Comparison of the Pharmacokinetics of Gadolinium-Based and Iron Oxide-Based Contrast Agents inside the Lymphatic Structure using Magnetic Resonance Lymphangiography.

PURPOSE: Gadolinium (Gd)-based contrast agents are primarily used for contrast-enhanced magnetic resonance lymphangiography (MRL). However, overcoming venous contamination issues remains challenging. This study aims to assess the MRL efficacy of the newly developed iron-based contrast agent (INV-001) that is specially designed to mitigate venous contamination issues. The study further explores the optimal dosage, including both injection volume and concentration, required to achieve successful visualization of the popliteal lymph nodes and surrounding lymphatic vessels. PROCEDURES: All animals utilized in this study were male Sprague-Dawley (SD) rats weighing between 250 and 300 g. The contrast agents prepared were injected intradermally in the fourth phalanx of both hind limbs using a 30-gauge syringe in SD rats. MRL was performed every 16 min on a coronal 3D time-of-flight sequence with saturation bands using a 9.4-T animal machine. RESULTS: Contrary to Gd-DOTA, which exhibited venous contamination in most animals irrespective of injection dosages and conditions, INV-001 showed no venous contamination. For Gd-DOTA, the popliteal lymph nodes and lymphatic vessels reached peak enhancement 16 min after injection from the injection site and then rapidly washed out. However, with INV-001, they reached peak enhancement between 16 and 32 min after injection, with prolonged visualization of the popliteal lymph node and lymphatic vessels. INV-001 at 0.45 µmol (15 mM, 30 µL) and 0.75 µmol (15 mM, 50 µL) achieved high scores for qualitative image analysis, providing good visualization of the popliteal lymph nodes and lymphatic vessels without issues of venous contamination, interstitial space enhancement, or lymph node enlargement. CONCLUSION: In MRL, INV-001, a novel T1 contrast agent based on iron, enables prolonged enhancement of popliteal lymph nodes and lymphatic vessels without venous contamination.

Ultrasmall Mn-doped iron oxide nanoparticles with dual hepatobiliary and renal clearances for T1 MR liver imaging.

Although magnetic nanoparticles demonstrate significant potential as magnetic resonance imaging (MRI) contrast agents, their negative contrasts, liver accumulation, and limited excretion hinder their application. Herein, we developed ultrasmall Mn-doped iron oxide nanoparticles (UMIOs) with distinct advantages as T1 MRI contrast agents. Exceptionally small particle sizes (ca. 2 nm) and magnetization values (5 emu gMn+Fe-1) of UMIOs provided optimal T1 contrast effects with an ideally low r2/r1 value of ∼1. Furthermore, the use of Mn as a dopant facilitated hepatocyte uptake of the particles, allowing liver imaging. In animal studies, UMIOs exhibited significantly enhanced contrasts for sequential T1 imaging of blood vessels and the liver, distinguishing them from conventional magnetic nanoparticles. UMIOs were systematically cleared via dual hepatobiliary and renal excretion pathways, highlighting their safety profile. These characteristics imply substantial potential of UMIOs as T1 contrast agents for the accurate diagnosis of liver diseases.

G-CSF-induced hematopoietic stem cell mobilization from the embryonic hematopoietic niche does not require neutrophils and macrophages.

Hematopoietic stem cell transplantation requires the collection of hematopoietic cells from patients or stem cell donors. Granulocyte colony-stimulating factor (G-CSF) is widely used in the clinic to mobilize hematopoietic stem and progenitor cells (HSPCs) from the adult bone marrow niche into circulation, allowing a collection of HSPCs from the blood. The mechanism by which G-CSF acts to mobilize HSPCs is unclear, with some studies showing a direct stimulation of stem cells and others suggesting that myeloid cells are required. In this study, we developed a heat-inducible G-CSF transgenic zebrafish line to study HSPC mobilization in vivo. Live imaging of HSPCs after G-CSF induction revealed an increase in circulating HSPCs, demonstrating a successful HSPC mobilization. These mobilized HSPCs went on to prematurely colonize the kidney marrow, the adult zebrafish hematopoietic niche. We eliminated neutrophils or macrophages using a nitroreductase-based cell ablation system and found that G-CSF still mobilizes HSPCs from the niche. Our findings indicate that neutrophils and macrophages are not required for G-CSF-induced HSPC mobilization from the embryonic hematopoietic niche.

