability was fixed at 1. The maximum observed plasma concentration after SC injection was 92.1 ± 76.8 ng mL–1. Behavioral changes were observed after both routes. The pharmacokinetic profile of IV methadone was characterized by a high Cl ss and large Vd ss , with high bioavailability and absorption rate after SC administration. Half-life was short and mean plasma methadone concentrations stayed above the minimum effective concentration (MEC) reported in humans only after SC administration for 5 minutes, but remained above that reported in dogs for 45 minutes following both routes. Further studies investigating the MEC and pharmacodynamics of methadone in ferrets are warranted. [ABSTRACT FROM AUTHOR]

Pancreatic β-cell dysfunction caused by obesity can be associated with alterations in the levels of miRNAs. However, the role of miRNAs in such processes remains elusive. Here, we show that pancreatic islet miR-27a-5p, which is markedly increased in obese mice and impairs insulin secretion, is mainly delivered by visceral adipocyte–derived extracellular vesicles (EVs). Depleting miR-27a-5p significantly improved insulin secretion and glucose intolerance in db / db mice. Supporting the function of EV miR-27a-5p as a key pathogenic factor, intravenous injection of miR-27a-5p–containing EVs showed their distribution in mouse pancreatic islets. Tracing the injected adeno-associated virus (AAV)-miR-27a-5p (AAV-miR-27a) or AAV-FABP4-miR-27a-5p (AAV-FABP4-miR-27a) in visceral fat resulted in upregulating miR-27a-5p in EVs and serum and elicited mouse pancreatic β-cell dysfunction. Mechanistically, miR-27a-5p directly targeted L-type Ca2+ channel subtype CaV1.2 (Cacna1c) and reduced insulin secretion in β-cells. Overexpressing mouse CaV1.2 largely abolished the insulin secretion injury induced by miR-27a-5p. These findings reveal a causative role of EV miR-27a-5p in visceral adipocyte–mediated pancreatic β-cell dysfunction in obesity-associated type 2 diabetes mellitus. Article Highlights: miR-27a-5p expression in the islets is increased in obesity-associated diabetes mouse models. miR-27a-5p overexpression in β-cells impairs β-cell function in vitro and in vivo. Visceral adipocyte–derived extracellular vesicles and their cargo miR-27a-5p lead to β-cell insulin secretion injury and glucose intolerance by targeting L-type Ca2+ channel subtype CaV1.2. Blockage of visceral adipocyte extracellular vesicle miR-27a-5p expression improves β-cell insulin secretion and glucose tolerance in db / db mice. [ABSTRACT FROM AUTHOR]

Paclitaxel-induced peripheral neurotoxicity (PIPN) is a potentially dose-limiting side effect in anticancer chemotherapy. Several animal models of PIPN exist, but their results are sometimes difficult to be translated into the clinical setting. We compared 2 widely used PIPN models characterized by marked differences in their methodologies. Female C57BL/6JOlaHsd mice were used, and they received only paclitaxel vehicle (n = 38) or paclitaxel via intravenous injection (n = 19, 70 mg/kg) once a week for 4 weeks (Study 1) or intraperitoneally (n = 19, 10 mg/kg) every 2 days for 7 times (Study 2). At the end of treatment and in the follow-up, mice underwent behavioral and neurophysiological assessments of PIPN. At the same time points, some mice were killed and dorsal root ganglia, skin, and sciatic and caudal nerve samples underwent pathological examination. Serum neurofilament light levels were also measured. The differences in the neurotoxicity parameters were analyzed using a nonparametric Mann-Whitney test, with significance level set at P < 0.05. Study 1 showed significant and consistent behavioral, neurophysiological, pathological, and serological changes induced by paclitaxel administration at the end of treatment, and most of these changes were still evident in the follow-up period. By contrast, study 2 evidenced only a transient small fiber neuropathy, associated with neuropathic pain. Our comparative study clearly distinguished a PIPN model recapitulating all the clinical features of the human condition and a model showing only small fiber neuropathy with neuropathic pain induced by paclitaxel. [ABSTRACT FROM AUTHOR]

Importance: The intravenous administration of adipose tissue-derived mesenchymal stem cells (AdMSCs) in veterinary medicine is a promising regenerative therapy, but it can lead to severe complications, including pulmonary thromboembolism (PTE). Objective: As part of an ongoing study, this study examined the impact of medications, such as heparin, aspirin, and sodium nitroprusside (SNP), on the factors linked to PTE after an intravenous injection of canine mesenchymal stem cell into experimental animals. Methods: Fluorescently labeled canine AdMSCs were administered intravenously into the tail veins of five-week-old male BALB/c hairless mice. This study compared the survival rates, biodistribution, platelet counts, D-dimer levels, and histological examination results among the drug treatment experimental and the control groups. Results: The final survival rates in the SNP, control aspirin, and heparin groups were 25%, 33%, 50%, and 100%, respectively. Ex vivo imaging confirmed fluorescence exclusively in the lungs of all subjects who died during the injection, with no fluorescence detected in the other organs. On the other hand, in the heparin experimental group, the surviving individuals exhibited fluorescence in the lungs and the liver on day one. Histological biopsies revealed PTE in all deceased individuals within the medication experimental groups (p = 0.029). Conclusions and Relevance: Heparin was highly effective, with no PTE-related deaths observed when used alongside cell injections. Aspirin revealed moderate effectiveness, surpassing the control group. On the other hand, the efficacy of SNP was inferior to that of the other two drugs. [ABSTRACT FROM AUTHOR]

