Search

Simple Summary: Horses subjected to an unaccustomed increase in exercise intensity can experience damage and subsequent acute inflammation within the skeletal muscle tissue that may hinder the performance of the horse by causing muscle swelling and soreness. Hyaluronic acid injection may suppress this exercise-induced inflammatory response by acting as an anti-inflammatory in the muscle. Adult Thoroughbred horses were injected intravenously with a commercial sodium hyaluronate product for 3 weeks prior to performing an exercise stress test. Muscle biopsy samples were obtained before and after the exercise stress test was performed. The results indicate that horses receiving the hyaluronic acid supplement had decreased expression of inflammatory genes within skeletal muscle, but no genes remained suppressed after the induction of inflammation through exercise. These results demonstrate that hyaluronic acid supplementation does act as an anti-inflammatory in skeletal muscle tissue, but does not have long-term suppressive effects when inflammation does occur. Following strenuous exercise, skeletal muscle experiences an acute inflammatory state that initiates the repair process. Systemic hyaluronic acid (HA) is injected to horses routinely as a joint anti-inflammatory. To gain insight into the effects of HA on skeletal muscle, adult Thoroughbred geldings (n = 6) were injected with a commercial HA product weekly for 3 weeks prior to performing a submaximal exercise test. Gluteal muscle (GM) biopsies were obtained before and 1 h after exercise for gene expression analysis and HA localization. The results from RNA sequencing demonstrate differences in gene expression between non-injected controls (CON; n = 6) and HA horses. Prior to exercise, HA horses contained fewer (p < 0.05) transcripts associated with leukocyte activity and cytokine production than CON. The performance of exercise resulted in the upregulation (p < 0.05) of several cytokine genes and their signaling intermediates, indicating that HA does not suppress the normal inflammatory response to exercise. The transcript abundance for marker genes of neutrophils (NCF2) and macrophages (CD163) was greater (p < 0.05) post-exercise and was unaffected by HA injection. The anti-inflammatory effects of HA on muscle are indirect as no differences (p > 0.05) in the relative amount of the macromolecule was observed between the CON and HA fiber extracellular matrix (ECM). However, exercise tended (p = 0.10) to cause an increase in ECM size suggestive of muscle damage and remodeling. The finding was supported by the increased (p < 0.05) expression of CTGF, TGFβ1, MMP9, TIMP4 and Col4A1. Collectively, the results validate HA as an anti-inflammatory aid that does not disrupt the normal post-exercise muscle repair process. [ABSTRACT FROM AUTHOR]

In medicine, ozone therapy is used in many instances. This study aims to understand the knowledge and attitudes of healthcare professionals towards ozone therapy. We conducted a cross-sectional survey in a comprehensive hospital between November 2020 and January 2021. In addition to evaluating the sociodemographic characteristics of the healthcare professionals, we performed evaluations through a data collection form that we prepared based on the literature. A total of 544 people were included in the study. We found ozone therapy to be the fifth-most frequently heard (72.2%) and experienced (2%) application among traditional and complementary medical applications. Of the participants, 20.8% (n=113) correctly answered the questions regarding the methods of application of ozone therapy. We found that the most common route of administration was intravenous administration, with a rate of 56.5% (n=307). The number of correct answers received for the questions regarding ozone therapy was related to professional experience, sex, and occupation (P = .035, P < .001, and P < .001, respectively). We determined that the knowledge and attitudes of healthcare professionals towards ozone therapy are not satisfactory. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) is a debilitating condition that results in impaired sensory and motor function due to the limited self-regenerative ability of the spinal cord. To address this issue, combination therapy has been proposed as an effective treatment strategy for SCI regeneration. In this study, Platelet-Rich Plasma (PRP)-derived exosomes loaded with dexamethasone were utilized in a mouse model of SCI compression. PRP-derived exosomes loaded with dexamethasone (Dex) were prepared using ultracentrifugation and sonication methods and were administered to the mice via intravenous injection. Following a four-week duration, behavioral assessments were administered to assess functional recuperation, and diverse metrics encompassing the expression of genes associated with apoptosis and antiapoptosis, serum cytokine concentrations and tissue sampling were subjected to thorough examination. The results of this study demonstrated that mice treated with PRP-derived exosomes loaded with Dex (ExoDex) exhibited altered levels of TNF-a and IL-10, along with decreased Bax and increased Bcl2 expression in comparison to the model group. Furthermore, intravenously injected ExoDex reduced the size of the lesion site, lymphocyte infiltration, vacuolation, cavity size and tissue disorganization while also improving locomotor recovery. We propose that the utilization of exosome-loaded Dex therapy holds potential as a promising and clinically relevant approach for injured spinal cord repair. However, further extensive research is warranted in this domain to validate and substantiate the outcomes presented in this study. [ABSTRACT FROM AUTHOR]

The aim of this study was to measure the concentrations of enrofloxacin (ERFX) and other fluoroquinolones; orbifloxacin (OBFX), marbofloxacin (MBFX), and ofloxacin (OFLX) in the plasma and bile of rabbits after a single intravenous (IV) injection. Twenty male rabbits were divided into four groups and given each drug by IV injection into the ear vein at a dose of 5.0 mg/kg BW. The concentration of ERFX, ciprofloxacin (CPFX), OBFX, MBFX and OFLX in plasma and bile were determined by HPLC. CPFX, metabolite of ERFX, was also measured by HPLC in plasma and bile of rabbits receiving ERFX. Several pharmacokinetic parameters in plasma were calculated and biliary clearance (CLbile) was calculated from extent of biliary excretion and accumulation of AUC of each drug. After IV injection, elimination half-life (t1/2β) was 4.13, 3.68, 6.60, 5.14 hr; volume of distribution at a steady state (Vdss was 1.24, 0.503, 0.771, 1.02 L/kg; and total body clearance (CLtot) was 1.05, 0.418, 0.271, 0.453 L/kg/hr, respectively. The values for CLbile for ERFX, OBFX, MBFX, and OFLX were 0.0048, 0.0050, 0.0057, and 0.0094 L/kg/hr, respectively. These values represent 0.48%, 1.2%, 2.1%, and 2.3% of the total body clearance (CLtot) of each drug, respectively. The biliary clearance of CPFX was also measured and found to be 0.0199 L/kg/hr with ERFX administration. The results showed that ERFX, OBFX, MBFX, and OFLX were not excreted into the bile to a significant extent, making them safe drugs to use in rabbits. [ABSTRACT FROM AUTHOR]

A metabolic encephalopathy brought on by dangerously low blood glucose levels is called hypoglycemic encephalopathy. Transient hypoglycemic episodes are frequent, particularly in diabetic patients. This complication is seen in diabetes patients who are taking insulin/insulin secretagogues. Severe persistent hypoglycemia can result in seizures, a protracted state of coma, and a wide range of other global and focal neurologic impairments. The main pathological alterations in hypoglycemic encephalopathy include widespread denaturation and necrosis of the neurons as a result of a lack of energy, which is accompanied by a significant number of glial cells entering the brain. In our case, the patient had recurrent hypoglycemic episodes, which led to the development of hypoglycemic encephalopathy caused by insulin. It is important for clinicians to be aware of this potential complication and to closely monitor patients with diabetes who are being treated with insulin. [ABSTRACT FROM AUTHOR]

The letter to the editor discusses a study on the prognostic significance of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in predicting outcomes of COVID-19. The authors raise questions about potential factors that were not considered in the study, such as medication use, timing of blood sampling, and other variables that could impact the results. They hope that their reflections will contribute to improving future research design and interpretation of study results. The authors, Jiahua Zhang and Xinjie Wang, declare no conflicts of interest and state that the article is based on previously conducted studies without involving human patients or animals. [Extracted from the article]

Bacille Calmette-Guérin (BCG) vaccine has been used increasingly in immunotherapy, including treatment of non-muscle-invasive bladder cancer, as an adjuvant therapy in metastatic prostate cancer and metastatic melanoma. However, systemic infection from inadvertent intravenous (instead of intravesical) injection is uncommon and can have systemic ramifications. We encountered 3 patients with disseminated Mycobacterium bovis infection that ensued after intravenous BCG injection. [ABSTRACT FROM AUTHOR]

Pseudoaneurysm of the internal carotid artery caused by skull base osteomyelitis (SBO) is a lethal condition seen in immunocompromised patients, predominantly those with diabetes mellitus. Cranial nerve involvement is a common complication and generally indicates a poor prognosis. We report the case of a 62-year-old diabetic patient who presented with isolated sixth cranial nerve palsy. She had uncontrolled blood sugar levels and high erythrocyte sedimentation rate, and she suffered from pyelonephritis. Neuroimaging detected SBO with multiple secondary mycotic pseudoaneurysms prominent at the petrocavernous junction. Ischemia is the most common etiology for an isolated abducens nerve palsy, but in certain cases neuroimaging is warranted to prevent life-threatening complications. This case highlights the importance and urgency of identifying and managing such conditions. [ABSTRACT FROM AUTHOR]

