Injection Of Dose Research Articles

The impact of circadian rhythm disruption on oxaliplatin tolerability and pharmacokinetics in Cry1-/-Cry2-/- mice under constant darkness.

Circadian rhythms, the 24-h oscillations of biological activities guided by the molecular clock, play a pivotal role in regulating various physiological processes in organisms. The intricate relationship between the loss of circadian rhythm and its influence on the tolerability and pharmacokinetic properties of anticancer drugs is poorly understood. In our study, we investigated the effects of oxaliplatin, a commonly used anticancer drug, on Cry1-/- and Cry2-/- mice (Cry DKO mice) under darkness conditions, where they exhibit free-running phenotype. We administered oxaliplatin at a dosage of 12mg/kg/day at two distinct circadian times, CT8 and CT16, under constant darkness conditions to Cry DKO mice and their wild type littermates. Our results revealed a striking disparity in oxaliplatin tolerance between Cry DKO mice and their wild-type counterparts. Oxaliplatin exhibited severe toxicity in Cry DKO mice at both CT8 and CT16, in contrast to the wild type mice. Pharmacokinetic analyses suggested that such toxicity was a result of high concentrations of oxaliplatin in the serum and liver of Cry DKO mice after repeated dose injections. To understand the molecular basis of such intolerance, we performed RNA-seq studies using mouse livers. Our findings from the RNA-seq analysis highlighted the substantial impact of circadian rhythm disruption on gene expression, particularly affecting genes involved in detoxification and xenobiotic metabolism, such as the Gstm gene family. This dysregulation in detoxification pathways in Cry DKO mice likely contributes to the increased toxicity of oxaliplatin. In conclusion, our study highlights the crucial role of an intact molecular clock in dictating the tolerability of oxaliplatin. These findings emphasize the necessity of considering circadian rhythms in the administration of anticancer drugs, providing valuable insights into optimizing treatment strategies for cancer patients.

Detection of the Cingulate Island Sign by Early Perfusion Imaging in Dopamine Transporter SPECT With Multiple-Pinhole Collimators.

Multiple-pinhole collimators provide considerable improvement of SPECT system count sensitivity. This case report suggests that SPECT with brain-specific multiple-pinhole collimators enables cerebral perfusion imaging with diagnostic quality by an early 12 minutes scan immediately after injection of a standard dose of the dopamine transporter ligand 123I-FP-CIT. Thus, 123I-FP-CIT SPECT with multiple-pinhole collimators could assess nigrostriatal degeneration (late image) and extrastriatal involvement (early perfusion image) during the same imaging session. The early image may serve as an alternative to FDG PET in patients with suspicion of an atypical neurodegenerative parkinsonian syndrome. This could streamline diagnostic workflows by reducing the need for additional imaging modalities.

Lamp2 Deficiency Enhances Susceptibility to Oxidative Stress-Induced RPE Degeneration.

Autophagy and lysosomal degradation are vital processes that protect cells from oxidative stress. This study investigated the role of lysosome-associated membrane protein 2 (Lamp2), a lysosomal protein essential for autophagosome maturation and lysosome biogenesis, in maintaining retinal health under oxidative stress. To induce oxidative stress, young Lamp2 knockout (KO) and wild-type mice received an intravenous injection of a low dose (10mg/kg) of sodium iodate (NaIO3). We examined retinal histopathology and morphological changes in the RPE. The involvement of resident microglia or infiltrating macrophages was assessed using immunostaining, flow cytometry, and real-time PCR for chemokines and cytokines. After administering a low-dose NaIO3, Lamp2 KO mice showed significant RPE degeneration, whereas wild-type mice had minimal damage. Histological analysis and electron microscopy revealed significant thinning of the outer nuclear layer and loss of RPE epithelial polarity in Lamp2 KO mice. Additionally, there was a significant increase in ionized calcium-binding adaptor molecule 1-positive microglia and macrophages in the outer retina. Early proliferation of CD45lowMHC-IIlow resident microglia was followed by the infiltration of CD45highLy6Chigh monocytes and the engraftment of CD11b+CD45high monocyte-derived macrophages. Transcript levels of monocyte chemoattractant protein 1, macrophage inflammatory protein 1β, Il- 1β, and Il-6 also increased in the retinas of Lamp2 KO mice. Furthermore, pretreatment with the macrophage-depleting agent clodronate prevented NaIO3-induced RPE degeneration and macrophage infiltration in Lamp2 KO mice. Lamp2 deficiency, when combined with oxidative stress, leads to RPE degeneration in vivo. Lysosomal dysfunction also promotes macrophage engraftment and triggers neurotoxic inflammation.

