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Perfluoropropane droplets (PD) are nanometer-sized particles that can be formulated from commercially available contrast agents. The preferential retention of PDs in diseased microvascular beds can be detected by ultrasound imaging techniques after acoustic activation and offers an opportunity for the detection of such processes as scar formation or inflammation. We hypothesized that in the presence of ischemia/reperfusion (I/R) injury, retention of intravenously injected PDs would be enhanced. Using an established intravital microscopy model of rat cremaster microcirculation, we determined the retention and subsequent acoustic activation behavior of PDs in exteriorized rat cremaster tissue. DiI-labeled droplets (200 µL) were administered intravenously. Acoustic activation was achieved with a clinical ultrasound system at two ultrasound frequencies (1.5 and 7 MHz). Fluorescent microbubbles could be detected in the microvasculature after intravenous injection of PDs and subsequent acoustic activation. Increased retention of PDs was observed in the I/R group compared with control group with both ultrasound frequencies (p < 0.05). Using higher-resolution microscopy, we found evidence that some droplets extravasate to the outside of the endothelial border or are potentially engulfed by leukocytes. Our data indicate that targeted imaging of the developing scar zones might be possible with ultrasound activation of intravenously injected PDs, and a method of targeting therapies to these same regions could be developed. [ABSTRACT FROM AUTHOR]

• Simultaneous movement was selectively absent in dyads with a LPS-injected individual. • Subjects under LPS followed the interviewer's movements with a certain time delay. • Subjects under placebo showed a pattern of synchronization comparable to previous work. • LPS seem to impact on simultaneous synchrony of dyads. Interpersonal connectedness is a central feature of human interaction that can be compromised during illness. Nonverbal signals play a crucial role in this context, and humans, like other animals, have evolved a behavioral immune system that enables individuals to detect subtle cues of sickness in others. Conversely, sick individuals often tend to avoid social interaction, a key component of sickness behavior. The coordination of body movements between two individuals (movement synchrony) is a measure of the quality of relationships that could provide insights into an interlocutor's sickness state. In the present study, we explored the effect of lipopolysaccharide (LPS) administration, a naturalistic stimulus for inflammation-induced sickness, on movement synchrony in healthy volunteers randomly assigned to a double-blind interview with a non-treated interviewer conducted 2.5 h after intravenous injection of either LPS (N = 26) or placebo (N = 25). Movement synchrony was assessed by automated video analysis of subject's and interviewer's head movements. Lagged cross-correlations were used to objectively quantify coordination in dyads and to assess patterns of temporal movement synchronization. Data analysis revealed that dyads with subjects under placebo displayed a pattern of movement coordination comparable to that seen in previous studies. However, dyads with subjects under LPS showed a loss of simultaneous movement (i.e. moving at the same time) with the interview partner, which is normally the temporal domain providing the highest level of synchrony. Together, the findings suggest that immediate social interaction is attenuated when one interlocutor is exposed to systemic inflammation, while the other is unaffected. This effect can be attributed to both sickness behavior on one hand and correlates of the behavioral immune system on the other hand. [ABSTRACT FROM AUTHOR]

The therapeutic potential of (S)-Equol across various health domains, including mental health and oncology has been identified and studied enormously. However, the pharmacokinetic study on the enantiopure (S)-Equol in male and female rats under graded doses remain untouched, and the study concentrates on the same. Male and female CD(SD)IGS rats were grouped into 8 groups and some groups were administered with 20, 60 and 160 mg/kg body weight, orally and other administered with intravenous bolus injection at 10 mg/kg body weight of (S)-Equol. The plasma (S)-Equol concentrations were estimated by LC-MS/MS and the pharmacokinetic parameters determined from the concentration time data by non-compartmental PK analysis. The observed (S)-Equol Cmax was 66.78, 659.38, 2542.02 ng/mL in males and 392.08, 1661.97, 4879.36 in female rats, similarly, the observed (S)-Equol AUCLast was 118.96, 1130.32, 4876.00 h*ng/mL in males and 2164.01, 4883.09, 14067.94 in female rats at 20, 60 and 160 mg/kg dose respectively. The intravenous bolus administration of (S)-Equol showed 8563.25, 8642.91 ng/mL of Cmax and 3742.98, 3551.90 h*ng/mL AUCLast at 10 mg/kg dose in male and female rats respectively. The oral bioavailability of (S)-Equol was found to be 1.59, 5.03, 8.14% in male rats and 30.46, 22.91, 66.01% in female rats at doses of 20, 60 and 160 mg/kg of (S)-Equol administration respectively. These data suggesting that gender related differences in plasma exposure, increased plasma exposure was observed in female rats, plasma exposure at 60 mg/mL in female rats were comparable to the exposures at 160 mg/mL in males rats. [ABSTRACT FROM AUTHOR]