Background: SHR8554 is a novel μ-opioid receptor-biased agonist. It has analgesic effects by selectively activating the G protein-coupled pathway. Additionally, it can weakly activate the ß-arrestin-2 pathway, resulting in a limited number of side effects, such as gastrointestinal inhibition. Previous studies have shown that SHR8554 has good analgesic effects, safety and tolerability, but the pharmacokinetic characteristics of SHR8554 in humans have not been reported. This study was designed to investigate the pharmacokinetics and safety of SHR8554 in healthy Chinese male subjects. Methods: A single 1 mg/41.3 μCi intravenous dose of [14C]SHR8554 was administered to six healthy male subjects. Blood, urine and faecal samples were collected at continuous time points to analyse SHR8554 parent drug levels and their metabolites. The total radioactivity in blood, plasma, urine and faeces was detected by using a liquid scintillation counter. The dynamic changes of SHR8554 and its metabolite concentration were by liquid chromatographytandem mass spectrometry (LC/MS), and then pharmacokinetic analysis. The safety of the drug on the subjects was also observed after a single intravenous injection. Results: The total recovery of radioactivity in urine and faeces was 99.68% ± 0.79% in 216 h, including 76.22% ± 1.12% in urine and 23.46% ± 1.36% in faeces. Seventeen major metabolites in blood, urine and faeces were analysed and identified. The main metabolic pathways of SHR8554 in the human body involve 1) N-dealkylation; 2) O-deethylation; 3) mono-oxidation; 4) glucuronidation, etc. The primary mechanism of SHR8554 clearance in the human body is through urinary excretion, primarily in its parent drug and metabolite forms. The drug has good safety, and no serious adverse effects were observed. Conclusion: SHR8554 showed favourable pharmacokinetic characteristics and safety profiles in this study. SHR8554 is extensively metabolized in human body. The main metabolic pathways include N-dealkylation and O-deethylation, as well as mono-oxidation and glucuronidation. The main excretion route of SHR8554 and its metabolites is through urine. Clinical Trial Registration: http://www.chinadrugtrials.org.cn/, identifier CTR20220450 [ABSTRACT FROM AUTHOR]

Herein, biotin (Bio)‐conjugated poly(acrylic acid) (PAA)‐grafted ultrasmall gadolinium oxide nanoparticles (Bio‐PAA‐Gd2O3 NPs) were synthesized for enhanced tumor imaging using Bio as a tumor‐targeting ligand. The average particle diameter of Gd2O3 NPs was 2.1 nm. The Bio‐PAA‐Gd2O3 NPs exhibited excellent colloidal stability (i. e., no precipitation) and a high longitudinal water proton spin relaxivity (r1) of 23.8 s−1 mM−1 (r2/r1=1.6 and r2=transverse water proton spin relaxivity), which was ∼6 times higher than those of commercial Gd‐chelated magnetic resonance imaging (MRI) contrast agents. Cytotoxicity tests using two cell lines showed that the Bio‐PAA‐Gd2O3 NPs were almost non‐toxic up to the measured concentration of 500 μM Gd. The enhanced tumor imaging of the Bio‐PAA‐Gd2O3 NPs was demonstrated through their higher positive contrasts and longer contrast retention at the tumor after intravenous injection in T1 MR images, compared with those of the control PAA‐Gd2O3 NPs. [ABSTRACT FROM AUTHOR]

The impact of genetic ablation of SOS1 or SOS2 is evaluated in a murine model of KRASG12D-driven lung adenocarcinoma (LUAD). SOS2 ablation shows some protection during early stages but only SOS1 ablation causes significant, specific long term increase of survival/lifespan of the KRASG12D mice associated to markedly reduced tumor burden and reduced populations of cancer-associated fibroblasts, macrophages and T-lymphocytes in the lung tumor microenvironment (TME). SOS1 ablation also causes specific shrinkage and regression of LUAD tumoral masses and components of the TME in pre-established KRASG12D LUAD tumors. The critical requirement of SOS1 for KRASG12D-driven LUAD is further confirmed by means of intravenous tail injection of KRASG12D tumor cells into SOS1KO/KRASWT mice, or of SOS1-less, KRASG12D tumor cells into wildtype mice. In silico analyses of human lung cancer databases support also the dominant role of SOS1 regarding tumor development and survival in LUAD patients. Our data indicate that SOS1 is critically required for development of KRASG12D-driven LUAD and confirm the validity of this RAS-GEF activator as an actionable therapeutic target in KRAS mutant LUAD. Critical regulators of RAS signaling pathways in oncogenic RAS-driven tumors remain to be explored. Here, the authors show the development of KRAS(G12D)-driven lung adenocarcinoma is dependent on SOS1, with dual roles in both tumor and stroma. [ABSTRACT FROM AUTHOR]

Calcium (Ca2+) is essential for mitochondrial homeostasis and function coordination, particularly in cancer cells that metabolize frequently to sustain their growth. Photochemistry mediated calcium overload has attracted lots of attention as an effective way to achieve tumor suppression. Herein, we developed a photonanomedicine to synergistically induce calcium overload via cell-surface photochemistry and thus tumor suppression. Specifically, the photosensitizer, protoporphyrin IX (PpIX) was loaded onto upconversion nanoparticles (UCNP), which was subsequently modified by a polymer bearing photo-crosslinking cinnamate (CA) groups. The resulting nanoparticle was further functionalized by anti-CD20 aptamers (Apt), to give photonanomedicine. The interaction between CD20 receptors and anti-CD20 aptamers allowed photonanomedicine to accurately attach onto the Raji cell surface after an intravenous injection. Following the local application of a 980 nm NIR laser, the photonanomedicine was able to capture the NIR light and convert it into ultraviolet (UV) light. On one hand, the converted UV light led the crosslinking of cinnamate groups in photonanomedicine, further stimulating the clustering of CD20 receptors and causing Ca2+ influx. On the other hand, the UV light could simultaneously excited PpIX to generate reactive oxygen species (ROS) in situ to break down the integrity of cell membrane and lead to an influx of Ca2+. The synergistic Ca2+ overload mediated by photonanomedicine exhibited an enhanced and superior anti-tumor efficacy. We believe this photonanomedicine expands the toolbox to manipulate intracellular Ca2+ concentration and holds a great potential as an anti-tumor therapy. [ABSTRACT FROM AUTHOR]

Atherosclerosis can form intimal plaques in the arteries and undergo plaque rupture with followed stroke or myocardial infarction under certain pathological conditions. However, suboptimal intraplaque accumulation, along with severe off‐target effects, remain formidable obstacles for efficient pharmacotherapy of atherosclerosis. A characteristic feature of the progression of atherosclerosis is the continuous recruitment of inflammatory monocytes that differentiate into foamy macrophages with the generation of legumain in the plaques. In this study, a bio‐activatable nano‐shuttle based on human serum albumin is conceived that contained curcumin to allow the precise inhibition of atherosclerosis progression. Following intravenous injection, the nano‐shuttles are almost exclusively engulfed by inflammatory monocytes in an efferocytosis‐mimetic manner and selectively co‐migrated with the monocytes towards the plaques. The nano‐shuttles are readily activated to release the initially arrested curcumin in response to the generation of legumain upon the differentiation of monocytes into foamy macrophages within the plaques. Treatment assessments on atheroprone apolipoprotein‐E‐deficient mice indicated that the nano‐shuttles substantially inhibit the progression of atherosclerosis by attenuating the plaque inflammation burden without any obvious adverse effects. The integration of highly selective accumulation and specific drug activation of the nano‐shuttles in plaques can arouse an advanced therapeutic strategy to prevent atherosclerotic cardiovascular disease. [ABSTRACT FROM AUTHOR]

T cells play an important role in the development of focal segmental glomerulosclerosis (FSGS). The mechanism underlying such T cell‐based kidney disease, however, remains elusive. Here the authors report that activated CD8 T cells elicit renal inflammation and tissue injury via releasing miR‐186‐5p‐enriched exosomes. Continuing the cohort study identifying the correlation of plasma level of miR‐186‐5p with proteinuria in FSGS patients, it is demonstrated that circulating miR‐186‐5p is mainly derived from activated CD8 T cell exosomes. Renal miR‐186‐5p, which is markedly increased in FSGS patients and mice with adriamycin‐induced renal injury, is mainly delivered by CD8 T cell exosomes. Depleting miR‐186‐5p strongly attenuates adriamycin‐induced mouse renal injury. Supporting the function of exosomal miR‐186‐5p as a key circulating pathogenic factor, intravenous injection of miR‐186‐5p or miR‐186‐5p‐containing T cell exosomes results in mouse renal inflammation and tissue injury. Tracing the injected T cell exosomes shows their preferential distribution in mouse renal tubules, not glomerulus. Mechanistically, miR‐186‐5p directly activates renal tubular TLR7/8 signal and initiates tubular cell apoptosis. Mutating the TLR7‐binding sequence on miR‐186‐5p or deleting mouse TLR7 largely abolishes renal tubular injuries induced by miR‐186‐5p or adriamycin. These findings reveal a causative role of exosomal miR‐186‐5p in T cell‐mediated renal dysfunction. [ABSTRACT FROM AUTHOR]