Ultrasound-triggered sonodynamic therapy (SDT), with high safety and acceptance, has become a promising tumor treatment. However, the dense stroma, hypoxic microenvironment of tumor, and the unpredictable treatment timing limit the effectiveness of sonosensitizers and the antitumor therapeutic effect. Thus, it is crucial to develop an imaging-guided sensitization strategy for hypoxic tumor sonosensitization to improve the efficacy of SDT. In this study, we developed a biohybrid system CB@HPP, which genetically engineered bacteria to express catalase (CB) and modified nanosonosensitizers (HPP) to the surface of these bacteria. Tumor hypoxia relief, tumor targeting, biocompatibility, and antitumor efficacy were evaluated through in vitro and in vivo experiments. In addition, the photoacoustic (PA), ultrasound (US), and fluorescence (FL) imaging effects of CB@HPP were evaluated in vivo and in vitro. After intravenous injection, CB@HPP was able to target tumor tissue. CB@HPP possessed efficient catalase activity and successfully degraded hydrogen peroxide to produce oxygen. Increased oxygen levels relief intratumoral hypoxia, thereby enhancing CB@HPP-mediated. In addition, CB@HPP showed FL/PA/US multimodal imaging capabilities, which reflects the aggregation effect of CB@HPP in the tumor and suggest the timing of treatment. The biohybrid system CB@HPP significantly alleviates tumor hypoxia, and multimodal imaging-mediated oxygen-producing SDT effectively suppresses tumors. This integrated imaging and therapeutic biohybrid system provides a more efficient and attractive cancer treatment strategy for SDT. This study developed a sensitizing SDT strategy for imaging-guided drug-targeted delivery and in situ oxygen production. We designed a biohybrid system CB@HPP, which was hybridized by the engineered bacteria with catalytic oxygen production and nanosonosensitizer with multimodal imaging capability. CB@HPP significantly alleviates tumor hypoxia, and multimodal imaging-mediated oxygen-producing SDT effectively suppresses tumors. This integrated imaging and therapeutic biohybrid system provides a more efficient and attractive cancer treatment strategy for SDT. [Display omitted] [ABSTRACT FROM AUTHOR]

Background/Aim: In the pursuit of translating stem cell therapy technology into clinical practice, ensuring the safety and efficacy of treatments is paramount. Despite advancements, the effectiveness of stem cell applications often falls short of clinical requirements. This study aimed to address the challenge of limited efficacy by investigating the safety and effectiveness of canine adipose tissue-derived mesenchymal stem cells (cATMSCs) preconditioned with deferoxamine (DFO). Materials and Methods: Different concentrations of DFO were used to evaluate its impact on cATMSC activity. The therapeutic potential of these preconditioned cells was validated using a mouse model of systemic inflammation. Comprehensive evaluations, including clinical hematological and radiological assessments before and after intravenous injection of preconditioned cells were conducted. Results: The study showed a notable reduction in inflammatory markers and an overall decrease in the inflammatory response in the mouse model. The data collected from the clinical hematological and radiological assessments provided essential insights. Conclusion: This study lays the groundwork for the future clinical deployment of DFO-preconditioned cATMSCs, demonstrating their potential to improve the efficacy and safety of stem cell therapies. [ABSTRACT FROM AUTHOR]

Background: Uricase, or urate oxidase (Uox) is a key enzyme in uric acid (UA) metabolism and has been applied in clinical treatment of human hyperuricemia (HUA). However, the current clinically applied uricases, despite their potent urate-lowering capacity, tend to form anti-drug antibodies because of their immunogenicity, leading to increased risk of anaphylaxis, faster drug clearance and reduced or even complete loss of therapeutic effect, limiting their clinical application. In this study, we constructed engineered macrophages that stably expressed uricase, which might serve as a promising alternative to the direct injection of uricases. Materials and Methods: Engineered macrophages RAW264.7 cells were injected intravenously to treat hyperuricemic KM mice. Serum uric acid and bio-indicators for renal and hepatic functions were detected by an automatic biochemical analyzer; inflammatory cytokines were determined by ELISA; the livers and kidneys of the mice were sectioned for histological examination. Results: The uricase-expressing macrophages reduced UA levels from 300 ± 1.5 μmol/L to 101 ± 8.3 μmol/L in vitro. And in an HUA mouse model established by gavage with yeast extract, intravenous injection of the engineered macrophages could reduce the serum uric acid (sUA) of mice to normal level on the 14th day of modeling, with a decrease of 48.6%, and the urate-lowering effect was comparable to that of the first-line clinical drug allopurinol. In terms of safety, engineered macrophages did not cause liver or kidney dysfunction in mice, nor did they induce systemic immune response. Conclusions: Using macrophages as a chassis to deliver uricase might be a new, safe and effective strategy for the treatment and control of hyperuricemia. [ABSTRACT FROM AUTHOR]

The majority of anticancer agents have a reduced or even complete loss of a therapeutic effect within hypoxic tumors. To overcome this limitation, research efforts have been devoted to the development of therapeutic agents with biological mechanisms of action that are independent of the oxygen concentration. Here we show the design, synthesis, and biological evaluation of the incorporation of a ruthenium (Ru) catalyst into polymeric nanoreactors for hypoxic anticancer therapy. The nanoreactors can catalyze the oxidation of glutathione (GSH) to glutathione disulfide (GSSG) in hypoxic cancer cells. This initiates the buildup of reactive oxygen species (ROS) and lipid peroxides, leading to the demise of cancer cells. It also stimulates the overexpression of the transient receptor potential melastatin 2 (TRPM2) ion channels, triggering macrophage activation, leading to a systemic immune response. Upon intravenous injection, the nanoreactors can systemically activate the immune system, and nearly fully eradicate an aggressive osteosarcoma tumor inside a mouse model. Hypoxic tumor microenvironment (TME) limits the therapeutic efficacy of anticancer drugs. Here this group reports a ruthenium-based nanocatalyst alleviating hypoxic TME, activating protein transient receptor potential melastatin 2 ion channel, promoting systemic immune response thereby eliciting its therapeutic efficacy against osteosarcoma. [ABSTRACT FROM AUTHOR]