Hemoglobin-based oxygen carriers have been developed to compensate the needs of blood for transfusions. Most of them were based on intracellular hemoglobin extracted from bovine or human blood, but unfortunately, this type of hemoglobin did not pass through the last steps of clinical trials. In this context, HEMARINA discovered a natural extracellular hemoglobin, possessing several advantages avoiding intracellular hemoglobin-related side effects. Many preclinical studies assessed the safety of M101 used in intravenous (IV) injection in rodents. To explore the safety of IV injections of M101 in large mammals, six dogs received each a single injection of liquid M101 according to a dose escalation with a 48 h follow-up. Then, two monkeys received multiple IV injections of the same dose of M101 every hour for seven hours. This study showed that single and multiple IV injections in dogs and monkeys did not cause clinical or histological lesions, nor did they induce immunological reactions. This makes M101 the best candidate to date for human use in emergency situations requiring blood and, in several diseases, causing hypoxia problems. [ABSTRACT FROM AUTHOR]

AbstractObjectiveMethodConclusionFor patients with contraindications to hormone therapy, the absence of effective treatments for ovarian dysfunction post chemotherapy represents a critical issue requiring resolution. Local administration of mitochondria may enhance ovarian function in premature ovarian insufficiency (POI) by ameliorating diminished mitochondrial activity. Nevertheless, there is a paucity of literature on the efficacy of mitochondrial transplantation through intravenous injection, a less invasive and more convenient method than local injection, for the improvement of ovarian function in POI following chemotherapy.Mitochondria were isolated from mouse livers, their activity and integrity were validated with MitoTracker Red and their localization was examined via confocal microscopy, real-time quantitative PCR and enzyme-linked immunosorbent assay post tail vein injection. An ovarian insufficiency animal model induced by chemotherapy was developed, and ovarian function was assessed through ovarian diameter, vaginal smear, body weight, sex hormone levels and histological analysis. The impact of mitochondrial transplantation on an ovarian cell model was examined through the assessment of mitochondrial function, apoptosis and levels of reactive oxygen species.Tail vein injection of isolated mitochondria has the potential to enhance ovarian functions in an animal model of POI induced by cyclophosphamide, increase mitochondrial activity in impaired ovarian cells and decrease the rate of apoptosis. [ABSTRACT FROM AUTHOR]

Objective: The objective of this study was to explore the possibility of treating heart failure in rats by delivering mRNA of 24-dehydrocholesterol reductase (DHCR24) into the body through lipid nanoparticles (LNPs). Methods: We established a heart failure rat model using doxorubicin. The experiment was divided into blank, model, mRNA stock solution cardiac injection, mRNA stock solution intravenous injection, LNP-mRNA stock solution cardiac injection, and LNP-mRNA stock solution intravenous injection groups. We directly injected DHCR24-mRNA or LNP-DHCR24-mRNA into the myocardium in three regions through an insulin needle passing through the intercostal space under the guidance of B-ultrasound. We recorded the mortality rate, body weight, 6-min walk test return times, and organ weight of rats after administration and detected the cardiac structure and function using B-ultrasound and transmission electron microscopy (TEM). Additionally, we tested for HE staining; PRDX2, Sirt3, and TRX1 protein expression; and IL-1 β, IL-10, VEGF, NT proBNP, and BNP cytokine concentrations. Results: Compared with the model group, the administration of DHCR24-mRNA significantly reduced mortality; decreased weight loss, the ratio of heart to tibia length, and spleen weight; and improved rat motility. The administration of DHCR24-mRNA can postpone the pathological morphological alterations of myocardial cells and reduce inflammatory infiltration. In terms of biochemistry, the administration of DHCR24-mRNA can increase the expression of the PRDX2, Sirt3, and TRX1 proteins; increase the concentrations of IL-10 and VEGF; and reduce the concentrations of IL-1β, NT proBNP, and BNP. The administration of DHCR24-mRNA can also delay the process of heart failure. The delivery and therapeutic effect of DHCR24-mRNA encapsulated in LNPs were better when compared to the other groups. Conclusions: DHCR24-mRNA encapsulated in LNPs can be effectively administered to rats with heart failure and exhibits some curative effects. [ABSTRACT FROM AUTHOR]