Background. Mediating glucose absorption in the small intestine and renal clearance, sodium glucose cotransporters (SGLTs) have emerged as an attractive therapeutic target in diabetic patients. A substantial fraction of patients, however, only achieve inadequate glycemic control. Thus, we aimed to assess the potential of the SGLT-targeting PET radiotracer alpha-methyl-4-deoxy-4-[18F]fluoro-D-glucopyranoside ([18F]Me4FDG) as a noninvasive intestinal and renal biomarker of SGLT-mediated glucose transport. Methods. We investigated healthy rats using a dedicated small animal PET system. Dynamic imaging was conducted after administration of the reference radiotracer 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG), or the SGLT-targeting agent, [18F]Me4FDG either directly into the digestive tract (for assessing intestinal absorption) or via the tail vein (for evaluating kidney excretion). To confirm the specificity of [18F]Me4FDG and responsiveness to treatment, a subset of animals was also pretreated with the SGLT inhibitor phlorizin. In this regard, an intraintestinal route of administration was used to assess tracer absorption in the digestive tract, while for renal assessment, phlorizin was injected intravenously (IV). Results. Serving as reference, intestinal administration of [18F]FDG led to slow absorption with retention of 89.2 ± 3.5 % of administered radioactivity at 15 min. [18F]Me4FDG, however, was rapidly absorbed into the blood and cleared from the intestine within 15 min, leading to markedly lower tracer retention of 18.5 ± 1.2 % (P < 0.0001). Intraintestinal phlorizin led to marked increase of [18F]Me4FDG uptake (15 min, 99.9 ± 4.7 %; P < 0.0001 vs. untreated controls), supporting the notion that this PET agent can measure adequate SGLT inhibition in the digestive tract. In the kidneys, radiotracer was also sensitive to SGLT inhibition. After IV injection, [18F]Me4FDG reabsorption in the renal cortex was significantly suppressed by phlorizin when compared to untreated animals (%ID/g at 60 min, 0.42 ± 0.10 vs. untreated controls, 1.20 ± 0.03 ; P < 0.0001). Conclusion. As a noninvasive read-out of the concurrent SGLT expression in both the digestive tract and the renal cortex, [18F]Me4FDG PET may serve as a surrogate marker for treatment response to SGLT inhibition. As such, [18F]Me4FDG may enable improvement in glycemic control in diabetes by PET-based monitoring strategies. [ABSTRACT FROM AUTHOR]

Purpose: We investigated whether immature reticulocyte fraction (IRF) and the immature reticulocytes to red blood cells ratio (IR/RBC) are sensitive and specific biomarkers for microdose recombinant human erythropoietin (rHuEPO) and whether the inclusion of reticulocyte percentage (RET%) and the algorithm "abnormal blood profile score (ABPS)" increased the athlete biological passport (ABP) sensitivity compared with hemoglobin concentration ([Hb]) and the OFF-hr score ([Hb]-60 x √RET%). Methods: Forty-eight (♀ = 24, ♂ = 24) participants completed a 2-wk baseline period followed by a 4-wk intervention period with three weekly intravenous injections of 9 IU⋅kg-1⋅bw-1 epoetin β (♀ = 12, ♂ = 12) or saline (0.9% NaCl, ♀ = 12, ♂ = 12) and a 10-d follow-up. Blood samples were collected weekly during baseline and intervention as well as 3, 5, and 10 d after treatment. Results: The rHuEPO treatment increased [Hb] (time-treatment, P < 0.001), RET% (time-treatment, P < 0.001), IRF (time-treatment, P < 0.001) and IR/RBC (time-treatment, P < 0.001). IRF and IR/RBC were up to ~58% (P < 0.001) and ~141% (P < 0.001) higher compared with placebo, and calculated thresholds provided a peak sensitivity across timepoints of 58% and 54% with ~98% specificity, respectively. To achieve >99% specificity for IRF and IR/RBC, sensitivity was reduced to 46% and 50%, respectively. Across all timepoints, the addition of RET% and ABPS to the ABP increased sensitivity from 29% to 46%. Identification of true-positive outliers obtained via the ABP and IRF and IR/RBC increased sensitivity across all timepoints to 79%. Conclusions: In summary, IRF, IR/RBC, RET% and ABPS are sensitive and specific biomarkers for microdose rHuEPO in both men and women and complement the ABP. [ABSTRACT FROM AUTHOR]

Introduction: Asparaginase is an indispensable drug in treating childhood acute lymphoblastic leukemia (ALL). Hypersensitivity reactions (HSR) are the most common side effects and interfere with the antineoplastic activity of the drug. This study aims to compare the intramuscular (IM) and intravenous (IV) administration routes of Native Escherichia coli Lasparaginase (L-ASNase) in terms of hypersensitive reactions. Methods: L-ASNase was randomly administered IV or IM to newly diagnosed ALL patients and HSR was monitored in all patients for 1 h following the end of the IV infusion and for 2 h following the end of the IM administration of L-ASNase. Based on a retrospective review of clinical charts, reactions were identified. In order to determine the severity of each allergic reaction, we used the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 for allergic reactions. Results: A total of 1032 doses of L-ASNase were administered to 85 patients (42 males and 43 females) during the study period. Among 85 patients, 30 reactions were recorded, which means that 35% of the patients reacted. According to the CTCAE, twenty-nine out of 30 reactions (97%) were grade 2, while one (3%) was grade 4. In terms of individual doses, there was a non-significant trend toward increased incidence of reactions with IV administration (3.8% versus 0.9%, p = 0.064). The rate of reactions was higher in patients who received all IV doses (n : 60) as compared to those who received all IM doses (n : 25) (31.7% vs. 3.5%; chi-square= 8.415, p value=0.04). Based on the risk groups and HSR incidence, it was found that high risk group (HRG) patients were significantly more likely to develop HSR compared to the standart risk group (SRG) and intermediate risk group (MRG) patients (chi-square p = 0.003, CI: 95%; odds ratio: 3.12 and 5.91, respectively). Conclusions: In conclusion, IM administration of L-ASNase causes significantly less HSR to L-ASNase than the IV route. Patients with HRGALL have a higher risk of HSR. Since L-ASNase is still used in many developing countries and there are problems in the supply of Erwinia chrysanthemi ASNase (Erwinia), LASNase can be administered IM to reduce the frequency of HSR. [ABSTRACT FROM AUTHOR]

Background Electroconvulsive therapy (ECT) is an effective short-term treatment for schizophrenia and depression, amongst other disorders. Lidocaine is typically added to reduce pain from intravenous propofol injection. However, depending on the dose used in the ECT setting, it can shorten seizure duration. The aim of this study was to investigate the effect of lidocaine dose on seizure duration. Methods This retrospective, naturalistic cohort study included 169 patients treated with ECT. We examined 4714 ECT sessions with propofol or propofol plus lidocaine. Ictal quality was manually rated by visual inspection. The main outcome of this study was the relation of lidocaine with seizure duration after controlling for socio-demographic, ECT, and other anesthetic variables. Results There was a significant negative association between lidocaine usage and seizure duration. Multivariate analyses showed that seizure duration was shortened by an average of 3.21 s in sessions with lidocaine. Moreover, in this subgroup, there was a significant negative dose-dependent association between lidocaine dose and seizure length. Complementarily, a significant positive association between preictal BIS and seizure length was found in the subgroup of sessions where preictal was used. Conclusions We provide additional evidence highlighting the importance of caution regarding lidocaine dosing due to the effect on seizure length in the ECT setting. It is advisable for clinicians to exercise caution when administering lidocaine regarding its dosing and seizure length in ECT settings. Future investigation is needed to assess causal relationships by studying certain vulnerable groups or employing other charge calculation techniques, such as the titration method. [ABSTRACT FROM AUTHOR]

Cancer is a disease that causes millions of deaths per year worldwide because conventional treatments have disadvantages such as unspecific tumor selectivity and unwanted toxicity. Most human solid tumors present hypoxic microenvironments and this promotes multidrug resistance. In this study, we present "Magnetogene nanoparticle vector" which takes advantage of the hypoxic microenvironment of solid tumors to increase selective gene expression in tumor cells and reduce unwanted toxicity in healthy cells; this vector was guided by a magnet to the tumor tissue. Magnetic nanoparticles (MNPs), chitosan (CS), and the pHRE-Luc plasmid with a hypoxia-inducible promoter were used to synthesize the vector called "Magnetogene nanoparticles" by ionic gelation. The hypoxic functionality of Magnetogene vector nanoparticles was confirmed in the B16F10 cell line by measuring the expression of the luciferase reporter gene under hypoxic and normoxic conditions. Also, the efficiency of the Magnetogene vector was confirmed in vivo. Magnetogene was administered by intravenous injection (IV) in the tail vein and directed through an external magnetic field at the site of tumor growth in C57Bl/6 mice. A Magnetogene vector with a size of 50 to 70 nm was directed and retained at the tumor area and gene expression was higher at the tumor site than in the others tissues, confirming the selectivity of this vector towards hypoxic tumor areas. This nanosystem, that we called the "Magnetogene vector" for systemic delivery and specific gene expression in hypoxic tumors controlled by an external magnetic designed to target hypoxic regions of tumors, can be used for cancer-specific gene therapies. [ABSTRACT FROM AUTHOR]

Background: Contrast Induced Sialadenitis or Iodide Mumps refers to non-suppurative inflammation of salivary glands following intravenous iodinated contrast administration. It is a rare adverse effect of iodinated contrast with only a few cases reported worldwide. It is hypothesized to be an idiosyncratic reaction due to toxic accumulation of iodine in salivary glands. Case Report: We report a case of a 40-year-old female patient who underwent CECT brain after intravenous injection of 40ml of non-ionic iodinated contrast and developed symmetric painless swelling in bilateral submandibular triangles within five hours of contrast administration. Ultrasound with color doppler and MR imaging was performed which confirmed the diagnosis of contrast induced sialadenitis. Sialadenitis was managed conservatively and resolved slowly over eight days. Conclusion: Though it is a rare self-limiting adverse event of iodinated contrast, it must be known to the radiologist as well as the clinician to avoid unnecessary work up and manage the patient better. [ABSTRACT FROM AUTHOR]