Background: To potentially lessen injuries and associated complications, fluorescence cholangiography has been suggested as a technique for enhancing the visualization and identification of extrahepatic biliary anatomy. The most popular way to administer indocyanine green (ICG) is intravenously, as there is currently little data on ICG injections directly into the gallbladder. In order to visualize extrahepatic biliary anatomy during laparoscopic cholecystectomy (LC), we compared the two different ICG administration techniques. We also examined variations in visualization time, as well as the effectiveness, benefits, and drawbacks of each modality. Methods: In this prospective randomized clinical study, 60 consecutive adult patients with chronic and acute gallbladder disease were included. Our study conducted from 2022 to 2024 in Surgical Department of Theodor Bilharz Research Institute. Thirty patients underwent LC with intravenous ICG administration (IV-ICG), thirty patients received a direct injection of gallbladder through transhepatic ICG (IC-ICG) and Preoperative, intraoperative, and postoperative patient data were examined. Results: In terms of their perioperative and demographic features, the groups were similar. Without a statistically significant difference, the IV-ICG group's total operating time was less than that of the IC-ICG group (p 0.140). Compared to the transhepatic IC-ICG method, IV-ICG was more accurate in identifying the duodenum and the common hepatic duct (p = 0.029 and p = 0.016, respectively). In the transhepatic IC-ICG and IV-ICG groups, the cystic duct could be identified prior to dissection in 66.6% and 73.3% of cases, respectively, and this increased to 86.6% and 93.3% following dissection. In the transhepatic IC-ICG group, the common bile duct was visible in 93.3% of cases; in the IV-ICG group, it was visible in 90% of cases. Two cases in the IC-ICG group and every case following IV-ICG administration had liver fluorescence (6.6% versus 100%; p < 0.001). Conclusion: The current study shows that for both administration methods, ICG-fluorescence cholangiography can be useful in identifying the extrahepatic biliary anatomy during Calot's triangle dissection. By avoiding hepatic fluorescence, the transhepatic IC-ICG route can increase the bile duct-to-liver contrast with less expense and no risk of hypersensitivity reactions than the intravenous ICG injection method. We recommend to use both techniques in case of acute cholecystitis with cystic duct obstruction. In cases of liver cirrhosis, we recommend transhepatic IC-ICG as IV-ICG is limited. [ABSTRACT FROM AUTHOR]

The objective of this study is to investigate the effects of various doses of esketamine on the median effective concentration (EC50) of propofol required for inhibiting body movement during hysteroscopy. Additionally, this research aims to explore the pharmacodynamic interactions between esketamine and propofol. Prospective, double-blind, up-down sequential allocation study. Operating room, post-anesthesia care unit (PACU), and general ward. A total of 90 patients were allocated into three groups in a randomized, double-blinded manner as follows: 0.1 mg/kg esketamine combined with propofol intravenous injection (EP0.1) group, 0.2 mg/kg esketamine combined with propofol intravenous injection (EP0.2) group, 0.3 mg/kg esketamine combined with propofol of intravenous injection (EP0.3) group. For the initial patient in each group, the starting effector target concentration of propofol was set at 4 µg/ml. Each patient received an initial intravenous injection of 0.04 mg/kg midazolam, followed by the administration of the appropriate dose of esketamine. Ten seconds after the esketamine injection, propofol was administered intravenously to achieve the target concentration. In accordance with the sequential method principle, the concentration of propofol for the subsequent patient was adjusted based on the response of the previous patient. Effective inhibition of body movement was defined as the absence of any involuntary body movements throughout the entire surgical process. If the previous patient exhibited body movements, the propofol concentration for the next patient was increased by 0.5 µg/ml; conversely, if no movements were observed, it was decreased by 0.5 µg/ml. The up-down sequential allocation method and probit regression were used to calculate the EC50 of propofol. Hospital Anxiety and Depression Scale-Anxiety (HADS-A) and Depression (HADS-D) score, adverse events, hemodynamic changes, demographic data and clinical characteristics. The EC50 of propofol was 3.849 μg/ml (95% CI: 3.419–4.281) in the EP0.1 group, 3.641 μg/ml (95% CI: 2.807−4.200) in the EP0.2 group, and 3.417 μg/ml (95% CI: 2.845–3.852) in the EP0.3 group. These findings suggest that esketamine can dose-dependently reduce the EC50 of propofol. Esketamine can dose-dependently reduce the EC50 of propofol in hysteroscopy, while concurrently lowering patients' HADS-A and HADS-D scores 24 h post-operation. It is concluded that the optimal dose of esketamine, when combined with propofol for hysteroscopy, is 0.3 mg/kg. [ABSTRACT FROM AUTHOR]

Objective: Human umbilical cord mesenchymal stem cells (hUCMSCs) hold significant promise across various clinical applications. Therefore, regulatory requirements necessitate a thorough investigation of the hUCMSCs safety before clinical trials and potential allergic reactions after transplantation. Methods: Abnormal toxicity test employed mice and guinea pigs dosed daily at 0.5×106 cells and 5×106 cells, respectively for 7 days. Acute toxicity test employed low, medium, and high doses of hUCMSCs injected into mice once, followed by observations for 23 days. In systemic allergy test, guinea pigs received low and high dose of hUCMSCs, with sensitization and excitation stages at day 14 and 21, respectively. Results: The abnormal toxicity test of hUCMSC injections revealed no abnormal reactions over a seven-day observation period, indicating the safety of this administration route. In acute toxicity studies, the high-dose hUCMSCs group resulted in fatalities due to pulmonary embolism. Conversely, the low-dose group exhibited no toxic reactions or deaths. The maximum tolerated dose was determined to be >2×107 cells/kg. Systemic active allergy test showed that high doses of hUCMSC intravenous injections did not induce allergic reactions. Conclusion: This research affirms hUCMSC injections meet safety standards for clinical cell therapy, emphasizing their safe and promising clinical utility. [ABSTRACT FROM AUTHOR]

Hereditary Angioedema (HAE) is an autosomal dominant disease characterized by episodic swelling, arising from genetic deficiency in C1-esterase inhibitor (C1INH), a regulator of several proteases including activated Plasma kallikrein (Pka). Many existing C1INH treatments exhibit short circulatory half-lives, precluding prophylactic use. Hexahistidine-tagged truncated C1INH (trC1INH lacking residues 1–97) with Mutated N-linked Glycosylation Sites N216Q/N231Q/N330Q (H6-trC1INH(MGS)), its murine serum albumin (MSA) fusion variant (H6-trC1INH(MGS)-MSA), and H6-MSA were expressed in Pichia pastoris and purified via nickel-chelate chromatography. Following intravenous injection in mice, the mean terminal half-life of H6-trC1INH(MGS)-MSA was significantly increased versus that of H6-trC1INH(MGS), by 3-fold, while remaining ~35% less than that of H6-MSA. The extended half-life was achieved with minimal, but significant, reduction in the mean second order rate constant of Pka inhibition of H6-trC1INH(MGS)-MSA by 33% relative to that of H6-trC1INH(MGS). Our results validate albumin fusion as a viable strategy for half-life extension of a natural inhibitor and suggest that H6-trC1INH(MGS)-MSA is worthy of investigation in a murine model of HAE. [ABSTRACT FROM AUTHOR]