Intracalvariosseous injection: an approach for central nervous system drug delivery through skull bone marrow with a preclinical research in stroke.

Central nervous system (CNS) accessibility constitutes a major hurdle for drug development to treat neurological diseases. Existing drug delivery methods rely on breaking the blood-brain barrier (BBB) for drugs to penetrate the CNS. Researchers have discovered natural microchannels between the skull bone marrow and the dura mater, providing a pathway for drug delivery through the skull bone marrow. However, there has been no research on the feasibility, safety, and efficacy of this delivery method for drug treatment of stroke. We used a microporous method for intracalvariosseous (ICO) injection to deliver drugs directly into brain parenchyma through skull bone marrow. Safety of ICO was assessed by monitoring changes in skull and peripheral blood neutrophil counts, and FITC-dextran extravasation across the BBB. Drug delivery pathways were observed through transparent skull-dura mater-brain tissue. In a rodent stroke model, NA-1 or Y-3 neuroprotective agents were administered via ICO to evaluate safety and efficacy by assessing neurological deficits, infarct size, neuroinflammatory factors, neuronal apoptosis, and liver/kidney function. Drug concentration in tissues was measured using fluorescence tracing and high-performance liquid chromatography to gauge ICO delivery efficiency. ICO injection delivers drugs to the brain parenchyma through microchannels between the skull bone marrow and the dura mater, offering higher delivery efficiency than intravenous injection. After ICO injection, there were no changes in neutrophil counts in the skull bone marrow and peripheral blood, and the amount of FITC-dextran passing through the BBB remained unchanged. This confirmed that ICO injection does not cause skull infection or break BBB, which suggested ICO injection is safe and feasible. In the treatment of stroke with neuroprotective agents, although the drug dosage of ICO injection was lower than intravenous injection, drug accumulation in the brain increased after ICO injection, which helped repair nerve damage, reduce neuronal apoptosis, and decrease the expression of inflammatory factors. ICO injection is a central nervous system drug delivery method that utilizes natural microchannels between the skull and dura mater for efficient drug delivery. Our results assessed the feasibility and safety of ICO injection at the preclinical level and evaluated its efficacy in animal models of stroke. The findings provided a foundation for the clinical translation of ICO injection. This study was supported by The National Natural Science Foundation of China (No. 82425101); Beijing Municipal Science & Technology Commission (No. Z231100004823036); Capital's Funds for Health Improvement and Research (2022-2-2045); National Key Research & Development Program of China (2022YFF1501500, 2022YFF1501501, 2022YFF1501502, 2022YFF1501503, 2022YFF1501504, 2022YFF1501505).

The effect of intracerebroventricular injection of melatonin on the period of acquisition, expression, extinction, and reinstatement of morphine conditioned place preference in the male rat: A behavioral and biochemical study.

Behavior in both humans and animals is significantly influenced by the brain's reward system. Many studies have shown that this dopaminergic system is the root of drug addiction and abuse. Melatonin, an indoleamine neurohormone, has been studied for its potential negative effects on addictive drugs such as morphine. This study evaluates the effect of intraventricular melatonin injection during different phases of morphine conditioning. Rats were conditioned with morphine [5 mg/kg; subcutaneously (SC)] for three days. The changes in conditioned place preference (CPP) scores following the injection of different doses of melatonin [25, 50, and 100 μg/kg; intracerebroventricular (ICV)] were investigated during the acquisition, expression, extinction, and reinstatement phases of morphine conditioning. After completing these steps, the c-Fos level in the nucleus accumbens (NAc) was measured using the ELISA technique. The results indicated that daily injections of 50 and 100 μg/kg melatonin during the acquisition and expression phases caused a dose-dependent decrease in the conditioning score. During the extinction phase, melatonin administration reduced its duration incrementally. Notably, only the 100 μg/kg dose significantly decreased morphine reinstatement. In terms of c-Fos levels, which were elevated after morphine consumption, melatonin administration led to a significant reduction across all phases. This study demonstrates the neural interaction between melatonin and the opioid system. The evidence suggests that melatonin may be effective at decreasing drug-related rewards and has potential utility in preventing addiction.