To evaluate the effect of intravenous (IV) hydromorphone alone or in combination with midazolam or dexmedetomidine on intraocular pressure (IOP) in dogs. Prospective, randomized, blinded, crossover study. A group of seven healthy, ophthalmologically normal, adult Beagle dogs. A total of four IV drug combinations were evaluated: hydromorphone 0.1 mg kg–1 (H); hydromorphone 0.1 mg kg–1 and dexmedetomidine 0.001 mg kg–1 (HD); hydromorphone 0.1 mg kg–1 and midazolam 0.2 mg kg–1 (HM2); and hydromorphone 0.1 mg kg–1 and midazolam 0.4 mg kg–1 (HM4). Treatment order was randomized, with a 2 week washout period between treatments. IOP and sedation scores were obtained before (T0) and 3, 30, 60, 240 and 480 minutes after drug injection. To account for repeated measurements for each dog across treatments and time points, mixed models were used to compare IOP at T0 by eye and to describe changes from T0 in IOP (averaged across eyes) and sedation scores. In treatment H, IOP increased significantly from baseline levels [predicted mean increase of 5.5 mmHg [95% confidence interval (CI): 3.7–7.3] at T3 (p < 0.001) and 2.7 mmHg (95% CI: 0.9–4.5) at T30 (p = 0.005)]. In treatment HD, mean IOP increased from baseline by 2.3 mmHg (95% CI: 0.5–4.1) at T30 (p = 0.014). In treatment HM2, mean IOP increased by 2.5 mmHg (95% CI: 0.2–4.9) at T30 (p = 0.035). In treatment HM4, IOP did not change significantly from baseline at any time point. Sedation scores over time did not differ significantly between treatments. Injection of IV hydromorphone alone (0.1 mg kg–1) caused a transient increase in IOP and might not be appropriate if an acute increase in IOP is undesirable. Addition of dexmedetomidine or midazolam to hydromorphone, at the doses studied, appears to attenuate this increase in IOP. [ABSTRACT FROM AUTHOR]

Rationale: Isobutyryl-carfentanyl is the most recently discovered fentanyl analogue with a chemical structure that is similar to that of carfentanyl. Its analogue, carfentanyl, is regarded as one of the most lethal drugs in the world, with a potency of 10,000 times that of morphine. Therefore, isobutyryl-carfentanyl may possess a comparably high potency and its harmful effects cannot be ignored. Objectives: This study was designed to assess the analgesic effect of isobutyryl-carfentanyl and the potential risks associated with its misuse. Methods: In this study, we assessed the acute toxicity of isobutyryl-carfentanyl by up-and-down-procedure, the analgesic efficacy by hot-plate test, the abuse potential by conditioned place preference (CPP), drug self-administration, and drug discrimination tests, and compared it with fentanyl and carfentanyl. Results: The estimated median lethal dose (LD50) of isobutyryl-carfentanyl administered were 175 mg/kg (intragastric administration, IG), 15.84 mg/kg (intraperitoneal injection, IP), 15.84 mg/kg (subcutaneous injection, SC), and 1.6 mg/kg (intravenous injection, IV), respectively. The 50% maximal analgesic effect (ED50) of isobutyryl-carfentanyl was determined to be 0.00319 mg/kg, with an analgesic potency 14 times that of fentanyl and 0.82 times that of carfentanyl. Isobutyryl-carfentanyl exhibited a significant positional preference at a minimum dose of 0.1 mg/kg, while fentanyl exhibited a significant positional preference at a minimum dose of 0.3 mg/kg. In the heroin (0.05 mg/kg/infusion) self-administration substitution experiment, isobutyryl-carfentanyl showed significant self-administration behaviour at doses of 0.0005–0.001 mg/kg/infusion, with the maximum number of infusions observed at a dose of 0.001 mg/kg. In the heroin (1 mg/kg) drug discrimination experiment, fentanyl (0.005–0.02 mg/kg), carfentanyl (0.0005–0.002 mg/kg), and isobutyryl-carfentanyl (0.001–0.005 mg/kg) were tested in the dose-effect curves. The results showed that all three drugs exhibit dose-dependent increase in the number of drug-associated nose pokes responses and reduction in the rate of nose pokes. The subjective effect potency of isobutyryl-carfentanyl was found to be 4.4 times that of fentanyl and 0.5 times that of carfentanyl. Conclusions: In summary, isobutyryl-carfentanyl has high acute toxicity and analgesic effect, with strong psychological dependence approximately 5 times that of fentanyl and 0.5 times that of carfentanyl, and has extremely high abuse potency. [ABSTRACT FROM AUTHOR]