The Effect of Boron (B) and Copper (Cu) on the Microstructure and Graphite Morphology of Spheroidal Graphite Cast Iron.

This study examines the impacts of copper and boron in parts per million (ppm) on the microstructure and mechanical properties of spheroidal graphite cast iron (SCI). Boron's inclusion increases the ferrite content whereas copper augments the stability of pearlite. The interaction between the two significantly influences the ferrite content. Differential scanning calorimetry (DSC) analysis indicates that boron alters the enthalpy change of the α + Fe3C → γ conversion and the α → γ conversion. Scanning electron microscope (SEM) analysis confirms the locations of copper and boron. Mechanical property assessments using a universal testing machine show that the inclusion of boron and copper decreases the tensile strength and yield strength of SCI, but simultaneously enhances elongation. Additionally, in SCI production, the utilization of copper-bearing scrap and trace amounts of boron-containing scrap metal, especially in the casting of ferritic nodular cast iron, offers potential for resource recycling. This highlights the importance of resource conservation and recycling in advancing sustainable manufacturing practices. These findings provide critical insights into the effects of boron and copper on SCI's behavior, contributing to the design and development of high-performance SCI materials.

Transcription factor induction of vascular blood stem cell niches in vivo.

The hematopoietic niche is a supportive microenvironment composed of distinct cell types, including specialized vascular endothelial cells that directly interact with hematopoietic stem and progenitor cells (HSPCs). The molecular factors that specify niche endothelial cells and orchestrate HSPC homeostasis remain largely unknown. Using multi-dimensional gene expression and chromatin accessibility analyses in zebrafish, we define a conserved gene expression signature and cis-regulatory landscape that are unique to sinusoidal endothelial cells in the HSPC niche. Using enhancer mutagenesis and transcription factor overexpression, we elucidate a transcriptional code that involves members of the Ets, Sox, and nuclear hormone receptor families and is sufficient to induce ectopic niche endothelial cells that associate with mesenchymal stromal cells and support the recruitment, maintenance, and division of HSPCs in vivo. These studies set forth an approach for generating synthetic HSPC niches, in vitro or in vivo, and for effective therapies to modulate the endogenous niche.

Repair of severed recurrent thenar branch of median nerve after open carpal tunnel release.

An anatomical understanding of median nerve variation is essential for successful decompression of carpal tunnel syndrome (CTS). Although iatrogenic injury of the thenar branch after carpal tunnel release (CTR) has not been reported in many cases, it can cause serious damage to the patient. In case of rapidly progressing thenar atrophy after CTS surgery, thenar branch of median nerve injury should be suspected. Nerve conduction examination and ultrasound before surgery can be a useful tool for diagnosis.

Quality assurance of hematopoietic stem cells by macrophages determines stem cell clonality.

Tissue-specific stem cells persist for a lifetime and can differentiate to maintain homeostasis or transform to initiate cancer. Despite their importance, there are no described quality assurance mechanisms for newly formed stem cells. We observed intimate and specific interactions between macrophages and nascent blood stem cells in zebrafish embryos. Macrophage interactions frequently led to either removal of cytoplasmic material and stem cell division or complete engulfment and stem cell death. Stressed stem cells were marked by surface Calreticulin, which stimulated macrophage interactions. Using cellular barcoding, we found that Calreticulin knock-down or embryonic macrophage depletion reduced the number of stem cell clones that established adult hematopoiesis. Our work supports a model in which embryonic macrophages determine hematopoietic clonality by monitoring stem cell quality.

The Effects of Switching from Sevoflurane to Short-Term Desflurane prior to the End of General Anesthesia on Patient Emergence and Recovery: A Randomized Controlled Trial.