Evaluating the antagonist effect of naltrexone implant via opioid challenge tests with escalating doses of hydromorphone injection in former heroin dependent patients

Evaluating the antagonist effect of naltrexone implant via opioid challenge tests with escalating doses of hydromorphone injection in former heroin dependent patients

510. Bacteriophages as Drug Delivery Vehicles for Polymyxin B

Abstract Background The goal of this project is to develop a safer, more effective formulation of polymyxin B for E. coli bacteremia. Polymyxins are a family of cyclic lipopeptides that display exceptional antibiotic activities toward gram-negative pathogens such as E. coli, Pseudomonas aeruginosa, and Acinetobacter baumannii. The PMB label includes an FDA black box warning for serious nephrotoxicity and neurotoxicity. However, today, with the growing emergence of “superbugs” and a dry antibiotic discovery pipeline, PMB is increasingly used as a last-line therapy to treat systemic infections. Thus, although PMB is a potent antibacterial agent, its toxicity currently prevents its use as an earlier or more widespread treatment. Transmission electron microscopy (TEM; negative stain) images of anti-LPS phage bound to gram-negative organisms. Phages were labeled with gold nanoparticles (dark spheres) coated with antibodies against pVIII, allowing phages to be easily identified (red darts). Gold-labeled anti-LPS phage are shown (A) without bacteria; or incubated with (B) E. coli DH5α; (C) E. coli ATCC BAA 1161; (D) A. baumannii ATCC 19606. Phage width is increased by the labeling reagents. Scale bars = 500 nm. Methods We engineered M13 to bind the core antigen of lipopolysaccharide (LPS), enabling binding to a variety of top-priority pathogenic gram-negative bacterial species, including E. coli, P. aeruginosa, A. baumannii, Klebsiella pneumoniae, and Burkholderia cepacia. Since the anti-LPS phages are able to bind but do not infect (nonviable), they are not cytotoxic by themselves. However, delivery of PMB by the anti-LPS phage confers antibiotic activity. Thus, in our strategy, PMB molecules are conjugated to the anti-LPS phage capsid, and delivered specifically to gram-negative bacterial cells through the specificity and high affinity of the anti-LPS binding domain. We have shown that the PMB – anti-LPS phage conjugate (termed “PMB–Phage” hereafter) effectively lowers the minimal inhibitory concentration of PMB by multiple orders of magnitude in vitro compared to PMB sulfate. MIC and MBC of PMB and PMB-Phage, determined in vitro for several gram-negative organisms. The heat map corresponds to the MIC or MBC values. Equivalent PMB concentrations for PMB-Phage MIC and MBC were calculated from the measured phage concentration and the average amount of PMB loaded per virion. * = resistant. ND = not determined due to technical limitation on phage concentration. Results We have already demonstrated following results.A broad-spectrum anti-LPS phage was engineered and verified to bind to several gram-negative bacterial species including E. coli.Polymyxin B was conjugated to the anti-LPS phage, creating PMB-Phage, which was highly antibacterial in vitro.PMB-Phage is non-toxic to mammalian cells in vitro and non-toxic in mice.PMB-Phage is distributed to various organs within 1 hour and has an elimination half-life of approximately 1 day.PMB-Phage appears to be effective in treating E. coli bacteremia in a mouse model. PMB-Phage Biodistribution Figure 9: Time course biodistribution of PMB-Phage in various organs, over time in male mice with (red) or without (blue) 1×10^7cfu (non-lethal dose) of E. coli ATCC BAA 1161 injected (n=3). Signals are measured as a percentage of the injected dose (ID) per volume (per cc). Representative biodistribution images (j) of 1 animal. Conclusion PMB-Phage will greatly reduce the nephrotoxicity of PMB, enabling safe treatment for a broader patient population. Liver and kidney blood biomarkers at end point of 7-day toxicity studies. Animals in experimental groups were injected 100µL of test materials through IV tail vein injection daily for 7 consecutive days. Experimental group animals for each condition (N=3), receiving either PMB or PMB-Phage at different doses show no significant difference comparing to control groups of animals group receiving no treatment (N=5) and 1xPBS buffer (N=3), in light and dark grey columns respectively. The only exception being all animals receiving 72 mg/kg body weight PMB (N=3) did not survive a single dose and died on day 1 (indicated by red cross in figure). Disclosures All Authors: No reported disclosures