Enhancement of the joint capsule, fibrovascular tissue, and synovial membrane in the rotator cuff interval using MRI can aid the identification of adhesive capsulitis following intravenous gadolinium injection. This study assesses the thickness of the coracohumeral ligament (CHL) in the cases of recurrent shoulder dislocation and identifies the status of the CHL in these cases. A 3T MRI machine was used to perform the imaging. Patients were included with a history of at least two episodes of shoulder dislocation at the radiology department of King Abdulaziz University Hospital (KAUH), Jeddah, Saudi Arabia, from January 2017 to May 2020. A total of 177 patients were diagnosed with recurrent shoulder dislocation through its associated symptoms, out of which 107 had a history of shoulder dislocation. A mean CHL thickness was reported in the control group as 1.6 (± 0.49) mm, while in patients with shoulder dislocation it was reported as 2.84 (± 0.91) mm. A statistically significant relationship was observed between CHL thickness and the presence of Hill-Sachs and Bankart lesions. The study concluded that increased CHL thickness is strongly correlated with shoulder dislocation: there is a good predictability of shoulder dislocation based on the presence of thickened CHL. [ABSTRACT FROM AUTHOR]

Problem: Considerable evidence suggests that placental extracellular vesicles (EVs) interact with most types of leukocytes in vitro but in vivo biodistribution studies question whether these interactions are reflective of the situation in vivo. Method of Study: CellTracker Red CMTPX stained human placental micro‐EVs were isolated from first trimester placental explant cultures. Equivalent amounts of micro‐EVs were cultured with murine leukocytes in vitro or injected into pregnant or non‐pregnant mice. After intravenous injection, on day 12.5 of gestation, major organs and blood samples were harvested 30 min or 24 h post injection. Results: We screened cryosections of the organs and confirmed that human placental EVs were specifically localised to the spleen, liver and the lungs 30 min or 24 h after injection. Immunohistochemistry showed that most of the EVs interacted with macrophages in those three organs and some of them also associated with T and B lymphocytes in the spleen or endothelial cells in the lungs and liver. Flow cytometry demonstrated that there was very little interaction between circulating leukocytes and EVs in vivo. While minimal, significantly more EVs interacted with leukocytes in pregnant than nonpregnant mice. Conclusion: The major interaction between human placental micro‐EVs and maternal leukocytes appear to be with macrophages predominantly in the splenic marginal zone, liver and lungs with little interaction between EVs and circulating leukocytes. Since marginal zone macrophages induce tolerance after phagocytosing apoptotic bodies it is likely that phagocytosis of placental EVs by marginal zone macrophages may also contribute to maternal immune tolerance. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) are nanoscale particles that facilitate intercellular communication. They are regarded as a promising natural drug delivery system for transporting and delivering bioactive macromolecules to target cells. Recently, researchers have engineered EVs with FKBP12/FRB heterodimerization domains that interact with rapamycin to load and deliver exogenous proteins for both in vitro and in vivo applications. In this study, we examined the tissue distribution of EVs using near‐infrared fluorescent imaging. We evaluated the effectiveness of EV‐mediated delivery of Cre recombinase specifically to hepatocytes in the livers of Ai9 Cre‐loxP reporter mice. Intravenous injection resulted in more efficient Cre protein delivery to the liver than intraperitoneal injections. Depleting liver‐resident macrophages with clodronate‐encapsulated liposome pre‐treatment did not enhance EV‐mediated Cre delivery to hepatocytes. Moreover, we demonstrated that multiple intravenous injections of Cre‐EVs facilitated functional Cre delivery to hepatocytes. To the best of our knowledge, this is the first study to simultaneously investigate the tissue distribution of FKBP12/FRB‐engineered EVs and their subsequent intracellular protein delivery in Ai9 Cre‐loxP reporter mice. These insights can inform preclinical research and contribute to developing next‐generation EV‐based platforms for delivering therapeutic proteins or genome editing technologies targeting the liver. [ABSTRACT FROM AUTHOR]

Myocardial dysfunction is the most serious complication of sepsis. Sepsis-induced myocardial dysfunction (SMD) is often associated with gastrointestinal dysfunction, but its pathophysiological significance remains unclear. The present study found that patients with SMD had higher plasma gastrin concentrations than those without SMD. In mice, knockdown of the gastrin receptor, cholecystokinin B receptor (Cckbr), aggravated lipopolysaccharide (LPS)-induced cardiac dysfunction and increased inflammation in the heart, whereas the intravenous administration of gastrin ameliorated SMD and cardiac injury. Macrophage infiltration plays a significant role in SMD because depletion of macrophages by the intravenous injection of clodronate liposomes, 48 h prior to LPS administration, alleviated LPS-induced cardiac injury in Cckbr -deficient mice. The intravenous injection of bone marrow macrophages (BMMs) overexpressing Cckbr reduced LPS-induced myocardial dysfunction. Furthermore, gastrin treatment inhibited toll-like receptor 4 (TLR4) expression through the peroxisome proliferator-activated receptor α (PPAR- α) signaling pathway in BMMs. Thus, our findings provide insights into the mechanism of the protective role of gastrin/CCKBR in SMD, which could be used to develop new treatment modalities for SMD. Gastrin/CCKBR inhibits the expression of TLR4 by stimulation of the transcription of PPAR- α , and thereby inhibits the activation of LPS/TLR4/NF- κ B axis, and eventually attenuates sepsis-induced myocardial dysfunction. [Display omitted] [ABSTRACT FROM AUTHOR]

Stapled peptides with significantly enhanced pharmacological profiles have emerged as promising therapeutic molecules due to their remarkable resistance to proteolysis and performance to penetrate cells. The all-hydrocarbon peptide stapling technique has already widely adopted with great success, yielding numerous potent peptide-based molecules. Based on our prior efforts, we conceived and prepared a double-stapled peptide in this study, termed FRNC-1, which effectively attenuated the bone resorption capacity of mature osteoclasts in vitro through specific inhibition of phosphorylated GSK-3 β. The double-stapled peptide FRNC-1 displayed notably improved helical contents and resistance to proteolysis than its linear form. Additionally, FRNC-1 effectively prevented osteoclast activation and improved bone density for ovariectomized (OVX) mice after intravenous injection and importantly, after oral (intragastric) administration. The double-stapled peptide FRNC-1 is the first orally effective peptide that has been validated to date as a therapeutic candidate for postmenopausal osteoporosis (PMOP). The double-stapled peptide FRNC-1 is for the first time identified as the orally effective peptide a therapeutic candidate for postmenopausal osteoporosis (PMOP). [Display omitted] [ABSTRACT FROM AUTHOR]

Copyright of Vascular Access is the property of Canadian Vascular Access Association and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: Chronic infection with Clonorchis sinensis can cause hepatobiliary fibrosis and even lead to hepatobiliary carcinoma. Epstein-Barr virus-induced gene 3 protein (EBI3) is a subunit of interleukin 35, which can regulate inflammatory response and the occurrence of fibrotic diseases. Previous studies have reported that the expression of EBI3 in the serum of patients with liver cirrhosis is reduced. The present study aims to investigate the biological effects of EBI3 on liver fibrosis caused by C. sinensis and the underlying molecular mechanisms. Methods: We first established a mouse model of liver fibrosis induced by C. sinensis infection and then measured the serum expression of EBI3 during the inflammatory and fibrotic phase. GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analyses were performed to investigate the potential role of EBI3 in liver fibrosis by regulating the extracellular matrix structural constituent and collagen catabolic process. Recombinant protein EBI3 (rEBI3) was added to hepatic stellate cells (HSCs) in vitro with C. sinensis antigen to explore its function. Finally, the therapeutic effect of rEBI3 was verified by intravenous injection into C. sinensis-infected mice. Results: The results showed that the serum expression of EBI3 increased in the inflammatory response phase but decreased in the fibrotic phase. The excretory-secretory products of C. sinensis (Cs.ESP) were able to stimulate HSC activation, while rEBI3 reduced the activation of HSCs induced by Cs.ESP. Also, the protein expression of gp130 and downstream protein expressions of JAK1, p-JAK1, STAT3 and p-STAT3 in HSCs were increased after rEBI3 incubation. Finally, intravenously injected rEBI3 inhibited hepatic epithelial-mesenchymal transition in C. sinensis-infected mice by inhibiting HSC activation and reducing liver injury. Conclusion: This study confirms that rEBI3 can attenuate C. sinensis-induced liver fibrosis by inhibiting HSC activation and may be one of the potential treatments for liver fibrosis. [ABSTRACT FROM AUTHOR]