While sevoflurane and desflurane have been regarded as inhalation agents providing rapid induction and emergence, previous studies demonstrated the superiority of desflurane-anesthesia compared to sevoflurane-anesthesia in the postoperative recovery in obese and geriatric patients. We investigated whether a short-term switch of sevoflurane to desflurane at the end of sevoflurane-anesthesia enhances patient postoperative recovery profile in non-obese patients. We randomly divide patients undergoing elective surgery (n = 60) into two groups: sevoflurane-anesthesia group (Group-S, n = 30) and sevoflurane-desflurane group (Group-SD, n = 30). In Group-S, patients received only sevoflurane-anesthesia until the end of surgery (for >2 hours). In Group-SD, sevoflurane was stopped and switched to desflurane-anesthesia before the completion of sevoflurane-anesthesia (for approximately 30 minutes). We assessed the intergroup differences in the times to get eye-opening, extubation, and a bispectral index of 80 (BIS-80). Group-SD showed significantly shorter times to get eye-opening (438 ± 101 vs. 295 ± 45 s; mean difference, 143 s; 95% confidence interval [CI], 101-183; p < 0.001), extubation (476 ± 108 vs. 312 ± 42 s; mean difference, 164 s; 95% CI, 116-220; p < 0.001), and BIS-80 (378 ± 124 vs. 265 ± 49 minutes; mean difference, 113 s; 95% CI, 58-168 p < 0.001) compared to Group-S. There was no between-group difference in postoperative nausea, vomiting, and hypoxia incidences. Our results suggested that the short-term (approximately 30 minutes) switch of sevoflurane to desflurane at the end of sevoflurane-anesthesia can facilitate the speed of postoperative patient recovery.

Comparison of bolus administration effects of lidocaine on preventing tourniquet-induced hypertension in patients undergoing general anesthesia: a randomized controlled trial.

BACKGROUND: This study assessed the effect of a single bolus administration of lidocaine on the prevention of tourniquet-induced hypertension (TIH) and compared the effect of lidocaine to that of ketamine in patients undergoing general anesthesia. METHODS: This randomized, controlled, double-blind study included 75 patients who underwent lower limb surgery using a tourniquet. The patients were administered lidocaine (1.5 mg/kg, n = 25), ketamine (0.2 mg/kg, n = 25) or placebo (n = 25). The study drugs were administered intravenously 10 min before tourniquet inflation. Systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR) were measured before tourniquet inflation, after tourniquet inflation for 60 min at 10 min intervals, and immediately after tourniquet deflation. The incidence of TIH, defined as an increase of 30% or more in SBP or DBP during tourniquet inflation, was also recorded. RESULTS: SBP, DBP, and HR increased significantly over time in the control group compared to those in the lidocaine and ketamine groups for 60 min after tourniquet inflation (P < 0.001, P < 0.001, and P = 0.007, respectively). The incidence of TIH was significantly lower in the lidocaine (n = 4, 16%) and ketamine (n = 3, 12%) group than in the control group (n = 14, 56%) (P = 0.001). CONCLUSION: Single-bolus lidocaine effectively attenuated blood pressure increase due to tourniquet inflation, with an effect comparable to that of bolus ketamine.

Pseudo single domain NiZn-γFe2O3colloidal superparamagnetic nanoparticles for MRI-guided hyperthermia application.

Magnetic resonance imaging (MRI)-guided magnetic nanofluid hyperthermia (MNFH) is highly desirable in cancer treatment because it can allow for diagnosis, therapeutics, and prognosis simultaneously. However, the application of currently developed iron-oxide based superparamagnetic nanoparticles (IOSPNPs) for an MRI-guided MNFH agent is technically limited by the low AC heat induction power at the physiologically tolerable range of AC magnetic field (HAC,safe), and the low transverser2-relaxivity responsible for the insufficient heating of cancers, and the low resolution of contrast imaging, respectively. Here, pseudo single domain colloidal NixZn1-x-γFe2O3(x = 0.6) superparamagnetic nanoparticle (NiZn-γFe2O3PSD-SPNP) physically and theoretically designed at theHAC,safe, specifically by the applied frequency, is proposed for a highly enhanced MRI-guided MNFH agent application. The NiZn-γFe2O3PSD-SPNP showed the superparamagnetic characteristics, significantly enhanced AC heat induction performance (ILP = 6.3 nHm2kg-1), highly improved saturation magnetization (Ms= 97 emu g-1Fe, 3.55 × 105A m-1) andr2-relaxivity (r2 = 396 mM-1s-1) that are desirable for highly efficient MRI-guided MNFH agent applications. According to the analyzed results, the remarkably enhanced effective relaxation time constant and its dependent out-of-phase magnetic susceptibility, as well as the DC/AC magnetic softness optimized by the PSD-SPNP at theHAC,safewere revealed as the main physical reason for the significance. All the fundamentalin vitroandin vivoexperimental results demonstrated that the physically designed NiZn-γFe2O3PSD-SPNP is bio-technically feasible for a highly efficient MRI-guided MNFH agent for future cancer nanomedicine.