Methods for producing drugs directly at the cancer site, particularly using bioorthogonal metal catalysts, are being explored to mitigate the side effects of therapy. Albumin‐based artificial metalloenzymes (ArMs) catalyze reactions in living mice while protecting the catalyst in the hydrophobic pocket. Here, we describe the in situ preparation and application of biocompatible tumor‐targeting ArMs using circulating albumin, which is abundant in the bloodstream. The ArM was formed using blood albumin through the intravenous injection of ruthenium conjugated with an albumin‐binding ligand; the tumor‐targeting unit was conjugated to the ArM using its catalytic activity, and the ArM was transported to the cancer site. The delivered ArM catalyzed a second tagging reaction of the proapoptotic peptide on the cancer surface, successfully suppressing cancer proliferation. This approach, which efficiently leveraged the persisting reactivity twice in vivo, holds promise for future in vivo metal‐catalyzed drug synthesis utilizing endogenous albumin. [ABSTRACT FROM AUTHOR]

Treatment for Parkinson's disease (PD) has been impeded by inefficient treatment results and multiple membrane barriers during drug delivery. This study reports the design, synthesis, and application of microneedles (MNs) loaded with mitochondrion-targeted liposome encapsulated iron (Fe)-isolated single-atom nanozymes (Mito@Fe-ISAzyme, MFeI), called MFeI MNs, for in situ drug delivery into the brain parenchyma and efficient enrichment of drugs in lesion sites. In in vitro experiments, MFeI can scavenge reactive oxygen species (ROS) and protect the neurons via mitochondrial targeting, guaranteeing the subsequent treatment of PD. Using PD mouse models, we compared the intravenous injection of MFeI with the brain in situ administration of MFeI MNs (in situ MFeI MNs). Results showed that in situ MFeI MNs significantly improved the deep penetration of the drug into brain parenchyma, especially in the vital pathological sites such as the substantia nigra pars compacta and striatum. Importantly, ROS elimination and neuroinflammatory remission in the lesion site were observed, thereby efficiently alleviating the behavioral disorders and pathological symptoms of PD mice. Therefore, the MNs system for in situ single-atom nanozyme liposome delivery exhibits great potential in PD treatment. [ABSTRACT FROM AUTHOR]

Sonodynamic therapy (SDT) has garnered significant attention in cancer treatment, however, the low-yield reactive oxygen species (ROS) generation from sonosensitizers remains a major challenge. In this study, titanium boride nanosheets (TiB 2 NSs) with photo-enhanced sonodynamic efficiency was fabricated for SDT of glioblastoma (GBM). Compared with commonly-used TiO 2 nanoparticles, the obtained TiB 2 NSs exhibited much higher ROS generation efficiency under ultrasound (US) irradiation due to their narrower band gap (2.50 eV). Importantly, TiB 2 NSs displayed strong localized surface plasmon resonance (LSPR) effect in the second near-infrared (NIR II) window, which facilitated charge transfer rate and improved the separation efficiency of US-triggered electron–hole pairs, leading to photo-enhanced ROS generation efficiency. Furthermore, TiB 2 NSs were encapsulated with macrophage cell membranes (CM) and then modified with RGD peptide to construct biomimetic nanoagents (TiB 2 @CM-RGD) for efficient blood-brain barrier (BBB) penetrating and GBM targeting. After intravenous injection into the tumor-bearing mouse, TiB 2 @CM-RGD can efficiently cross BBB and accumulate in the tumor sites. The tumor growth was significantly inhibited under simultaneous NIR II laser and US irradiation without causing appreciable long-term toxicity. Our work highlighted a new type of multifunctional titanium-based sonosensitizer with photo-enhanced sonodynamic efficiency for GBM treatment. Titanium boride nanosheets (TiB 2 NSs) with photo-enhanced sonodynamic efficiency was fabricated for SDT of glioblastoma (GBM). The obtained TiB 2 NSs displayed strong localized surface plasmon resonance (LSPR) effect in the second near-infrared (NIR II) window, which facilitated charge transfer rate and improved the separation efficiency of US-triggered electron-hole pairs, leading to photo-enhanced ROS generation efficiency. Furthermore, TiB 2 NSs were encapsulated with macrophage cell membranes (CM) and then modified with RGD peptide to construct biomimetic nanoagents (TiB 2 @CM-RGD) for efficient blood-brain barrier (BBB) penetrating and GBM targeting. After intravenous injection into the tumor-bearing mouse, TiB 2 @CM-RGD can efficiently cross BBB and accumulate in the tumor sites. The tumor growth was significantly inhibited under simultaneous NIR II laser and US irradiation without causing appreciable long-term toxicity. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: In addition to their classic genomic effects, glucocorticoids also manifest rapid non genomic effects. We speculate that dexamethasone has the potential prompt onset of analgesic effects. The objective of this study is to investigate the influence of a single preoperative dose of dexamethasone on the half maximal effective concentration (EC50) of remifentanil when combined with dexmedetomidine for pain relief during pancreatic extracorporeal shockwave lithotripsy (P-ESWL). Methods: A total of 60 patients undergoing P-ESWL were enrolled and randomized at 1:1 ratio into the dexamethasone (DXM) group and the placebo group. Before anesthesia induction, patients in DXM group received an intravenous injection of 8 mg dexamethasone, while subjects in placebo group received an equal dose of physiological saline. Monitored anesthesia care (MAC) was performed based on remifentanil in combination with dexmedetomidine. Remifentanil was administered by TCI with an initial target concentration of 2.5 µg/mL for both groups. A positive response was defined as that VAS score > 3 by the patient at any time during the procedure. Subsequent target concentrations were adjusted by Dixon up-down sequential method, where dose modifications were performed by 0.3 ng/mL intervals, based on the response of the previous patient. The EC50 of remifentanil for pain relief during P-ESWL treatment was calculated using Dixon's up-and-down method. Hemodynamic variables, oxygen saturation and adverse events were also recorded. Results: Dixon up-and-down method revealed that the EC50 of remifentanil was significantly higher in placebo group (2.65 ± 0.28 ng/mL) than in DXM group (2.02 ± 0.23 ng/ml) (P < 0.001). Hemodynamic parameter exhibited a significant decrease in mean arterial pressure (MAP) and heart rate (HR) before and after induction in placebo group; however, data of the two groups were comparable (P>0.05). Less adverse events occurred in DXM group, including the incidence of postoperative nausea and vomiting (PONV) and analgesia requirement with in the first 24 h following the procedure at ward. Conclusion: Dexamethasone exerted analgesic effects with a rapid onset, and patients received dexamethasone 8 mg preoperative had a lower required EC50 of remifentanil during P-ESWL. It is also associated with reduced PONV in addition to reduced postoperative analgesic consumption in the first postoperative 24 h. Trial registration: Registered in the Chinese Clinical Trial Registry (ChiCTR2300078171) on 30/11/2023. [ABSTRACT FROM AUTHOR]