Background: The blood brain barrier limits entry of macromolecular diagnostic and therapeutic cargos. Blood brain barrier transcytosis via receptor mediated transport systems, such as the transferrin receptor, can be used to carry macromolecular cargos with variable efficiency. Transcytosis involves trafficking through acidified intracellular vesicles, but it is not known whether pH-dependent unbinding of transport shuttles can be used to improve blood brain barrier transport efficiency. Methods: A mouse transferrin receptor binding nanobody, NIH-mTfR-M1, was engineered to confer greater unbinding at pH 5.5 vs 7.4 by introducing multiple histidine mutations. The histidine mutant nanobodies were coupled to neurotensin for in vivo functional blood brain barrier transcytosis testing via central neurotensin-mediated hypothermia in wild-type mice. Multi-nanobody constructs including the mutant M1R56H, P96H, Y102H and two copies of the P2X7 receptor-binding 13A7 nanobody were produced to test proof-of-concept macromolecular cargo transport in vivo using quantitatively verified capillary depleted brain lysates and in situ histology. Results: The most effective histidine mutant, M1R56H, P96H, Y102H-neurotensin, caused > 8 °C hypothermia after 25 nmol/kg intravenous injection. Levels of the heterotrimeric construct M1R56H, P96H, Y102H-13A7-13A7 in capillary depleted brain lysates peaked at 1 h and were 60% retained at 8 h. A control construct with no brain targets was only 15% retained at 8 h. Addition of the albumin-binding Nb80 nanobody to make M1R56H, P96H, Y102H-13A7-13A7-Nb80 extended blood half-life from 21 min to 2.6 h. At 30–60 min, biotinylated M1R56H, P96H, Y102H-13A7-13A7-Nb80 was visualized in capillaries using in situ histochemistry, whereas at 2–16 h it was detected in diffuse hippocampal and cortical cellular structures. Levels of M1R56H, P96H, Y102H-13A7-13A7-Nb80 reached more than 3.5 percent injected dose/gram of brain tissue after 30 nmol/kg intravenous injection. However, higher injected concentrations did not result in higher brain levels, compatible with saturation and an apparent substrate inhibitory effect. Conclusion: The pH-sensitive mouse transferrin receptor binding nanobody M1R56H, P96H, Y102H may be a useful tool for rapid and efficient modular transport of diagnostic and therapeutic macromolecular cargos across the blood brain barrier in mouse models. Additional development will be required to determine whether this nanobody-based shuttle system will be useful for imaging and fast-acting therapeutic applications. [ABSTRACT FROM AUTHOR]

Background: Mesenchymal stem/stromal cells (MSCs) have been used in clinical trials for various diseases. These have certain notable functions such as homing to inflammation sites, tissue repair, and immune regulation. In many pre-clinical studies, MSCs administered into peripheral veins demonstrated effective therapeutic outcomes. However, most of the intravenously administered MSCs were entrapped in the lung, and homing to target sites was less than 1%. This occurred mainly because of the adhesion of MSCs to vascular endothelial cells in the lung. To prevent this adhesion, we modified the surface of MSCs with polyethylene glycol (PEG; a biocompatible polymer) using the avidin–biotin complex (ABC) method. Methods: The surface of MSCs was modified with PEG using the ABC method. Then, the cell adhesion to mouse aortic endothelial cells and the tissue distribution of PEG-modified MSCs were evaluated. Moreover, the homing to the injured liver and therapeutic effect of PEG-modified MSCs were evaluated using carbon tetrachloride-induced acute liver failure model mice. Results: The PEG modification significantly suppressed the adhesion of MSCs to cultured mouse aortic endothelial cells as well as the entrapment of MSCs in the lungs after intravenous injection in mice. PEG-modified MSCs efficiently homed to the injured liver of carbon tetrachloride-induced acute liver failure model mice. More importantly, the cells significantly suppressed serum transaminase levels and leukocyte infiltration into the injured liver. Conclusion: These results indicate that PEG modification to the surface of MSCs can suppress the lung entrapment of intravenously administered MSCs and improve their homing to the injured liver. [ABSTRACT FROM AUTHOR]

Background: Nanodiamonds (NDs) have gained a rapidly growing interest in biomedical applications; however, little is known regarding their biokinetics owing to difficulties in measurements and limited synthesis/purification technologies. In this study, we investigated the distribution kinetics of detonation-synthesized NDs in mice via intravenous injection to evaluate the parameters that determine the behavior of the particles. We prepared two distinctive NDs that controlled the sp3/sp2 carbon ratio and particle size by coating them with serum proteins. The four control samples were intravenously injected into mice, and tissue distribution and clearance were evaluated at 30 min and 1, 7, and 28 days post-injection. Results: The sp3/sp2 carbon ratio showed no correlation with the organ distribution of the NDs. However, hydrodynamic size showed an excellent correlation with organ distribution levels: a negative correlation in the liver and positive correlations in the spleen and lungs. Furthermore, the deposition levels of NDs in the lung suggest that particles smaller than 300 nm could avoid lung deposition. Finally, a similar organ distribution pattern was observed in mice injected with carbon black nanoparticles controlled hydrodynamic size. Conclusions: In conclusion, the tissue distribution of NDs is modulated not by the sp3/sp2 carbon ratio but by the hydrodynamic size, which can provide helpful information for targeting the tissue of NDs. Furthermore, the organ distribution pattern of the NDs may not be specific to NDs but also can apply to other nanoparticles, such as carbon black. [ABSTRACT FROM AUTHOR]

Nanomedicines are increasingly researched and used for the treatment of chronic inflammatory diseases. Herein, the effect of the size of nanoparticles on their distribution and retention in chronic inflammatory sites, as compared to healthy tissues, was studied in a mouse model with chronic inflammation in one of the hind footpads. Using PEGylated gold nanoparticles of 2, 10, 100, and 200 nm, we found that although the smaller nanoparticles of 2 and 10 nm showed greater distribution and slower clearance in the inflamed footpad than the relatively larger nanoparticles of 100 and 200 nm, the larger nanoparticles of 100 and 200 nm were more selectively distributed in the inflamed hind footpad than in the healthy hind footpad in the same mouse. Based on these findings, we prepared protein nanoparticles of 100–200 nm with albumin, IgG antibody, or anti-TNF-α monoclonal antibody (mAb). The nanoparticles can release proteins in response to high redox activity and/or low pH, conditions seen in chronic inflammation sites. We then showed that upon intravenous injection, those stimuli-responsive protein nanoparticles distributed more selectively in the inflamed footpad than free proteins and remained longer in the inflamed footpad than similar protein nanoparticles that are not sensitive to high redox activity or low pH. These findings support the feasibility of increasing the selectivity of nanomedicines and protein therapeutics to chronic inflammation sites and prolonging their retention at the sites by innovative nanoparticle engineering. [ABSTRACT FROM AUTHOR]

Rationale: There is currently no treatment for spinocerebellar ataxias (SCAs), which are a group of genetic disorders that often cause a lack of coordination, difficulty walking, slurred speech, tremors, and eventually death. Activation of KCa2.2/KCa2.3 channels reportedly exerts beneficial effects in SCAs. Here, we report the development and validation of an analytical method for quantitating a recently developed positive allosteric modulator of KCa2.2/KCa2.3 channels (compound 2q) in mouse plasma. Methods: Mouse plasma samples (10 μL) containing various concentrations of 2q were subjected to protein precipitation in the presence of a structurally similar internal standard (IS). Subsequently, the analytes were separated on a C18 ultrahigh‐performance liquid chromatography column and detected by a tandem mass spectrometer. The method was validated using US Food and Drug Administration (FDA) guidelines. Finally, the validated assay was applied to the measurement of the plasma concentrations of 2q in plasma samples taken from mice after single intravenous doses of 2 mg/kg of 2q, and the pharmacokinetic parameters of 2q were determined. Results: The calibration standards were linear (r2 ≥ 0.99) in the range of 1.56–200 nM of 2q with intra‐ and inter‐run accuracy and precision values within the FDA guidelines. The lower limit of quantitation of the assay was 1.56 nM (0.258 pg on the column). The recoveries of 2q and IS from plasma were >94%, with no appreciable matrix effect. The assay showed no significant carryover, and the plasma samples stored at −80°C or the processed samples stored in the autosampler at 10°C were stable for at least 3 weeks and 36 h, respectively. After intravenous injection, 2q showed a bi‐exponential decline pattern in the mouse plasma, with a clearance of 30 mL/min/kg, a terminal volume of distribution of 1.93 mL/kg, and a terminal half‐life of 45 min. Conclusions: The developed assay is suitable for preclinical pharmacokinetic–pharmacodynamic studies of 2q as a potential drug candidate for ataxias. [ABSTRACT FROM AUTHOR]

Biomimetic sonosensitizers are prepared by camouflaging polymer-based sonosensitizers with cancer cell membranes, and they achieve efficient sonodynamic ablation of deep-seated tumors. [Display omitted] • Synthesis of biomimetic sonosensitizers with cancer cell membrane camouflage. • Strong sonodynamic effects of sonosensitizers upon irradiation with ultrasound. • Long blood circulation half-life and homologous targeting ability. • Efficient ablation of deep-seated tumors due to strong sonodynamic effects. Ultrasound (US)-triggered therapies are promising in cancer treatments, and their effectiveness can be enhanced through the proper camouflage of sonosensitizers. Herein, we have constructed cancer cell membrane (CCM)-camouflaged sonosensitizers for homotypic tumor-targeted sonodynamic therapy (SDT). The camouflaged sonosensitizers have been prepared by encapsulating hemoporfin molecules in poly(lactic acid) polymers (H@PLA) and extruding with CCM from Colon Tumor 26 (CT26) cells, forming the H@PLA@CCM. Under excitation with US, the hemoporfin encapsulated in H@PLA@CCM can convert O 2 into cytotoxic 1O 2 , which exerts an efficient sonodynamic effect. The H@PLA@CCM nanoparticles show enhanced cellular internalization to CT26 cells compared to H@PLA, and they also can be more efficiently engulfed by CT26 cells than by mouse breast cancer cells, due to the homologous targeting ability of CT26 CCM. After the intravenous injection, the blood circulation half-life of H@PLA@CCM is determined to be 3.23 h which is 4.3-time that of H@PLA. With high biosafety, homogeneous targeting ability, and sonodynamic effect, the combination of H@PLA@CCM and US irradiation has induced significant apoptosis and necrosis of tumor cells through the efficient SDT, achieving the strongest inhibition rate of tumors among other groups. This study provides insights into designing efficient and targeted cancer therapies using CCM-camouflaged sonosensitizers. [ABSTRACT FROM AUTHOR]