Background/Aim: This study aimed to investigate the safety and efficacy of deferoxamine (DFO) pretreated feline adipose tissue derived mesenchymal stem cells (fATMSCs) for the treatment of inflammatory disorders. Materials and Methods: fATMSCs were isolated from feline adipose tissue and characterized using flow cytometry for surface marker expression and differentiation assays for adipogenic, osteogenic, and chondrogenic lineages. Different concentrations of DFO were used to evaluate its impact on fATMSC activity. The therapeutic potential of these preconditioned cells was validated using a mouse model of acute lung injury (ALI) by LPS injection. Comprehensive evaluations, including clinical, hematological, and radiological assessments, were conducted before and after intravenous injection of preconditioned cells in three feline subjects. Results: 25 μM DFO pretreatment significantly upregulated immunomodulatory genes (Tgfb, Hgf, and Tsg-6) in fATMSCs. In the mouse ALI model, DFO-pretreated fATMSCs exhibited enhanced anti-inflammatory effects, reducing inflammatory cytokines (Tnfa, Il1b, Il6). Clinical safety assessment in felines showed no immediate adverse effects, structural alterations, or tumorigenesis. Conclusion: Utilizing a mouse model of acute lung injury, we demonstrated the potential of DFO-pretreated fATMSCs as a safe and effective therapeutic approach for inflammatory disorders. [ABSTRACT FROM AUTHOR]

Background/Aim: Acute lung injury (ALI) is an important pathological process in acute respiratory distress syndrome; however, feasible and effective treatment strategies for ALI are limited. Recent studies have suggested that stem cell-derived exosomes can ameliorate ALI; however, there remains no consensus on the protocols used, including the route of administration. This study aimed to identify the appropriate route of administration of canine stem cell-derived exosomes (cSC-Exos) in ALI. Lipopolysaccharides were used to induce ALI. Materials and Methods: Mice with ALI were treated with cSC-Exos by intratracheal instillation or intravenous injection. The efficacy of the route of administration was confirmed by determining the total cell count in the bronchoalveolar lavage fluid and histopathological changes. The treatment mechanism was confirmed by measuring cytokine levels and immune cell changes in M2 macrophages (CD206+ cells) and regulatory T cells (FOXP+ cells). Results: When cSC-Exos were injected, inflammation was alleviated, pro-inflammatory cytokine levels were reduced, and FOXP3+ and CD206+ cells were activated. Following intratracheal instillation, an enhanced inflammationrelieving response was observed. Conclusion: This study compared the effects of stem cell-derived exosomes on alleviating lung inflammation according to injection routes in an ALI mouse model. It was confirmed that direct injection of exosomes into the airway had a greater ability to alleviate lung inflammation than intravenous injection by polarizing M2 macrophages and increasing regulatory T cells. [ABSTRACT FROM AUTHOR]

AbstractCurcumin has diverse biological functions, especially antioxidant and anti-inflammatory properties, but clinical trials have been hindered by its low bioavailability and pharmacokinetic properties. To achieve therapeutic efficacy, understanding curcumin’s in vivo metabolism is crucial. We reviewed current research on curcumin metabolism in PubMed, Google Scholar, and CNKI. This article outlines curcumin’s metabolic processes in the body via oral and intravenous injection. It suggests that upon entering the human body, curcumin may undergo oxidation, reduction, binding, and microbial community influence. [ABSTRACT FROM AUTHOR]