Background: A combination of remimazolam and propofol could produce more stable sedation. A good medication regimen should consider not only efficacy but also safety, especially hypotension. The aim of the current study was to compare the incidence and amount of hypotension by propofol versus remimazolam-propofol combinations in day-surgery hysteroscopy. Methods: Patients were randomly assigned to receive either propofol (Group P, n = 125) or remimazolam-propofol combinations (Group RP, n = 125) at a 1:1 ratio. Intravenous injection of sufentanil 0.1ug/kg were administered before sedative medication. In group P, a bolus of 2.5 mg/kg propofol was administered. In group RP, intravenous anesthesia was commenced with 0.125 mg/kg remimazolam and 1 mg/kg propofol. After loss of consciousness, propofol was maintained at 6 mg/kg/h. The primary outcomes were the incidence and amount of hypotension during surgery. Hypotension was defined as a MAP less than 65mmHg for at least 1 min. The amount of hypotension was assessed by time-weighted average intraoperative MAP under a threshold of 65 mmHg. The secondary outcomes were various anesthesia related parameters and some adverse events. Results: In group P, 25 patients (20.0%) experienced hypotension during hysteroscopy compared with 9 patients (7.2%) in group RP, for a difference of 12.8% (RR 2.778, 95%CI [1.352–5.709]). The combination of remimazolam and propofol resulted in significantly lower TWA (Time Weighted Average) threshold 0.14 (0.10–0.56) mmHg in group RP compared to 0.31 (0.15–0.67) mmHg in group P. The total dose of propofol was nearly double in group P compared to group RP. A significantly higher frequency of injection pain and low oxygen saturation was observed in the group P than that of the group RP. Hiccup was observed only in group RP. The incidences of body movement, bradycardia and vomiting were no significant difference between groups. Conclusion: The incidence and amount of hypotension by remimazolam-propofol combinations was significantly less than that by propofol sedation in day-surgery hysteroscopy. The optimization of medication regimen would attenuate the harm of hypotension and contribute to patients' rapid recovery in day surgery. Trial registration : Chinese Clinical Trial Registry, ChiCTR2400079888 (date: 15/01/2024), [ABSTRACT FROM AUTHOR]

The oxidized form of Macrophage Migration Inhibitory Factor (oxMIF) has been identified as the disease-related isoform of MIF, exerting pathological functions in inflamed tissue. In this study, we aimed to explore the in vivo effects of the neutralizing anti-oxMIF antibody ON104 in a rat model of crescentic glomerulonephritis (CGN), to better understand its disease modifying activities. WKY rats received a single intravenous injection of a rabbit nephrotoxic serum (NTS), targeting rat glomerular basement membrane to induce CGN. On day 4 and day 6, ON104 was given intraperitoneally (i.p.) and on day 8 urine, blood and kidney tissue were collected. ON104 substantially attenuated the severity of CGN demonstrated by reduced proteinuria, hematuria, as well as lower levels of kidney injury molecule (KIM)-1. ON104 treatment preserved the glomerular morphology and suppressed crescent formation, a hallmark of the disease. On the cellular level, oxMIF neutralization by ON104 strongly reduced the number of macrophages and neutrophils within the inflamed kidneys. In vitro, we identified human neutrophils, but not monocytes, as main producers of oxMIF among total peripheral cells. The present study demonstrates that oxMIF is a pertinent therapeutic target in a model of CGN which mechanistically resembles human immune mediated CGN. In this model, neutralization of oxMIF by ON104 leads to an improvement in both urinary abnormalities and histological pathological characteristics of the disease. ON104, thus has the potential to become a novel disease-modifying drug for the treatment of glomerulonephritis and other inflammatory kidney diseases. [ABSTRACT FROM AUTHOR]

Background: to analyze, at one year, the efficacy and safety of treat-and-extend (T&E) intravitreal (IV) Brolucizumab in patients affected by macular neovascularization (MNV). Both naïve and previously treated (i.e., switched) patients were included, and the data from the two groups were compared. Methods: anatomical (i.e., central subfoveal thickness, CST; presence of fluid), functional (i.e., best corrected visual acuity, BCVA) and treatment-related (i.e., number of IV injections within the study period; number of patients reaching a 12-weeks interval between treatments) data from 41 eyes of 41 subjects (20 naïve and 21 switched) were analyzed. Patients were treated with 3 monthly IV injections followed by a T&E regimen based on a disease activity assessment performed at each scheduled IV treatment. Results: significant CST reduction (from 412.1 ± 115.8 to 273.2 ± 61.6; p < 0.05) and BCVA (mean; p) improvement were observed in the naïve group, while in the switched cohort, both parameters were almost stable. In the naïve and switched groups, 55% and 33.5% of patients, respectively, reached a 12-week IV interval at one year, with a mean of 6.55 ± 1 and 7.43 ± 0.68 IV treatments, respectively. One patient with mild anterior uveitis without sequelae was recorded. Conclusion: In patients with MNV, IV Brolucizumab injections following a T&E regimen demonstrated great efficacy and a good safety profile, with greater anatomical and functional results in naïve patients. Trial registration: This study was approved by the Local Ethics Committee (protocol number 155/2020, general registry number n°11486, InterHospital Ethics Committee, San Luigi Gonzaga Hospital, Orbassano, Italy). [ABSTRACT FROM AUTHOR]