Melasma is a common, relapsing, multifactorial disease for which the treatment decision remains extremely difficult. This study was designed to compare the efficacy and safety of the combination of tranexamic acid (TA) injection and electro-optical synergy (ELOS) versus TA injection alone in treating melasma. A retrospective study was undertaken for patients with facial epidermal or mixed-type melasma to compare clinical data between 15 patients receiving a combination regimen and 15 patients with TA injection only. The study administered TA through intravenous injection to the combination group (twice weekly for 12 weeks) followed by ELOS therapy (once a month for three times). The TA group, on the other hand, received only TA injection (twice weekly for 12 weeks). The evaluation of clinical effectiveness was based on comparing the Melasma Area Severity Index (MASI) scores before and one month after treatment (at 4 months). The Physician Global Assessment (PGA) and Patient satisfaction were documented, and adverse reactions were recorded. All patients were followed up for one year to observe the relapse. After treatment, the MASI scores and melasma severity were significantly reduced in both groups. The combination group showed better efficacy than the TA only group (P < 0.05). The Physician Global Assessment (PGA) and Patient satisfaction showed superior efficacies of the combination group. No significant difference was observed between the two groups in terms of treatment-related side effects. Both groups experienced a certain degree of recurrence during the one-year follow-up, but the TA only group had a significantly higher recurrence rate than the combination group (P < 0.01). Together, the combination of TA injection and ELOS is a safe and effective treatment strategy for melasma and should be promoted. [ABSTRACT FROM AUTHOR]

Background: Serial killing by doctors or nurses is rare. When it occurs, it is generally only detected after multiple homicides by the same perpetrator have escaped detection in the past. The persons at greatest risk are multimorbid elderly patients whose sudden death for natural reasons would not come as a surprise. However, patients' risk of falling victim to homicide is increased only if such vulnerable patients are exposed to perpetrators with certain personality traits. In this situation, homicides can be committed in which little or no evidence of the crime is left behind. In this review, we address the frequency, nature, and circumstances of serial killings and attempted serial killings in hospitals, nursing homes, and nursing care. Methods: This review is based on publications retrieved by a selective review of the literature in monographs, medical databases, specialty journals, general-interest media, and the Internet. Results: An evaluation of searchable, published case descriptions of serial killings and attempted serial killings in hospitals, nursing homes, and nursing care, mainly from Europe and the English-speaking countries, enables identification of the type of patients at risk, the modes of homicide, and the personality traits of the perpetrators. Multimorbid, care-dependent and nursing-dependent persons are the main victims. The perpetrators (men and women) generally act alone and have often been working in patient care for many years. The most common method of homicide is by drug injection; violent physical homicide is rarer. In many cases, irregularities in drug stocks, erratic behavior of a staff member, and/or a cluster of sudden deaths are indeed noticed, but are too slowly acted upon. Conclusion: Irregularities in drug stocks, inexplicably empty drug packages and used syringes, erratic behavior of a staff member before and after a patient's death, or a cluster of unexpected deaths mainly involving elderly, multimorbid patients (detectable from internal mortality statistics) should always lead to further questioning and investigation. [ABSTRACT FROM AUTHOR]

An expanding body of evidence suggests that specifically targeting hydrogen sulfide (H2S) might potentially benefit both tumor diagnosis and treatment, but there is still a lack of cancer‐targeted molecular tools for in vivo applications. Here, we report the first ligand‐directed H2S‐specific near‐infrared fluorescent sensor PSMA‐Cy7‐NBD and scavenger PSMA‐Py‐NBD that target the prostate‐specific membrane antigen (PSMA). PSMA‐Cy7‐NBD displays a 53‐fold off–on fluorescence response to H2S at 803 nm with high specificity. PSMA‐Py‐NBD can scavenge H2S fast (k2=30.8 M−1 s−1 at 25 °C) without interference from biothiols. Both tools are highly water‐soluble and can be transported selectively into PSMA‐expressing prostate cancer cells. Endogenous H2S levels in murine 22Rv1 tumor models can be imaged and downregulated by intravenous injection of PSMA‐Cy7‐NBD and PSMA‐Py‐NBD, respectively. These tools could potentially help to investigate H2S cancer biology and with related therapies. [ABSTRACT FROM AUTHOR]

Pseudorabies virus (PRV) is one of the causative agents of common infectious diseases in swine herds. Enterococcus faecium is a probiotic belonging to the group of lactic acid bacteria and has excellent immunomodulatory effects. Vaccine immunization is an important approach to prevent animal diseases in the modern farming industry, and good immunization outcomes can substantially reduce the damage caused by pathogens to animals, improve the quality of animals' lives, and reduce economic losses. In the present study, we showed that inactivated E. faecium and inactivated PRV when co-injected intravenously significantly reduced the mortality of mice after inoculation with PRV. The inactivated E. faecium + inactivated PRV intravenous injection group induced more production of Th cells and Tc cells. Additionally, the inactivated E. faecium + inactivated PRV intravenous injection group showed higher concentrations of cytokines (IFN-γ and IL-10) and induced higher antibody production. Thus, the co-injection of inactivated E. faecium and inactivated PRV could remarkably prevent and control the lethality of PRV infection in mice, which is a critical finding for vaccination and clinical development. [ABSTRACT FROM AUTHOR]

Lactoferrin, IGF‐1 and IgG are three well‐known bioactive proteins found in bovine colostrum. We studied the effects of these three active ingredients on the levels of eight cytokines in serum and on the cellular communication networks in vivo by oral administration, intraperitoneal injection and intravenous injection. The results suggested that bioactive ingredients, especially biomacromolecules, can induce different effects, even opposite effects, on the immune system depending on the route of administration. These effects are related to both the functions of the bioactive ingredient in vivo and to its specific receptor binding in the gastrointestinal mucosa that activates different signalling pathways. [ABSTRACT FROM AUTHOR]

Objectives Rituximab has become the cornerstone of induction treatment in ANCA-associated vasculitis (AAV). B-cell depletion may increase the risk of hypogammaglobulinemia, potentially leading to severe infections. This study aims to assess factors associated with hypogammaglobulinemia in AAV patients treated with rituximab. Methods This retrospective cohort study included AAV patients treated with rituximab induction in 14 European centres. Severe adverse events (SAEs) were defined as episodes requiring hospitalization or intravenous antibiotics, malignancies, or death. Linear and logistic regression were used to identify predictors of IgG levels and of the risk of hypogammaglobulinemia, defined as IgG ≤7 g/l at 6 months. Results The study included 227 patients. IgG levels at 6 months were lower than baseline (P  < 0.001). Patients requiring intravenous antibiotics during the first 6 months had lower IgG levels at 6 months (P  = 0.004). Age [β (95% CI): −0.23 (−0.38, −0.08) per 10 years, P  = 0.003], oral glucocorticoid dose at induction [β (95% CI): −0.37 (−0.51, −0.24) per sqrt-transformed mg prednisone, P  < 0.001] and concomitant use of intravenous glucocorticoid pulses [β (95% CI): −0.88 (−1.73, −0.02), P  = 0.044] were associated with IgG levels at 6 months. Hypogammaglobulinemia was identified in 97 (42.7%) patients. In multivariable logistic regression, factors associated with the risk of hypogammaglobulinemia were age [OR (95% CI): 1.46 (1.15, 1.86) per 10 years, P  = 0.002] and oral glucocorticoid dose at induction [OR (95% CI): 1.52 (1.23, 1.89) per 10 mg prednisone, P  < 0.001]. Conclusions In AAV patients treated with rituximab, hypogammaglobulinemia at 6 months after induction is common, and lower IgG levels are associated with serious infections. The risk of hypogammaglobulinemia in these patients increases with age and higher glucocorticoid doses. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a neuromuscular ailment that affects people in their later years and causes both motor and non‐motor deficits. Receptor‐interacting protein‐1 (RIP‐1) is a critical participant in necroptotic cell death, possibly through an oxidant–antioxidant imbalance and cytokine cascade activation in PD pathogenesis. The present study examined the role of RIP‐1‐mediated necroptosis and neuroinflammation in the MPTP‐induced PD mouse model, as well as their protection by Necrostatin‐1s (an RIP signalling inhibitor), antioxidant DHA and their functional interaction. BALB/c mice were given acute MPTP therapy (4 injections of 15 mg/kg i.p. at 2‐h intervals) on day 1. After MPTP intoxication, Necrostatin‐1s (Nec‐1s; 8 mg/kg/day, i.p.) and DHA (300 mg/kg/day, p.o.) treatments were given once daily for 7 days. The Nec‐1s treatment prevented MPTP‐induced behavioural, biochemical and neurochemical alterations, and the addition of DHA increases Nec‐1s' neuroprotective impact. In addition, Nec‐1s and DHA significantly improve the survival of TH‐positive dopaminergic neurons and lower expression levels of the inflammatory cytokines, IL‐1β and TNF‐α. Furthermore, Nec‐1s dramatically reduced RIP‐1 expression, whereas DHA had little effect. Our research raises the possibility that neuroinflammatory signalling and acute MPTP‐induced necroptosis are both mediated by TNFR1‐driven RIP‐1 activity. In this study, RIP‐1 ablation through Nec‐1s and the addition of DHA showed a reduction in the levels of pro‐inflammatory and oxidative markers, as well as protection from MPTP‐driven dopaminergic degeneration and neurobehavioural changes, suggesting potential therapeutic applications. For a better understanding, additional research about the mechanism(s) behind Nec‐1s and DHA is required. [ABSTRACT FROM AUTHOR]