ВЛИЯНИЕ ПРЕПАРАТА ЭСТРОГЕНОВОГО РЯДА НА СОМАТОМЕТРИЧЕСКИЕ ПОКАЗАТЕЛИ ПОТОМСТВА ЖЕНСКОГО ПОЛА

The aim of research is to study the effect of the estrogen drug fulvestrant at a dose of 200 μg/kg on the somatometric parameters of female offspring. Objectives: to study the effect of the estrogen preparation fulvestrant at a dose of 200 μg/kg on somatometric parameters of female offspring and to carry out statis-tical processing of the data obtained in relation to somatometric parameters in the studied animals. The experiments were carried out on the offspring of laboratory mice, whose mothers on the 11th day of preg-nancy underwent a single intramuscular injection of various doses of an estrogen preparation, fulvestrant. The study analyzed two groups: the first (n=15) – intact without exposure, in the second experimental group fulvestrant 0.8 ml 0.0005% at a dose of 200 mcg/kg (F–200 mcg/kg) was administered once, intra-muscularly. The resulting offspring were subjected to somatometric studies of body weight, body length, nose-ear length, ear-ear length, tail length, foot length of the hind right foot, and anogenital distance. A comparative analysis of the somatometric parameters of the offspring of female white outbred laboratory mice with a single exposure to the drug fulvestrant with an intact group showed that body weight increases, the head length distance (nose-ear) decreases, the head width distance (ear-ear) increases, the length of the right foot increases, hind paw and the anogenital distance decreases. Thus, exposure to an estrogen drug in the prenatal period causes changes in the somatometric parameters of the offspring in laboratory mice, the changes in these measurements were dependent on the administered experimental doses. The development of a biological model of prenatal estrogen administration can help in timely diagnosis and de-velopment of a set of preventive measures during the period of organ laying. The obtained results testify to the urgency of the problem of limiting the dose-dependent action of estrogenic drugs in the period of prenatal development of organs.

Consensus on the Cosmetic Use of a Novel Botulinum Neurotoxin Type A Product (NEWLUX®) for Facial Expression Muscles: 2024 Guidelines and Discussions by Korean Experts

Background: Botulinum neurotoxin type A (BoNTA) is widely used in aesthetic facial rejuvenation medicine. The exponential growth in using BoNTA for cosmetic purposes in Korea necessitates an update to the existing practice guidelines, building upon the consensus established by Korean experts in 2013. Aims: This work aims to provide an updated Korean consensus guideline for the safe and effective use of a novel BoNTA product (NEWLUX) for facial expression muscles. Methods: A panel of ten Korean experts in dermatology, plastic surgery, aesthetic medicine, and clinical anatomy convened in February 2024. They reviewed prior guidelines, including the 2013 Korean consensus, and shared their expertise on dosage, injection techniques, and potential complications associated with the use of the novel BoNTA product for facial expression muscles. The recommendations aimed to guide the best practices of the average aesthetic healthcare professional. Results: The panel reached a consensus on various aspects of using the BoNTA product, including recommended injection sites, dosages, and techniques for different aesthetic conditions caused by facial expression muscles. The resulting guideline emphasizes safety and efficacy, with recommendations based on the collective experience of the expert panel. Conclusion: This updated consensus guideline provides practical recommendations from Korean experts on the use of the novel BoNTA product for facial expression muscles. The guidelines will ensure safe and effective treatments while reflecting the latest advancements in the field.

Numerical investigation on the differential injection angle effects of intrathecal anesthetic drug delivery