Background: A number of peptide incretin receptor agonists (IRAs) show promise as therapeutics for Alzheimer's disease (AD) and Parkinson's disease (PD). Transport across the blood–brain barrier (BBB) is one way for IRAs to act directly within the brain. To determine which IRAs are high priority candidates for treating these disorders, we have studied their brain uptake pharmacokinetics. Methods: We quantitatively measure the ability of four IRAs to cross the BBB. We injected adult male CD-1 mice intravenously with 125I- or 14C-labeled albiglutide, dulaglutide, DA5-CH, or tirzepatide and used multiple-time regression analyses to measure brain kinetics up to 1 hour. For those IRAs failing to enter the brain 1 h after intravenous injection, we also investigated their ability to enter over a longer time frame (i.e., 6 h). Results: Albiglutide and dulaglutide had the fastest brain uptake rates within 1 hour. DA5-CH appears to enter the brain rapidly, reaching equilibrium quickly. Tirzepatide does not appear to cross the BBB within 1 h after iv injection but like albumin, did so slowly over 6 h, presumably via the extracellular pathways. Conclusions: We find that IRAs can cross the BBB by two separate processes; one that is fast and one that is slow. Three of the four IRAs investigated here have fast rates of transport and should be taken into consideration for testing as AD and PD therapeutics as they would have the ability to act quickly and directly on the brain as a whole. [ABSTRACT FROM AUTHOR]

Brain endothelial cells (ECs) are essential elements of the blood–brain barrier (BBB), maintaining its integrity through both paracellular junctions and transcellular transport systems. Myosin IIA, a multifunctional protein, plays a significant role in various cellular processes, including cytoskeletal maintenance, cell division, and signal transduction. While Myosin IIA has been implicated in bleeding and ischemic stroke, its role in regulating BBB integrity under physiological conditions remains unclear. In this study, we investigated the impact of Myosin IIA deficiency on BBB integrity using intravenous tracer injections and models of epilepsy. Flow cytometry, Western blot, and real-time PCR were employed to isolate brain cells and assess changes in protein and mRNA levels. Additionally, immunofluorescence staining and electron microscopy were used to explore alterations in protein expression and the structure of BBB. Our results demonstrate that endothelial Myosin IIA deficiency increased BBB permeability and exacerbated symptoms in BBB-related diseases. Mechanistically, we found that Myosin IIA modulates β-catenin transcription and protein interactions. The overexpression of β-catenin in brain endothelial Myosin IIA deficiency mice improved BBB integrity and reduced disease severity. This study establishes Myosin IIA as a critical regulator of BBB integrity and suggests new therapeutic targets for vascular diseases. [ABSTRACT FROM AUTHOR]

Intravenous infusion has been used as the method of cell delivery in many preclinical studies as well as in some early clinical trials. Among its advantages are broad distribution, ability to handle a large-volume infusion, and ease of access. Progenitor cells used in cell-based therapy act through their secretomes, rather than their ability to differentiate into lineage-specific cell type. Since not all progenitor cells have similar secretome potency, the innate abilities of the secretome of cells used in clinical trials will obviously dictate their effectiveness. We previously found that cardiac neonatal mesenchymal stromal cells (nMSCs) are more effective in repairing the infarcted myocardium compared to adult mesenchymal stromal cells (aMSCs) due to their robust secretome (Sharma et al Circulation Research 120:816–834, 2017). In this study, we explored the efficacy of intravenous (IV) delivery of nMSCs for myocardial recovery. Six-week-old male Brown Norway rats underwent acute MI by ligation of the left anterior descending artery, followed by IV infusion of cell dose 5 × 106 nMSCs/rat body weight (kg) or saline on days 0 and 5. We found that cardiac parameters in the rodent ischemia model improved 1 month after nMSCs infusion, and the result is comparable with the intramyocardial injection of nMSCs. Tracking the infused cells in target organ revealed that their movement after IV delivery was mediated by the cell surface receptor CD44. Systemic injection of nMSCs stimulated immunomodulatory responses specifically by increasing FoxP3+ T-regulatory cell influenced anti-inflammatory macrophages (M2) in heart. These data demonstrate that nMSCs promote immunogenic tolerance via CD44-driven T-reg/M2 stimulation that helps nMSCs for longer viability in the injured myocardium for better functional recovery. Our data also demonstrate a rationale for a clinical trial of IV infusion of nMSCs to promote cardiac function improvement in the ischemic patients. [ABSTRACT FROM AUTHOR]

Background: Ultrapluse CO2 fractional laser technology has emerged as an effective treatment for scar management. However, one drawback of this modality is the pain caused during the procedure. This study aims to explore the efficacy and safety of dezocine (DZC) as preemptive analgesia for reduction of pain induced by ultrapulse CO2 fractional laser treatment for acne scars. Methods: The study cohort included 78 outpatients with acne scars between February and April 2023. Patients were randomly assigned into three groups with intravenous injection (iv) of DZC prior to laser treatment: (1) control, iv of saline; (2) DZC group 1 (DZC_1), iv of DZC at 0.15 mg/kg; and (3) DZC_2, iv of DZC at 0.20 mg/kg. After 30 min, one session of ultrapulse CO2 fractional laser treatment on acne scars was performed. Hemodynamics, visual analogue scale (VAS), and anxiety visual analog test (AVAT) were monitored prior to, during, and after the procedure. Results: Operative success rates for patients in the control, DZC_1, and DZC_2 groups were 34.6%, 84.6%, and 100%, respectively. DZC administered with either dosage significantly reduced the VAS and AVAT scores of patients in treatment groups as compared with the subjects in the control group during the course of ultrapulse CO2 fractional laser treatment. Patients in DZC_1 and DZC_2 groups did not show any significant difference in hemodynamic parameters, VAS, and AVAT scores. Temporary adverse effects such as nausea and dizziness were observed in some subjects after treatment; the symptoms were quickly dissolved after a rest in supine position. Conclusions: DZC as preemptive analgesia could effectively reduce pain and anxiety induced by ultrapulse CO2 fractional laser treatment in patients. This study provided an option of preemptive anesthesia to minimize the pain and discomforts associated with laser treatments in clinical practices. [ABSTRACT FROM AUTHOR]