Background- Subarachnoid block is a preferred mode of anesthesia for various lower abdominal, pelvic and lower limb orthopedic surgeries owing to its multiple advantages. However, it is not devoid of complications like hypotension and bradycardia. These hemodynamic complications result in significant morbidity and mortality. One of the ways to overcome hypotension is use of vasopressors, out of which Ephedrine is most commonly used vasopressor over the years. Dilemma exists on the better mode of administration. In this observational study, we compared the effectiveness of 30 mg prophylactic intramuscular ephedrine given 15 minutes before giving subarachnoid block with 6 mg intermittent intravenous doses given for treating subarachnoid block induced hypotension and side effects associated with both during routine surgeries performed under subarachnoid block. Results- Hemodynamic monitoring was done vital parameters (NIBP, PR, Spo2) were corelated with amount and duration of Injection Ephedrine administration. There was significant rise in Blood pressure and pulse rate after 15 minutes in patients who received prophylactic 30 mg Injection Ephedrine intramuscularly. Although, after giving subarachnoid block, both groups experienced a fall in average blood pressures, maximum fall being at 3 minutes and 5 minutes after administration, the fall was significantly higher in patients who did not receive the prophylactic bolus dose. These patients were supplemented with intravenous 6 mg doses of Injection Ephedrine whenever mean arterial pressure dropped below 20% of baseline values. 19 patients (59.38 %) developed clinically significant hypotension at 5 minutes after giving SAB and required 6 mg injection Ephedrine administration followed by 10 patients (31.25%) at 3 minutes after SAB, 6 patients (18.75%) at 10 minutes and 20 minutes after SAB and so on. Also, 15 patients required only 1 dose (6 mg) Injection ephedrine administration, 15 patients required 2 doses (12mg), 1 patient required 3 doses(18 mg) and 1 patient required 4 doses(24 mg) injection Ephedrine over the course of surgery. Conclusion- We concluded that, in patients who were given prophylactic intramuscular 30 mg ephedrine 15 minutes before giving subarachnoid block: 1. Intramuscular prophylactic ephedrine reduces or eliminates the possibility of hypotension after subarachnoid block, thus also avoiding side effects such as nausea and vomiting. 2. Majority of patients did not have any side effects such as hypertension and tachycardia and even those who had, settled uneventfully and conservatively. 3. So, intramuscular ephedrine given to ASA grade 1 and 2 patients is advisable and can improve patient's safety and outcome. In the patients who were given 6 mg injection ephedrine intravenous whenever mean arterial pressure dropped below 20% of preoperative values after giving the subarachnoid block: 1. The intravenous dose of ephedrine successfully treats hypotension after subarachnoid block. 2. This as per need dosing method of giving intravenous ephedrine, treats hypotension by minimally required drug amount, thus avoiding extra drug and its complications. 3. Especially in ASA grade 3 and above patients and patients with known history of hypertension or cardiac diseases can be considered for intravenous dosing regimen, thus optimizing the drug doses as per the condition of the patient. [ABSTRACT FROM AUTHOR]

The extremely low bioavailability of oral paclitaxel (PTX) mainly due to the complicated gastrointestinal environment, the obstruction of intestinal mucus layer and epithelium barrier. Thus, it is of great significance to construct a coordinative delivery system which can overcome multiple intestinal physicochemical obstacles simultaneously. In this work, a high-density PEGylation-based glycocholic acid-decorated micelles (PTX@GNPs) was constructed by a novel polymer, 9-Fluorenylmethoxycarbonyl-polyethylene glycocholic acid (Fmoc-PEG-GCA). The Fmoc motif in this polymer could encapsulate PTX via π ‒ π stacking to form the core of micelles, and the low molecular weight and non-long hydrophobic chain of Fmoc ensures the high-density of PEG. Based on this versatile and flexible carriers, PTX@GNPs possess mucus trapping escape ability due to the flexible PEG, and excellent intestine epithelium targeting attributed to the high affinity of GCA with apical sodium-dependent bile acid transporter. The in vitro and in vivo results showed that this oral micelle could enhance oral bioavailability of PTX, and exhibited similar antitumor efficacy to Taxol injection via intravenous route. In addition, oral PTX@GNPs administered with lower dosage within shorter interval could increase in vivo retention time of PTX, which supposed to remodel immune microenvironment and enhance oral chemotherapy efficacy by synergistic effect. A novel high-density PEGylation-based glycocholic acid-decorated micelles was constructed, which has the advantage of synergistically enhanced mucus penetration and intestinal epithelium transport, and can achieve sequential oral delivery of paclitaxel. [Display omitted] [ABSTRACT FROM AUTHOR]

Prodrug assembled nanoparticles integrate the merits of both prodrug and nanoparticle, which significantly improve pharmacokinetic parameters, enhance tumorous accumulation and decrease adverse effects, while they are challenged by disassembly upon dilution in blood, masking the superiority of nanoparticles (NPs). Herein, a reversibly "double locked" hydroxycamptothecin (HCPT) prodrug nanoparticle decorated with cyclic RGD peptide (cRGD) is developed for safe and efficient chemotherapy of orthotopic lung cancer in mice. HCPT prodrug is constructed from acetal (ace)-linked cRGD-PEG- ace -HCPT- ace -acrylate polymer, which is self-assembled into the nanoparticles with "the first lock" of HCPT. Then the nanoparticles undergo the in situ UV-crosslinking of the acrylate residues for constructing "the second lock" of HCPT. The obtained "double locked" nanoparticles (T-DLHN) with simple and well-defined construction are demonstrated to possess extremely high stability against 100-fold dilution and acid-triggered "unlock" including de-crosslinking and liberation of the pristine HCPT. In an orthotopic lung tumor of mouse model, T-DLHN reveals a prolonged circulation time of about 5.0 h, superb lung tumor-homing capacity with tumorous drug uptake of about 7.15%ID/g, resulting in significantly boosted anti-tumor activity and reduced adverse effects. Hence, these nanoparticles utilizing "double lock" and acid-triggered "unlock" strategies represent a unique and promising nanoplatform for safe and efficient drug delivery. Prodrug assembled nanoparticles have the unique properties of the well-defined structure, systemic stability, improved pharmacokinetics, passive targeting and decreased adverse effects. However, prodrug assembled NPs would disassemble against extensive dilution in the blood circulation when intravenously injected into the body. Herein, we have designed a cRGD-directed reversibly "double-locked" HCPT prodrug nanoparticle (T-DLHN) for safe and efficient chemotherapy of orthotopic A549 human lung tumor xenografts. Upon intravenous injection, T-DLHN can overcome the shortcoming of disassembly against extensive dilution, prolong the circulation time due to the "double locked" configuration and then mediate targeted drug delivery into the tumors. After uptaken into the cells, T-DLHN undergoes concurrent de-crosslinking and liberation of HCPT under acidic condition for enhanced chemotherapeutic efficacy with negligible adverse effects. [Display omitted] [ABSTRACT FROM AUTHOR]

The construction of a novel nanocarrier that can break the redox balance in tumor cell is a promising anti‐tumor strategy. Herein, a tumor microenvironment (TME)‐responsive nanocarrier VC@Lipo is rationally designed by embedding ultrasmall VOx nanozyme and photosensitizer chlorin e6 (Ce6) into liposomes. The size of VC@Lipo nanocarrier is ≈35 nm and can be degraded in the weakly acidic environment of TME. The VOx nanozyme exhibits peroxidase‐like activity and generates highly toxic hydroxyl radical ∙OH through Fenton‐like reaction and 1O2 in the presence of H2O2 independent of light, and more 1O2 can be generated by the photodynamic effect of Ce6. In addition, the VOx nanozyme can effectively deplete intracellular overexpressed glutathione (GSH) through redox reactions. In vivo experiments demonstrate that the nanocarrier shows excellent biocompatibility, presents the largest enrichment at the tumor site after 6 h of intravenous injection into mice with the highest tumor inhibition rate of 54.18% after laser irradiation. Compared with the single treatment mode, VC@Lipo shows the best synergistic effect of chemodynamic‐photodynamic therapy. This work provides a new paradigm for nanocatalytic therapy of cancer and is expected to provide new ideas for precision medicine in cancer. [ABSTRACT FROM AUTHOR]