In lumbar anesthesia surgery, the accurate determination of key parameters such as injection angle and dosage is facilitated by the real-time observation of intrathecal drug distribution. In this study, a non-invasive and visual computational fluid dynamics method was used to simulate drug injections in the “cloverleaf” lumbar thoracic segment with a multiphase mixture model, clarifying the intrathecal unsteady flow behaviors and the drug transport mechanisms. The transport properties of three clinically significant injection angles — [Formula: see text], [Formula: see text] and [Formula: see text]— were compared, determining the fastest and slowest block onset angles based on drug concentration levels in the thoracic vertebral plane. The calculation results are aligned with clinical practice trends, and it is found that significantly different drug amounts are required for different injection angles, with higher doses necessitated for ultrasound-assisted anesthesia. During anesthesia, a trend of increasing and then decreasing local anesthetic concentrations in each vertebral plane was observed, with the presence of a minimum effective dose of local anesthetic at the target block site. Injecting at the “concave” part of the cloverleaf ([Formula: see text] and [Formula: see text]) results in greater drug pulsation, faster diffusion and more efficient mixing than injecting at the positive “convex” part of the cloverleaf cross-section ([Formula: see text]). At the L2 vertebral plane, the flow rate and mixing ratios during injection for angles of [Formula: see text], [Formula: see text] and [Formula: see text] were approximately 1:4:2. Compared with orthostatic [Formula: see text] injections, [Formula: see text] and [Formula: see text] oblique injections resulted in higher drug concentrations in the T12-10 vertebral plane during the pre-transport period, with [Formula: see text] injections being the fastest. However, over a longer period of time, [Formula: see text] injections resulted in the lowest drug concentrations in the target block plane (T10), necessitating a higher dose. A faster anesthetic response was produced by [Formula: see text] injections at the same dose. Valuable insights for the application of appropriate drug dosages in clinical anesthesia practice are offered by the calculations.

Cefuroxime Induced Toxic-Maculopathy after Intracameral Injection of Standard Dose: A Case Report

Background: Cefuroxime-induced toxic maculopathy can occur when an incorrect or correct dilution is injected intracamerally during cataract surgery. Case Report: An 83-year-old male developed toxic maculopathy on the first postoperative day after uneventful cataract surgery. An investigation of the case confirmed that the patient developed sporadic toxic maculopathy after a standard intracameral cefuroxime dose. The patient showed complete recovery of vision during the first postoperative week. Conclusion: Cefuroxime-induced toxic maculopathy may occur sporadically and have a good visual outcome. It may be distinguished from toxic maculopathy induced by incorrect dilution based on its different clinical appearance and, in some cases, the guarded outcome. Correct dilution of cefuroxime is of utmost importance.

Rescue RM/CS-AKI by blocking strategy with one-dose anti-myoglobin RabMAb

Rhabdomyolysis or Crush syndrome-related AKI (RM/CS-AKI) has high mortality, and there is no effective early on-site treatment method. The critical pathogenic factor of RM/CS-AKI is the excessive free myoglobin (Mb) in blood circulation. Here, based on the concept of creating a “mobile barrier”, we develop an anti-Mb rabbit monoclonal antibody (RabMAb) with high specificity, affinity, stability, and broad species reactivity. A single dose of anti-Mb RabMAb injection is sufficient for emergency rescue in both homologous and heterologous RM/CS-AKI male animal models. The main goal of blocking the passage of free Mb through the glomerular filtration barrier has been achieved by using the anti-Mb RabMAb, which has a long-term stable therapeutic effect within 14 days and promotes phagocytosis of Mb. The optimal administration strategy, pharmacokinetic analysis, toxicity evaluation for anti-Mb RabMAb, and the distribution of its immune complexes in RM/CS-AKI mice are investigated. Thus, we develop effective prevention and control strategies for RM/CS-AKI.

Sex differences in aristolochic acid I-induced nephrotoxicity in mice and the effect of estradiol.

Aristolochic acid I (AAI), the most prominent component of aristolochic acids and found in nearly all aristolochic herbs, has been demonstrated significant nephrotoxicity. In this study, an acute nephrotoxicity model of AAI mice was established by a single dose injection of AAI. It was observed that there are differences of the sensitivity to AAI nephrotoxicity in female and male mice, with male mice exhibiting nephrotoxic effects even at lower doses. After the administration of estradiol (E2), serum levels of creatinine and urea nitrogen in male mice were observed to decrease. We used UPLC-MS/MS to determine the pharmacokinetics and renal tissue distribution of AAI and its metabolite aristololactam I (ALI). It was found that AAI had a longer plasma half-life in female mice, while the content of ALI in renal tissue of male mice was much higher than that in female. The administration of E2 was found to extend the half-life of AAI and reduce the levels of ALI in the kidneys of male mice. The proposed mechanism may involve the reduction of renal OATs transporter activity by E2, leading to decreased concentrations of ALI in the renal tubules. This reduction may mitigate its toxic effects on epithelial cells and diminish the production of its harmful metabolites, thereby alleviating AAI-induced nephrotoxicity.