Background: This study aims to evaluate the safety efficacy of combining the PD-1 antibody Tirelizumab with Sorafenib in the treatment of advanced hepatocellular carcinoma. Additionally we are committed to investigating the relationship between circulating tumor cell (CTC) counts/PD-L1 expression the prognosis of patients with advanced hepatocellular carcinoma. Methods: This study included 32 patients with unresectable primary liver cancer who received treatment with Tislelizumab in combination with Sorafenib. Tislelizumab was administered via intravenous injection at a dose of 200 mg every 3 weeks, while Sorafenib was given orally at a dose of 400 mg twice daily. Patients were evaluated every 3 cycles (9 weeks) to assess the safety and efficacy of the treatment regimen. Prior to enrollment, all patients underwent CTC counting and assessment of PD-L1 expression in circulating tumor cells. The primary endpoint was the objective response rate (ORR), evaluated by the investigator according to the RECIST v1.1 criteria. Secondary endpoints aimed to assess the relationship between circulating tumor cell (CTC) counts or programmed death ligand 1 (PD-L1) expression and the prognosis of patients with advanced hepatocellular carcinoma. Results: As of November 2022, a total of 32 patients have been enrolled in the study and received combination treatment. Among the 32 patients, 31 (96.8%) tested positive for circulating tumor cells (CTCs), with counts ranging from 1 to 45 and a median of 7 (3, 11). PD-L1-positive CTCs were detected in 25 patients (78.1%). All 32 patients were followed up for 2 to 14 months, with a median follow-up time of 6 months. Correlation analysis revealed that distant metastasis, vascular invasion, and the presence of more than 5 CTCs were significantly associated with PD-L1-positive CTCs. The one-year overall survival rates for patients with PD-L1-positive CTCs and those with PD-L1-negative CTCs were 78.5% vs 64.3% (P = 0.309). Additionally, the one-year overall survival rates for the group with rising CTC counts compared to the group with stable or declining counts were 34.3% vs 90% (P = 0.063). Conclusion: The combination of Tislelizumab and Sorafenib demonstrates promising antitumor activity in the first-line treatment of hepatocellular carcinoma, with a relatively high objective response rate (ORR) and acceptable safety profile. Baseline CTC PD-L1 positivity can serve as a predictive marker for selecting hepatocellular carcinoma patients for PD-1/PD-L1 blockade therapy, and dynamic measurement of CTC changes can be used to monitor treatment efficacy. [ABSTRACT FROM AUTHOR]

Introduction: Chemo-immunotherapy based on inducing tumor immunogenic cell death (ICD)with chemotherapy drugs has filled the gaps between traditional chemotherapy and immunotherapy. It is verified that paclitaxel (PTX) can induce breast tumor ICD. From this basis, a kind of nanoparticle that can efficiently deliver different drug components simultaneously is constructed. The purpose of this study is for the sake of exploring the scheme of chemotherapy-induced ICD combined with other immunotherapy to enhance tumor immunogenicity and inhibit the growth, metastasis, and recurrence of breast tumors, so as to provide a research basis for solving the tough problem of breast cancer treatment. Methods: Nanomedicine loaded with PTX, small interference RNA that suppresses CD47 expression (CD47siRNA, siCD47), and immunomodulator R848 were prepared by the double emulsification method. The hydrodynamic diameter and zeta potential of NP/PTX/siCD47/R848 were characterized. Established the tumor-bearing mice model of mouse breast cancer cell line (4T1) in situ and observed the effect of intravenous injection of NP/PTX/siCD47/R848 on the growth of 4T1 tumor in situ. Flow cytometry was used to detect the effect of drugs on tumor immune cells. Results: NP/PTX/siCD47/R848 nano-drug with tumor therapeutic potential were successfully prepared by double emulsification method, with particle size of 121.5 ± 4.5 nm and surface potential of 36.1 ± 2.5 mV. The calreticulin on the surface of cell membrane and extracellular ATP or HMGB1 of 4T1 cells increased through treatment with NPs. NP/PTX-treated tumor cells could cause activation of BMDCs and BMDMs. After intravenous injection, NP/PTX could quickly reach the tumor site and accumulate for 24 h. The weight and volume of tumor in situ in the breast cancer model mice injected with nanomedicine through the tail vein were significantly lower than those in the PBS group. The ratio of CD8+/CD4+ T cells in the tumor microenvironment and the percentage of dendritic cells in peripheral blood increased significantly in breast cancer model mice injected with nano-drugs through the tail vein. Discussion: Briefly, the chemotherapeutic drug paclitaxel can induce breast cancer to induce ICD. The nanomedicine which can deliver PTX, CD47siRNA, and R848 at the same time was prepared by double emulsification. NP/PTX/siCD47/R848 nano-drug can be enriched in the tumor site. The experiment of 4T1 cell tumor-bearing mice shows that the nano-drug can enhance tumor immunogenicity and inhibit breast tumor growth, which provides a new scheme for breast cancer treatment. (Graphical abstract) Intravenous injection of PTX-loaded nanomedicine based on PEG-PLGA causes immunogenic death of tumor cells and simultaneously reduces tumor cell immune escape, promotes macrophage polarization towards MI subtypes, and effectively activates DCs, thereby enhancing anti-tumor immunity. [ABSTRACT FROM AUTHOR]