Pseudo-single domain colloidal superparamagnetic nanoparticles designed at a physiologically tolerable AC magnetic field for clinically safe hyperthermia.

Magnetic nanofluid hyperthermia (MNFH) with pure superparamagnetic nanoparticles (P-SPNPs) has drawn a huge attraction for cancer treatment modality. However, the low intrinsic loss power (ILP) and attributable degraded-biocompatibility resulting from the use of a heavy dose of P-SPNP agents as well as low heat induction efficiency in biologically safe AC magnetic field (HAC,safe) are challenging for clinical applications. Here, we report an innovatively designed pseudo-single domain-SPNP (PSD-SPNP), which has the same translational advantages as that of conventional P-SPNPs but generates significantly enhanced ILP at HAC,safe. According to the analyzed results, the optimized effective relaxation time, τeff, and magnetic out-of-phase susceptibility, χ'', precisely determined by the particle size at the specific frequency of HAC,safe are the main reasons for the significantly enhanced ILP. Additionally, in vivo MNFH studies with colloidal PSD-SPNPs strongly demonstrated that it can be a promising agent for clinically safe MNFH application with high efficacy.

Reliable evaluation method of heating power of magnetic nanofluids to directly predict the tumor temperature during hyperthermia.

Reliable measurement of heating power of magnetic nanofluids (MNs) to accurately predict the AC heat-induction performance in tumors is highly desirable for clinical magnetic nanofluids hyperthermia (MNFH) application because it can save time for screening the performance of newly developed MNFH agent and minimize the over-use of animals dramatically. Here, a bio-mimicking phantom model, called Pseudo-Tumor Environment System (P-TES), biochemically designed by considering the external and internal critical factors related to the complex biological environments is proposed to provide a highly reliable evaluation method of heating performance of MNs for in-vivo MNFH applications. According to the experimentally analyzed results, the heating power of MNs measured using the P-TES is well accorded with the heating temperature measured in the tumors during in-vivo MNFH. This result strongly demonstrates that the proposed P-TES can be recommended as a standardized measurement method of heating performance of MNs for clinical MNFH application.

Concentration-dependent oscillation of specific loss power in magnetic nanofluid hyperthermia.

Magnetic dipole coupling between the colloidal superparamagnetic nanoparticles (SPNPs) depending on the concentration has been paid significant attention due to its critical role in characterizing the Specific Loss Power (SLP) in magnetic nanofluid hyperthermia (MNFH). However, despite immense efforts, the physical mechanism of concentration-dependent SLP change behavior is still poorly understood and some contradictory results have been recently reported. Here, we first report that the SLP of SPNP MNFH agent shows strong concentration-dependent oscillation behavior. According to the experimentally and theoretically analyzed results, the energy competition among the magnetic dipole interaction energy, magnetic potential energy, and exchange energy, was revealed as the main physical reason for the oscillation behavior. Empirically demonstrated new finding and physically established model on the concentration-dependent SLP oscillation behavior is expected to provide biomedically crucial information in determining the critical dose of an agent for clinically safe and highly efficient MNFH in cancer clinics.

Down-regulation of diesel particulate matter-induced airway inflammation by the PDZ motif peptide of ZO-1.

Although diesel airborne particulate matter (PM2.5) has been known to play a role in many human diseases, there is no direct evidence that therapeutic drugs or proteins can diminish PM2.5-induced diseases. Nevertheless, studies examining the negative control mechanisms of PM2.5-induced diseases are critical to develop novel therapeutic medications. In this study, the consensus PDZ peptide of ZO-1 inhibited PM2.5-induced inflammatory cell infiltration, pro-inflammatory cytokine gene expression, and TEER in bronchoalveolar lavage (BAL) fluid and AM cells. Our data indicated that the PDZ domain in ZO-1 is critical for regulation of the PM2.5-induced inflammatory microenvironment. Therefore, the PDZ peptide may be a potential therapeutic candidate during PM-induced respiratory diseases.