The visualization of bone imaging in vivo is of great significance for the understanding of some bone-related diseases or physiological processes. Herein, a bone-targeted NIR-II small molecule (TTQF-SO3), which was modified with multiple sulfonate groups, was successfully fabricated for the second near-infrared (NIR-II) bone imaging. In vitro studies revealed that TTQF-SO3 showed high affinity for hydroxyapatite and excellent macrophage accumulation ability. In in vivo assays, TTQF-SO3 displayed high bone uptake ability and high NIR-II bone imaging quality, demonstrating the specific bone-targeting ability of the sulfonate-containing probe. In addition, the noninvasive NIR-II imaging detection in bone calcium loss was successfully verified in osteoporosis mice models. Moreover, the negative charge characteristic of TTQF-SO3 showed efficient lymphoid enrichment in living mice by intravenous injection. Overall, these warrant that our TTQF-SO3 is an optimal bone-targeted diagnostic agent for high-quality NIR-II imaging, highlighting its potential promise for clinical translation. [ABSTRACT FROM AUTHOR]

Chronic intake of high amounts of fructose has been linked to the development of metabolic disorders, which has been attributed to the almost complete clearance of fructose by the liver. However, direct measurement of hepatic fructose uptake is complicated by the fact that the portal vein is difficult to access. Here we present a new, non-invasive method to measure hepatic fructose uptake and metabolism with the use of deuterium metabolic imaging (DMI) upon administration of [6,6'-²H2]fructose. Using both [6,6'-²H2]glucose and [6,6'-²H2]fructose, we determined differences in the uptake and metabolism of glucose and fructose in the mouse liver with dynamic DMI. The deuterated compounds were administered either by fast intravenous (IV) bolus injection or by slow IV infusion. Directly after IV bolus injection of [6,6'-²H2]fructose, a more than two-fold higher initial uptake and subsequent 2.5-fold faster decay of fructose was observed in the mouse liver as compared to that of glucose after bolus injection of [6,6'-²H2glucose. In contrast, after slow IV infusion of fructose, the ²H fructose/glucose signal maximum in liver spectra was lower compared to the ²H glucose signal maximum after slow infusion of glucose. With both bolus injection and slow infusion protocols, deuteriuml abeling of water was faster with fructose than with glucose. These observations are in line with a higher extraction and faster turnover of fructose in the liver, as compared with glucose. DMI with [6,6'-²H2]glucose and [6,6'-²H2]fructose could potentially contribute to a better understanding of healthy human liver metabolism and aberrations in metabolic diseases. [ABSTRACT FROM AUTHOR]

Objective: Rare disease Background: Spontaneous pancreatic and peripancreatic hemorrhage (SPH) is a rare subtype of spontaneous retroperitoneal hemorrhage. With diverse clinical manifestations and no specific presentations, early diagnosis of SPH becomes challenging. Patient-specific underlying causes and vital signs guide the SPH treatment approach. Case Reports: Case 1: A 39-year-old man reported unexplained hypogastralgia at the emergency department (ED). An abdominal MRI revealed a mixed hematoma and cystic lesions between the pancreatic head and descending duodenum, attributed to ruptured mucinous cystic neoplasms. Extensive hematoceles were identified around the liver and abdominal pelvis on an enhanced CT scan. After undergoing fasting, rehydration, proton pump inhibitor and somatostatin intravenous injections, and peritoneal puncture, his condition improved. He was discharged nine days post-admission. Case 2: A 44-year-old man arrived at the ED with back pain and right upper quadrant pain. Enhanced CT indicated peritoneal fluid and a hematoma between the pancreatic head and descending duodenum. He initially received conservative treatment. However, on the eighth day, he reported recurrent abdominal pain. Follow-up CT showed an enlarged hematoma and gastric content accumulation. The patient was fasted and put on parenteral nutrition, and by the 37th day of hospitalization, he had fully recovered and was discharged. Both patients, having stable hemodynamics, fully recovered following conservative management, with no surgical intervention required. Conclusions: Given its varied clinical presentations, SPH can easily be misdiagnosed. However, successful conservative management can lead to full recovery, as demonstrated in these case reports. [ABSTRACT FROM AUTHOR]

Simple Summary: Multiple studies have performed intravenous injections of indocyanine green (ICG) for lung cancer detection, including primary and metastatic lung cancers. However, there is no consensus regarding the optimization of the ICG injection method. We optimized the ICG injection method (2 mg/kg at 12 h before surgery) using a rabbit model of lung cancer for the first time. Additionally, ICG-based cancer identifications are limited to solid tumors, and no study has examined lung ground-glass nodules (GGNs). We investigated the feasibility of ICG-based lung cancer imaging in adenocarcinoma presenting with GGNs and a consolidation-to-tumor (C/T) ratio ≤ 50% for the first time. Overall, 51 cases of lung cancer with a C/T ratio > 50% were successfully revealed with a 95% detection rate. Therefore, this study may provide guidance regarding ICG use for lung cancer detection, especially early-stage lung cancer. ICG fluorescence imaging has been used to detect lung cancer; however, there is no consensus regarding the optimization of the indocyanine green (ICG) injection method. The aim of this study was to determine the optimal dose and timing of ICG for lung cancer detection using animal models and to evaluate the feasibility of ICG fluorescence in lung cancer patients. In a preclinical study, twenty C57BL/6 mice with footpad cancer and thirty-three rabbits with VX2 lung cancer were used. These animals received an intravenous injection of ICG at 0.5, 1, 2, or 5 mg/kg, and the cancers were detected using a fluorescent imaging system after 3, 6, 12, and 24 h. In a clinical study, fifty-one patients diagnosed with lung cancer and scheduled to undergo surgery were included. Fluorescent images of lung cancer were obtained, and the fluorescent signal was quantified. Based on a preclinical study, the optimal injection method for lung cancer detection was 2 mg/kg ICG 12 h before surgery. Among the 51 patients, ICG successfully detected 37 of 39 cases with a consolidation-to-tumor (C/T) ratio of >50% (TNR: 3.3 ± 1.2), while it failed in 12 cases with a C/T ratio ≤ 50% and 2 cases with anthracosis. ICG injection at 2 mg/kg, 12 h before surgery was optimal for lung cancer detection. Lung cancers with the C/T ratio > 50% were successfully detected using ICG with a detection rate of 95%, but not with the C/T ratio ≤ 50%. Therefore, further research is needed to develop fluorescent agents targeting lung cancer. [ABSTRACT FROM AUTHOR]

Recently, several types of systemic therapy using tyrosine kinase inhibitor (TKI) and immune checkpoint inhibitor (ICI) have been performed for advanced renal cell carcinoma (aRCC) patients; however, the optimal strategy of sequential treatment with these agents has not been well established. The objective of this study was to determine the differences of therapeutic effects according to timing for the introduction of TKI and ICI using a mouse RCC, RenCa model. The effects of combined treatment of TKI and/or ICI with axitinib, anti-mouse programmed death (PD)-1, or PD-ligand 1 (PD-L1) antibody on tumor growth and survival after subcutaneous and intravenous injection of RenCa cells, respectively, were compared according to three different treatment schedules: simultaneous administration, initial axitinib administration, and initial ICI administration. Infiltrating patterns of lymphocytes into tumors after combined treatments were evaluated by immunohistochemical staining. In mice treated with anti-PD-1 and anti-PD-L1 antibodies, significantly marked inhibitory effects on subcutaneous growth of tumors were observed in the simultaneous and initial ICI treatment groups, but not the group with the initial axitinib administration, compared to controls without treatment. Survival intervals of mice after intravenous injection of RenCa cells were significantly longer in the simultaneous and initial ICI administration, but not the initial axitinib administration, compared to the control. Furthermore, both CD8+ to CD3+ and CD8+ to CD11b+ T-lymphocyte ratios in subcutaneous RenCa tumors were significantly higher in the simultaneous and initial ICI administration, but not the initial axitinib administration, compared to the control. Favorable control against aRCC progression may be achieved by administering TKI and ICI simultaneously or ICI followed by TKI. [ABSTRACT FROM AUTHOR]

As a common tumor with high incidence, osteosarcoma possesses extremely poor prognosis and high mortality. Improving the survival of osteosarcoma patients is still a great challenge due to the precipice of advancement in treatment. In this study, a combination strategy of gene therapy and photothermal therapy (PTT) is developed for efficient treatment of osteosarcoma. Two-dimensional (2D) FePS3 nanosheets are synthesized and functionalized by poly-L-lysine-PEG-folic acid (PPF) to fabricate a multifunctional nanoplatform (FePS@PPF) for further loading microRNAs inhibitor, miR-19a inhibitor (anti-miR-19a). The photothermal conversion efficiency of FePS@PPF is up to 47.1% under irradiation by 1064 nm laser. In vitro study shows that anti-miR-19a can be efficiently internalized into osteosarcoma cells through the protection and delivery of FePS@PPF nanaocarrier, which induces up-regulation of PTEN protein and down-regulation p-AKT protein. After intravenous injection, the FePS@PPF nanoplatform specifically accumulates to tumor site of osteosarcoma-bearing mice. The in vitro and in vivo investigations reveal that the combined PTT-gene therapy displays most significant tumor ablation compared with monotherapy. More importantly, the good biodegradability promotes FePS@PPF to be cleared from body avoiding potential toxicity of long-term retention. Our work not only develops a combined strategy of NIR-II PTT and gene therapy mediated by anti-miR-19a/FePS@PPF but also provides insights into the design and applications of other nanotherapeutic platforms. [ABSTRACT FROM AUTHOR]