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]

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]

Background: The most frequent benign tumor in females is uterine myoma, which is derived from the myometrium of the uterus. Multiple studies have reported rates of occurrence were varying between twenty percent and forty percent. The histological diagnosis indicates a significantly higher frequency compared to the clinical diagnosis. Therefore, the treatment of the hemorrhage is contingent upon the estimation of the hemorrhage and the alterations that happen during the operation. So we aimed to compare the effectiveness of placebo and tranexamic acid during transabdominal myomectomy for reducing the bleeding. Methods: Blinded randomized controlled research, while 50 females with uterine fibroids were divided and equally classified among two groups, each group contained 25 females. Prior to the abdominal myomectomy, each woman received a slowly intravenous injection of tranexamic acid fifteen milligrams per kilogram or placebo over a period of between five and ten minutes. The amount of blood loss was assessed. Results: The tranexamic acid group showed low blood loss, participants needing blood transfer, or additional intervention, in comparison to the placebo group. Furthermore, the participants that received tranexamic acid injections showed higher hemoglobin and hematocrit levels than those that received placebo injections following surgery. Conclusions: The parameters that were assessed together with the adverse and beneficial consequences of the study drugs, showed as follows: The hematologic profile and hemodynamics may be established, which might result in tranexamic acid being more efficient compared to a placebo in reducing the need for blood transfusions. [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]

Background: This study aimed to clarify the prognosis of asymptomatic endolymphatic hydrops (EH) in healthy volunteers via five‐year follow‐ups with inner ear magnetic resonance imaging (MRI). Methods: Inner ear MRI was performed on 115 participants recruited as controls in a previous study on Meniere's disease. The endolymphatic space was visualized using Naganawa's method of contrast‐enhanced MRI with intravenous gadolinium injection and evaluated using Nakashima's method of 2D imaging analysis. Results: Cochlear or vestibular EH was present in 7.0% of participants (n = 8), with all cases being unilateral (laterality), moderate (severity), and asymptomatic (onset). Only cochlear‐localized EH, only vestibular‐localized EH, and both EH were present in 1.7% (n = 2) (C group), 4.3% (n = 5) (V group), and 0.9% (n = 1) (CV group) of participants, respectively. Conducting inner ear MRI after 5 years showed that EH had almost disappeared in two participants in the C and V groups (4/8, 50.0%). EH was still present in three participants in the V group and one in the CV group (4/8, 50.0%). One participant in the V group and another in the CV group presented with residual inner ear EH and developed typical symptomatic Meniere's disease (2/8, 25.0%). Conclusions: Approximately 7% of healthy participants showed asymptomatic EH. Therefore, EH is not the definitive marker for making a diagnosis of Meniere's disease or the suitable predictor for the development of Meniere's disease. Among these participants, 25% maintained EH and subsequently developed typical Meniere's disease within the next 5 years. Schellong‐positive participants maintained persistent EH in the inner ear, and participants with higher scores on the self‐rating depression scale developed Meniere's symptoms after 5 years. Level of evidence: 2a [ABSTRACT FROM AUTHOR]