Purpose: We aimed to identify a safe and effective method to assist older adults with pneumonia in tolerating the prone position for a longer duration. Methods: This was a randomized, controlled, double-blinded study performed at the Shanghai Fourth People's Hospital. Eighty patients with pneumonia aged ≥ 65 years were included. The patients were able to spontaneous breath in the prone position and were administered intravenous dexmedetomidine or an isotonic sodium chloride solution. The cumulative daily durations of prone positioning for all patients in the two groups were recorded. The primary outcome was the percentage of patients who completed ≥ 9 h/day in the prone position. The secondary outcomes included the incidence of complications in the prone position and patient outcomes. Results: Eighty patients were included (average age: 79.6 ± 8.9 years). The percentage of patients who completed ≥ 9 h/day in the prone position was significantly higher in the dexmedetomidine group than in the placebo group (P = 0.011). The percentage of patients who completed ≥ 12 h/day in the prone position was also significantly greater in the dexmedetomidine group than in the placebo group (P = 0.008). There were no significant differences in other variables between the two groups. Conclusions: The results of this study demonstrate that intravenous dexmedetomidine injection can significantly prolong the duration of spontaneous breathing in the prone position in elderly pneumonia patients without obvious adverse events. We provide a safe and effective method to help patients with pneumonia, especially those with delirium or cognitive impairment, who cannot tolerate the length of time needed for spontaneous breathing in the prone position to be effective. Trial registration: The study was registered with the Chinese Clinical Trial Center (registration number: ChiCRT2300067383) on 2023-01-05. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the safety and clinical outcome of bleomycin electrosclerotherapy (BEST) for treating extracranial slow-flow malformations. Methods: In this retrospective investigation of a multicenter cohort presenting symptomatic slow-flow malformations, patient records were analyzed with respect to procedural details and complications. A treatment-specific, patient-reported questionnaire was additionally evaluated, obtained 3–12 months after the last treatment, to assess the subjective outcomes, including mobility, aesthetic aspects, and pain, as well as the occurrence of postprocedural skin hyperpigmentation. All outcome parameters were compared according to patients' age. Results: Overall, 325 BEST treatments were performed in 233 patients after intralesional and/or intravenous bleomycin injection. The total complication rate was 10.2% (33/325), including 29/352 (8.9%) major complications. Patient-reported mobility decreased in 10/133 (8.8%), was stable in 30/113 (26.5%), improved in 48/113 (42.5%), and was rated symptom-free in 25/113 (22.1%) patients. Aesthetic aspects were rated impaired compared to baseline in 19/113 (16.8%), stable in 21/133 (18.6%), improved in 62/113 (54.9%), and perfect in 11/133 (9.7%) patients. Postprocedural skin hyperpigmentation occurred in 78/113 (69%) patients, remaining unchanged in 24/78 (30.8%), reduced in 51/78 (65.5%), and completely resolved in 3/78 (3.8%) patients. The median VAS pain scale was 4.0 (0–10) preprocedural and 2.0 (0–9) postprocedural. Children/adolescents performed significantly better in all parameters compared to adults (≥ 16 years) (mobility, p = 0.011; aesthetic aspects, p < 0.001; pain, p < 0.001). Conclusions: BEST is effective for treating slow-flow vascular malformations, with few but potentially significant major complications. Regarding patient-reported outcomes, children seem to benefit better compared to older patients, suggesting that BEST should not be restricted to adults. Clinical relevance statement: Bleomycin electrosclerotherapy is a safe and effective approach and therapy should not be restricted to adults due to good clinical outcomes in children. Key Points: In this multicenter study investigating 325 bleomycin electrosclerotherapies, high subjective response in mobility, aesthetic aspects, and pain was reported, accompanied by few but potentially severe complications. Skin hyperpigmentation after treatment is the most common side effect, which frequently fades in the postprocedural course. Children/adolescents (0–15 years) performed significantly better in all outcome parameters regarding mobility, aesthetic aspects, and pain, when compared to adults. [ABSTRACT FROM AUTHOR]

Objective: To systematically evaluate the efficacy of subcutaneous tocilizumab in the treatment of patients with severe COVID-19 and provide evidence for the rational use of subcutaneous tocilizumab in patients with severe COVID-19. Methods: This meta-analysis was carried out in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. We searched the Cochrane Library, PubMed, Embase, CNKI, SinoMed, and Wanfang Medical Network electronic databases up to 11 January 2023 to identify relevant studies. To obtain the most recent clinical studies of subcutaneous injection of tocilizumab for the treatment of patients with severe COVID-19, we also searched the preprint platforms medRxiv and ChinaXiv. Furthermore, we searched ClinicalTrials.gov for relevant unpublished studies. The studies were screened based on the PICOS principle. The included studies were classified and evaluated for quality based on research type. The RevMan 5.3 software was used to conduct the meta-analysis, and a descriptive analysis was performed to examine relevant outcome indicators. Results: Five observational studies were obtained, involving a total of 498 patients (240 patients in the subcutaneous injection group and 258 patients in the intravenous injection group). All of the studies were of the highest quality. The meta-analysis of the included studies revealed that the mortality rate of patients who received subcutaneous tocilizumab to treat COVID-19 was not significantly higher than that of the intravenous injection group [23.3% (45/193) vs. 18.4% (39/212), RD = 0.06, 95% CI = − 0.01 ~ 0.13, P = 0.11]. Furthermore, there was no significant difference in the proportion of patients requiring mechanical ventilation between the two groups [24.5% (35/143) vs. 22% (35/159), RD = 0.03, 95% CI = − 0.07 ~ 0.12, P = 0.56]. Conclusions: The meta-analyses do not provide evidence that subcutaneous and intravenous tocilizumab formulations for the treatment of severe COVID-19 infection differ regarding their effectiveness. Considering that the meta-analyses cannot replace an appropriately powered non-inferiority study, subcutaneous formulations still need to be used with caution and only when intravenous formulations are in short supply. At present, there is a lack of randomized controlled trials of subcutaneous injection of tocilizumab for the treatment of severe COVID-19, and more clinical research should be conducted. [ABSTRACT FROM AUTHOR]