Effect of propofol and ciprofol in patients undergoing bronchoscopy: protocol for a double-blind, randomised controlled trial

IntroductionPropofol is a fast-acting intravenous anaesthetic widely used for sedation and anaesthesia in gastrointestinal endoscopy, bronchoscopy, and the induction/maintenance of general anaesthesia in outpatients and inpatients; however, propofol has several...

Characterization of Microbubble Cavitation in Theranostic Ultrasound-mediated Blood-Brain Barrier Opening and Gene Delivery.

The characterization of microbubble activity has proven critical in assessing the safety and efficacy of ultrasound-mediated blood-brain barrier (BBB) opening and drug and gene delivery. In this study, we build upon our previous work on theranostic ultrasound (ThUS)-mediated BBB opening (ThUS-BBBO) and conduct for the first time a comprehensive characterization of the role of microbubble cavitation in ThUS-BBBO, as well as its impact on gene delivery with adeno-associated viruses (AAV). A repurposed imaging phased array was used throughout the study to generate focused transmits and record microbubble activity through high-resolution power cavitation imaging (PCI). The cavitation of microbubbles under ThUS pulses was first characterized in flow phantom using pulse lengths ranging from 1.5 to 20 cycles and under varying microbubble flow rates using a separate single-element transducer a passive cavitation detector (PCD). A comprehensive in vivo study in mice was then conducted to characterize the in vivo microbubble activity under ThUS and correlate the resulting cavitation with AAV-mediated transgene delivery and expression. The transcranial microbubble activity was first detected in two mice using a PCD, to confirm the findings of the flow phantom study. Next, three mouse studies were conducted to evaluate the relationship between cavitation and AAV delivery; one with three different microbubble size distributions using polydisperse and size-isolated microbubbles, one with variable burst length and burst repetition frequency, and one with different AAV serotypes and injection doses. Electronic beam steering was used to induce bilateral BBB opening with 1.5 cycle on the left and 10 cycles on the right hemisphere. Cavitation dose was correlated with BBB opening volume, AAV transgene expression was evaluated with immunofluorescence staining and histological safety was assessed with T2* imaging and Hematoxylin and Eosin staining. Frequency domain analysis in the phantoms revealed a broadband-cavitation dominance at the shorter pulse lengths, while harmonic cavitation components are significantly increased for longer pulses. The PCD was better at detecting higher frequency harmonics, while the signal received by the theranostic array was more broadband dominated. Analysis of signals in the time domain showed that the longer pulses induce higher microbubble collapse compared to short pulses. In the transcranial in vivo experiments, the PCD was able to detect increased harmonic cavitation for 10-cycle pulses. The microbubble study showed that 3-5 μm microbubbles resulted in the largest cavitation doses, BBBO volumes and AAV transgene expression compared to the smaller microbubble sizes. The burst sequence study revealed that the sequences with shorter bursts and faster burst repetition frequencies induce larger BBBO volumes and AAV transduction due to faster microbubble replenishment in the focal volume. Increased erythrocyte extravasation was observed on the hemisphere sonicated with 10-cycle pulses. Transgene expression was also increased with injection dose, without notable side effects during the three-week survival period. Finally, AAV9 was shown to be the serotype with the highest transduction efficiency compared to AAV2 and AAV5 at the same injected dose. This is the first comprehensive study into the microbubble cavitation under theranostic ultrasound. The phantom and in vivo studies show that the mechanism of ThUS-BBBO is mainly transient cavitation dominant, as microbubble collapse increases with pulse length despite the increased harmonic frequency response. Increased cavitation dose resulted in larger BBBO volumes and transgene expression in vivo . While ThUS induced microhemorrhage for most of the studied conditions, it did not have an impact on the survival and behavior of the mice.

A new model of experimental diabetic cardiomyopathy using combination of multiple doses of anomer-equilibrated streptozotocin and high fat diet: sex matters.