This study is to investigate the therapeutical effect and mechanisms of human-derived adipose mesenchymal stem cells (ADSC) in relieving adriamycin (ADR)-induced nephropathy (AN). SD rats were separated into normal group, ADR group, ADR+Losartan group (20 mg/kg), and ADR + ADSC group. AN rats were induced by intravenous injection with adriamycin (8 mg/kg), and 4 d later, ADSC (2 × 105 cells/mouse) were administrated twice with 2 weeks interval time (i.v.). The rats were euthanized after the 6 weeks' treatment. Biochemical indicators reflecting renal injury, such as blood urea nitrogen (BUN), neutrophil gelatinase alpha (NGAL), serum creatinine (Scr), inflammation, oxidative stress, and pro-fibrosis molecules, were evaluated. Results demonstrated that we obtained high qualified ADSCs for treatment determined by flow cytometry, and ADSCs treatment significantly ameliorated renal injuries in DN rats by decreasing BUN, Scr and NGAL in peripheral blood, as well as renal histopathological injuries, especially protecting the integrity of podocytes by immunofluorescence. Furthermore, ADSCs treatment also remarkably reduced the renal inflammation, oxidative stress, and fibrosis in DN rats. Preliminary mechanism study suggested that the ADSCs treatment significantly increased renal neovascularization via enhancing proangiogenic VEGF production. Pharmacodynamics study using in vivo imaging confirmed that ADSCs via intravenous injection could accumulate into the kidneys and be alive at least 2 weeks. In a conclusion, ADSC can significantly alleviate ADR-induced nephropathy, and mainly through reducing oxidative stress, inflammation and fibrosis, as well as enhancing VEGF production. [ABSTRACT FROM AUTHOR]

HSK21542 injection is a new peripheral kappa opioid receptor (KOR) agonist. To evaluate its safety, tolerability, pharmacokinetics and pharmacodynamics, this study was conducted in healthy volunteers, consisting of two parts: a single ascending dose (0.2–3.375 μg/kg, 15‐min infusion) and different infusion durations (0.2 and 1 μg/kg, 2‐ or 15‐min infusion). The area under the plasma concentration‐time curve (AUC) and peak concentration (Cmax) of HSK21542 were dose‐linear among 0.2–3.375 μg/kg. After intravenous injection, HSK21542 was rapidly eliminated with a half‐life (t1/2) of 1.5 h, and the majority (48.02%) of the dose was excreted unchanged in urine. Pharmacodynamic results showed that HSK21542 increased prolactin release and reached a peak at 1–2 h after administration but had no significant effect on vasopressin levels. There was a brief increase in urine volume within the initial 2 h after administration. HSK21542 was well tolerated; most of the adverse effects (AEs) in the trial group were grade 1, and only 2 cases (4.0%) were grade 2. The main AE was paresthesia, which appeared in 42% (21/50) in the trial group. No serious adverse event (SAE) was observed. No subject withdrew early due to AEs. These results suggest that HSK21542 may be a potential treatment for pain and pruritic conditions. [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]