Magnetic resonance imaging (MRI) is a non-invasive technique that requires the participant to be completely motionless. To date, MRI in awake and unrestrained animals has only been achieved with humans and dogs. For other species, alternative techniques such as anesthesia, restraint and/or sedation have been necessary. Anatomical and functional MRI studies with sheep have only been conducted under general anesthesia. This ensures the absence of movement and allows relatively long MRI experiments but it removes the non-invasive nature of the MRI technique (i.e., IV injections, intubation). Anesthesia can also be detrimental to health, disrupt neurovascular coupling, and does not permit the study of higher-level cognition. Here, we present a proof-of-concept that sheep can be trained to perform a series of tasks, enabling them to voluntarily participate in MRI sessions without anesthesia or restraint. We describe a step-by-step training protocol based on positive reinforcement (food and praise) that could be used as a basis for future neuroimaging research in sheep. This protocol details the two successive phases required for sheep to successfully achieve MRI acquisitions of their brain. By providing structural brain MRI images from six out of ten sheep, we demonstrate the feasibility of our training protocol. This innovative training protocol paves the way for the possibility of conducting animal welfare-friendly functional MRI studies with sheep to investigate ovine cognition. [ABSTRACT FROM AUTHOR]

Myocardial infarction accompanied by diabetes mellitus is accepted as the most serious type of coronary heart disease, and among the current treatment strategies, the precise delivery of protective drugs for inhibiting cardiomyocyte apoptosis is still a challenge. In this study, we developed a biodegradable nanoparticles‐based delivery system with excellent macrophage escape, cardiac targeting, and drug release properties to achieve targeted therapy of myocardial infarction. Specifically, a copolymer of p(DMA–MPC–CD) combining self‐adhesion, hydration lubrication, and targeting peptide binding site was successfully prepared by free radical copolymerization, and it was self‐assembled on the surface of melatonin‐loaded dendritic mesoporous silica nanoparticles (bMSNs) following the integration of adamantane‐modified cardiac homing peptide (CHP) based on supramolecular host–guest interaction. Importantly, a hydration layer formed around the zwitterionic phosphorylcholine groups of the multifunctional nanoparticles, which was confirmed by the enhancement in hydration lubrication and reduction in coefficient of friction, prevented the nanoparticles from phagocytosis by the macrophages. The in vivo bioluminescence imaging test indicated that the nanoparticles were endowed with satisfied cardiac targeting capability, and the in vivo mice study demonstrated that the intravenous injection of drug‐loaded nanoparticles (namely bMSNs–Mel@PDMC–CHP) effectively reduced cardiomyocyte apoptosis, alleviated myocardial interstitial fibrosis, and enhanced cardiac function. [ABSTRACT FROM AUTHOR]

Previous studies assessed the effect of extracorporeal shockwave therapy (ESWT) for knee osteoarthritis (OA) among different situations. Thus, results from a meta-analysis regarding this topic may not be reliable due to heterogeneity. A systematic review was conducted on three internet databases, namely Cochrane Library, PubMed, and Embase, gathering pertinent papers from their establishment to March 2024. The search phrases were as follows: "shockwave" OR "shock wave" OR "extracorporeal shockwave" OR "Extracorporeal Shockwave Therapy [MeSH Term]" AND "knee" AND ("osteoarthritis" OR "arthritis" OR "arthritic" OR "osteoarthritis [MeSH term]"). Twenty-four articles (n = 888) were included, with the resulting conclusions demonstrating that ESWT was effective for knee OA compared with sham ESWT; however, ESWT was not effective for patients with severe knee OA. Patients receiving higher energy or higher shock number had significant improvement than those receiving lower energy or less shock number, respectively. Adding ESWT in isokinetic muscular strengthening exercises (IMSE) was more effective than IMSE alone. The efficacy of ESWT was better than other therapies, including intravenously applied prostacyclin and bisphosphonate, corticosteroid injection, kinesiotherapy, hyaluronic acid injection, platelet-rich plasma injection, and physiotherapy. This review demonstrated that ESWT was effective for knee OA. Higher energy and more shock numbers could obtain better efficacy. ESWT could be used as a replacement for some other therapies. [ABSTRACT FROM AUTHOR]

Background: This study aims to report the phenomenon of Myelin oligodendrocyte glycoprotein antibody-associated encephalitis induced by Mycoplasma pneumoniae infections and promote the potential benefits of combining early immunotherapy and anti-M—pneumoniae therapy for these patients. Methods: Three children with MOG-IgG-associated encephalitis due to M. pneumoniae infections who were treated at our hospital from September to November 2023 were included in the study. We investigated and analyzed the background and clinical features of these patients. Results: Three patients developed headaches, seizures, and/or other neurological manifestations, elevated mononuclear cells in cerebrospinal fluid, intracranial lesions on cranial magnetic resonance imaging (MRI), and positive MOG-IgG in serum, within 10–14 days. They were diagnosed with MOG-IgG-associated encephalitis due to M. pneumoniae infections, the treatment consisted of intravenous immunoglobulin, glucocorticoid, and erythromycin, then they were completely recovered. Conclusion: Mycoplasma pneumoniae (M. pneumoniae) infections can cause oligodendrocyte glycoprotein (MOG) antibody-associated encephalitis. The recognition of this condition will promote the potential benefits of combining early immunotherapy and anti-M. pneumoniae therapy for patients with MOG-IgG-associated encephalitis. [ABSTRACT FROM AUTHOR]