Diabetes mellitus (DM) leads to a more rapid development of DM cardiomyopathy (dbCM) and progression to heart failure in women than men. Combination of high-fat diet (HFD) and freshly-injected streptozotocin (STZ) has been widely used for DM induction, however emerging data shows that anomer-equilibrated STZ produces an early onset and robust DM model. We designed a novel protocol utilising a combination of multiple doses of anomer-equilibrated STZ injections and HFD to develop a stable murine DM model featuring dbCM analogous to humans. Furthermore, we examined the impact of biological sex on the evolution of cardiometabolic dysfunction in DM. Our study included six experimental protocols (8 weeks) in male and female C57BL/6J mice (n=109): Fresh STZ+HFD, Anomer-equilibrated STZ+HFD, HFD, Fresh STZ, Anomer-equilibrated STZ, Control diet+vehicle. Animals were characterised by extensive phenotyping in vivo and ex vivo. Anomer-equilibrated STZ+HFD led to induction of stable experimental murine DM characterised by impaired glucose homeostasis, cardiometabolic dysfunction and altered metabolome of liver, skeletal muscle, kidney and plasma. dbCM was more severe in female mice including systolic dysfunction and reduced cardiac energy reserve. This study established a novel, robust model of inducible murine DM and emphasised the impact of biological sex on DM progression and severity.

Population attributable fractions for modifiable risk factors of neonatal, infant, and under-five mortality in 48 low- and middle-income countries.

Identifying the modifiable risk factors for childhood mortality using population-attributable fractions (PAFs) estimates can inform public health planning and resource allocation in low- and middle-income countries (LMICs). We estimated PAFs for key population-level modifiable risk factors of neonatal, infant, and under-five mortality in LMICs. We used the most recent Demographic and Health Survey data sets (2010-22) from 48 LMICs, encompassing 35 sub-Saharan African countries and 13 countries from South and Southeast Asia (n = 506 989). We used generalised linear latent mixed models to compute odds ratios (ORs), and we calculated the PAFs adjusted for commonality using ORs and prevalence estimates for key modifiable risk factors. The highest PAFs of neonatal mortality were attributed to delayed initiation of breastfeeding (>1 hour of birth) (PAF = 23.9; 95% confidence interval (CI) = 23.1, 24.8), uncleaned cooking fuel (PAF = 6.2; 95% CI = 6.4, 7.8), infrequent antenatal care (ANC) visits (PAF = 4.3; 95% CI = 3.3, 5.9), maternal lack of formal education (PAF = 3.9; 95% CI = 2.7, 5.3), and mother's lacking two doses of tetanus injections (PAF = 3.0; 95% CI = 1.9, 3.9). These five modifiable risk factors contributed to 41.4% (95% CI = 35.6, 47.0) of neonatal deaths in the 48 LMICs. Similarly, a combination of these five risk factors contributed to 40.5% of infant deaths. Further, delayed initiation of breastfeeding (PAF = 15.8; 95% CI = 15.2, 16.2), unclean cooking fuel (PAF = 9.6; 95% CI = 8.4, 10.7), mothers lacking formal education (PAF = 7.9; 95% CI = 7.0, 8.9), infrequent ANC visits (PAF = 4.0; 95% CI = 3.3, 4.7), and poor toilet facilities (PAF = 3.4; 95% CI = 2.6, 4.3) were attributed to 40.8% (95% CI = 36.4, 45.2) of under-five deaths. Given the current global economic climate, policymakers should prioritise these modifiable risk factors. Key recommendations include ensuring that women enter pregnancy in optimal health, prioritising the presence of skilled newborn attendants for timely and proper breastfeeding initiation, and enhancing home-based care during the postnatal period and beyond.

Efficacy and Safety of Intravitreal Dexamethasone Implant in Treatment-Resistant Diabetic Macular Edema: Six-month Results.

To investigate the efficacy and safety of intravitreal Dexamethasone implant (DEX-I) therapy in the treatment of diabetic macular edema (DME) refractory to intravitreal bevacizumab (IVB). This retrospective and cross-sectional study included 37 eyes of 37 patients who received 3 loading doses of IVB injections for DME with no response and underwent DEX-Iimplant. Best-corrected visual acuity (BCVA), intraocular pressure (IOP) measurements and central foveal thickness (CFT) measured by spectral domain optical coherence tomography (SD-OCT) were recorded and compared before DEX-I, at the first week, first, second, third and sixth months. Duration of DME, glycated hemoglobin (HbA1c) levels, DME types and lens status (phakic, pseudophakic) were also recorded. The mean age of the patients was 61.14 ±8.69 years (59.5% male, 40.5% female). 35.1% of the patients had cystoid macular edema, 64.9% had diffuse macular edema and 73 % were phakic and 27% were pseudophakic. BCVA, CFT and IOP values before DEX-Iinjection were 0.78 ±0.16 LogMAR, 493.73 ±107.6 µm and 13.05 ±2.59 mmHg, respectively. At 6 months after DEX-I, BCVA, CFT and IOP values were 0.64 ±0.11 LogMAR, 397.35 ±59.72µm and 16.3 ±2.51 mmHg, respectively. In all follow-ups, there was asignificant improvement in BCVA, asignificant decrease in CFT and asignificant increase in IOP compared to pre-injection. Ocular hypertension was observed in 0.8 % of patients and progression of cataract progression in 1% of patients after treatment. DEX-Itherapy is an effective and safe treatment option for DME refractory to IVB treatment.