Intravenous bolus (IVb) injection of fentanyl induces an immediate apnea, but the characteristics of the apnea and relevant mechanism remain unclear. Here, we tested whether IVb injection of fentanyl induced an immediate central and upper airway obstructive apnea associated with chest wall rigidity via activating vagal C-fibers (VCFs) and vagal afferent opioid receptors (ORs). Cardiorespiratory and electromyography of external and internal intercostal, thyroarytenoid, and superior pharyngeal constrictor muscles (EMGEI, EMGII, EMGTA, and EMGSPC) responses to IVb injection of fentanyl were recorded in anesthetized and spontaneously breathing rats with or without bilateral perivagal capsaicin treatment or intravagal microinjection of naloxone. An immunohistochemical approach was employed to define the presence of opioid mu-receptor (MOR) expression in vagal C-neurons, and a patch clamp technique was utilized to determine the evoked current responses of vagal C-neurons to fentanyl in vitro. Fentanyl induced an immediate apnea and subsequent respiratory depression. The apnea was characterized by cessation of EMGEI activity and augmentation of tonic discharges of EMGII, EMGTA, and EMGSPC, i.e., central expiratory apnea, laryngeal closure, and pharyngeal constriction/collapse accompanied with chest wall rigidity. The apneic response was abolished by blockade of VCF signal conduction and largely attenuated by antagonism of vagal afferent ORs. The latter significantly alleviated the initial (within 5-min postinjection), but not the latter, respiratory depression. Vagal C-neurons expressed MORs and were activated by fentanyl. We conclude that IVb injection of fentanyl causes a VCF- and vagal afferent OR-mediated immediate central apnea, upper airway obstruction, and chest wall rigidity. NEW & NOTEWORTHY: Intravenous bolus injection of fentanyl triggers an immediate apnea, but the nature of apnea and relevant mechanisms remain unknown. Results in this study reveal that this fentanyl injection concurrently triggers an immediate central and upper airway obstructive apnea associated with chest wall rigidity via activating vagal sensory C-fibers. [ABSTRACT FROM AUTHOR]

Administering fluids and drugs intravenously is crucial in caring for vulnerable patient cohorts such as critically ill patients as well as neonatal and paediatrics patient populations. Studies have revealed severe contamination of infusion solution that could be avoided by utilizing in-line filters. The filtration performance consequently depends on the geometry of the filter housing. The purpose of our numerical study was to analyse the flow situation in filter housings depending on the geometry (diameter of the filter housing and distance between entrance and membrane). We compared the flow of two circular filter system with different housing width (D = 25 mm; L = 1.5 mm/3.0 mm) by means of computational fluid dynamics (CFD). The filter membrane was modelled by a porous jump condition. Both filter systems showed a highly reduced inflow on the membrane compared to the velocity in the Luer Lock ports. The wide filter housing facilitates a more homogenous inflow on the membrane (>92% of the membrane area is applied within a range of 5% of the mean velocity) compared to the narrow filter housing. Despite that difference both filter housings induced a well distributed flow through the filter membrane. However, for large filter systems (>50 mm diameter) the design of the filter housing could play a crucial role in optimising filter performance and therefore CFD should be considered. [ABSTRACT FROM AUTHOR]

[Display omitted] The integration of reactive oxygen species (ROS) related photodynamic therapy (PDT) with the strategy of reshaping the tumor microenvironment (TME) has emerged as a potential approach for nanodiagnostic and therapeutic interventions. However, the therapeutic efficacy based on ROS treatments may be hindered by intracellular antioxidants such as glutathione (GSH) and tumor hypoxia. To address these challenges, a nanoplatform based on GSH-responsive multifunctional porphyrinic metal–organic framework (PCN-224@Au@MnO 2 @HA, PAMH) was proposed. It was developed through a layer-by-layer in-situ growth method. This method avoids the need for high-temperature calcination and complex modification processes while improving the stability of PCN-224 in a phosphate-rich environment. GSH depletion leads to oxidation–reduction imbalance in TME. With the inactivation of GSH peroxidase 4 (GPX4), the content of hydrogen peroxide (H 2 O 2) increases, ultimately triggering lipid peroxidation (LPO) and promoting ferroptosis. The catalase-like activity of Au nanozymes facilitates the generation of oxygen (O 2), thereby mitigating tumor hypoxia and downregulating hypoxia-inducing factors (HIF-1α). Due to the presence of porphyrin ligands in PCN-224, the generated O 2 can be further converted to toxic singlet oxygen (1O 2) under laser irradiation. Additionally, the platform allows near-infrared (NIR) fluorescence imaging, providing real-time information on intracellular GSH changes during PDT and ferroptosis. The PAMH nanoplatform has shown effective inhibition of tumor growth in subcutaneous models via both intravenous and intratumoral injection, indicating its potential in modulating reactive oxygen/sulfur species and reshaping TME, thereby facilitating imaging-guided cascaded nanocatalytic therapy. [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]

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]

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]

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]

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]

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]

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]

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]

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]

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: 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]

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]

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]

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]

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]

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]