Promotion of microfracture-mediated cartilage repair by the intra-articular injection of Mg2.

Magnesium ions (Mg2+) play an important role in promoting cartilage repair in cartilage lesions. However, no research has focused on the role of Mg2+ combined with microfracture (MFX) in hyaline-like cartilage repair mediated by cartilage injury. This study aimed to investigate the beneficial effects of the combination of MFX and Mg2+ in cartilage repair. A total of 60 rabbits were classified into five groups (n = 12 each): sham, MFX, and three different doses of Mg2+ treatment groups (0.05, 0.5, and 5 mol/L). Bone cartilage defects were created in the trochlear groove cartilage of rabbits. MFX surgery was performed after osteochondral defects. Mg2+ was injected into knee joints immediately and two and four weeks after surgery. At six and 12 weeks after surgery, the rabbits were killed. Cartilage damage was detected by gross observation, micro-CT, and histological analysis. The expression levels of related genes were detected by real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR). The histological results showed that the 0.5 mol/L Mg2+ group had deeper positive staining in haematoxylin-eosin (H&E), safranin O, Alcian blue, and type II collagen staining. The new cartilage coverage in the injury area was more complete, and the regeneration of hyaline cartilage was higher. The RT-qPCR results showed that sirtuin 1/bone morphogenetic protein-2/sex-determining region Y box 9 (SIRT1/BMP-2/SOX-9) and hypoxia-inducible factor 1-alpha (HIF-1α) messenger RNA levels were up-regulated after Mg2+ injection. MFX combined with Mg2+ treatment has a positive effect on cartilage repair. The Mg2+ injection dose of 0.5 mol/L is most effective in enhancing microfracture-mediated cartilage repair.

Brain distribution study of [14C]-Riluzole following intranasal administration in mice.

Amyotrophic lateral sclerosis (ALS) presents a substantial challenge due to its complex nature, limited effective treatment options, and modest benefits from current therapies in slowing disease progression. This study explores the potential of intranasal delivery to enhance the CNS delivery of riluzole (RLZ), a standard ALS treatment which is subject to blood-brain barrier efflux mechanisms. Additionally, the impact of elacridar (ELC), an efflux pump inhibitor, on IN RLZ CNS bioavailability was examined. To quantify RLZ in vivo in mice, [14C]-RLZ was synthesised using an optimised one-pot method. [14C]-RLZ yield was 21.3 ± 3.4 %, measured by High Performance Liquid Chromatography (HPLC), with a specific activity of 40.4 ± 3.9 µCi/mg measured by HPLC and liquid scintillation counting. RLZ synthesis was verified using proton nuclear magnetic resonance (1H NMR), and liquid chromatography-mass spectrometry. IN RLZ (5 mg/kg) produced double the maximum brain levels (1.11 ± 0.34 %Injected Dose (ID)/brain) at 30 min as oral RLZ (5 mg/kg). The uptake of RLZ in the liver was reduced by half for intranasal administration compared to oral administration. Intravenous ELC (5 mg/kg) substantially increased brain levels of IN RLZ to 3.52 ± 0.62 % injected dose/g brain at 60 min post-administration, compared to 1.87 ± 0.33 % injected dose/g brain in the absence of the efflux pump inhibitor. However, increased concentrations were also observed in the liver and blood. These results indicate that intranasal delivery of RLZ enhances brain targeting and reduces liver accumulation compared to the oral route. Brain uptake of IN RLZ was enhanced further by ELC, although not selectively as accumulation in the liver or blood was also observed. Further metabolic research using Chromatography-Mass spectrometry (LC-MS) or NMR along with excretion studies are warranted for a more comprehensive understanding of the pharmacokinetics of intranasal RLZ and intranasal RLZ/ELC. Additionally, employing suitable ALS animal models is crucial for understanding RLZ's effects on disease progression, mechanism of action, efficacy, and potential side effects to aid further development.