Magnetic Control of Axon Navigation in Reprogrammed Neurons.

While neural cell transplantation represents a promising therapy for neurodegenerative diseases, the formation of functional networks of transplanted cells with host neurons constitutes one of the challenging steps. Here, we introduce a magnetic guidance methodology that controls neurite growth signaling via magnetic nanoparticles (MNPs) conjugated with antibodies targeting the deleted in colorectal cancer (DCC) receptor (DCC-MNPs). Activation of the DCC receptors by clusterization and subsequent axonal growth of the induced neuronal (iN) cells was performed in a spatially controlled manner. In addition to the directionality of the magnetically controlled axon projection, axonal growth of the iN cells assisted the formation of functional connections with pre-existing primary neurons. Our results suggest magnetic guidance as a strategy for improving neuronal connectivity by spatially guiding the axonal projections of transplanted neural cells for synaptic interactions with the host tissue.

The correlation of heart rate between natural sleep and dexmedetomidine sedation.

BACKGROUND: Sedation by dexmedetomidine, like natural sleep, often causes bradycardia. We explored the nature of heart rate (HR) changes as they occur during natural sleep versus those occurring during dexmedetomidine sedation. METHODS: The present study included 30 patients who were scheduled to undergo elective surgery with spinal anesthesia. To assess HR and sedation, a pulse oximeter and bispectral index (BIS) monitor were attached to the patient in the ward and the operating room. After measuring HR and BIS at baseline, as the patients slept and once their BIS was below 70, HR and BIS were measured at 5-minute intervals during sleep. Baseline HR and BIS were also recorded before spinal anesthesia measured at 5-minute intervals after dexmedetomidine injection. RESULTS: During natural sleep, HR changes ranged from 2 to 19 beats/min (13.4 ± 4.4 beats/min), while in dexmedetomidine sedation, HR ranged from 9 to 40 beats/min (25.4 ± 8.5 beats/min). Decrease in HR was significantly correlated between natural sleep and dexmedetomidine sedation (R2 = 0.41, P < 0.001). The lowest HR was reached in 66 min during natural sleep (59 beats/min) and in 13 min with dexmedetomidine sedation (55 beats/min). The time to reach minimum HR was significantly different (P < 0.001), but there was no difference in the lowest HR obtained (P = 0.09). CONCLUSIONS: There was a correlation between the change in HR during natural sleep and dexmedetomidine sedation. The bradycardia that occurs when using dexmedetomidine may be a normal physiologic change, that can be monitored rather than corrected.

Design of Magnetically Labeled Cells (Mag-Cells) for in Vivo Control of Stem Cell Migration and Differentiation.

Cell-based therapies are attractive for treating various degenerative disorders and cancer but delivering functional cells to the region of interest in vivo remains difficult. The problem is exacerbated in dense biological matrices such as solid tissues because these environments impose significant steric hindrances for cell movement. Here, we show that neural stem cells transfected with zinc-doped ferrite magnetic nanoparticles (ZnMNPs) can be pulled by an external magnet to migrate to the desired location in the brain. These magnetically labeled cells (Mag-Cells) can migrate because ZnMNPs generate sufficiently strong mechanical forces to overcome steric hindrances in the brain tissues. Once at the site of lesion, Mag-Cells show enhanced neuronal differentiation and greater secretion of neurotrophic factors than unlabeled control stem cells. Our study shows that ZnMNPs activate zinc-mediated Wnt signaling to facilitate neuronal differentiation. When implemented in a rodent brain stroke model, Mag-Cells led to significant recovery of locomotor performance in the impaired limbs of the animals. Our findings provide a simple magnetic method for controlling migration of stem cells with high therapeutic functions, offering a valuable tool for other cell-based therapies.

Autophagy Is Pro-Senescence When Seen in Close-Up, but Anti-Senescence in Long-Shot.

When mammalian cells and animals face a variety of internal or external stresses, they need to make homeostatic changes so as to cope with various stresses. To this end, mammalian cells are equipped with two critical stress responses, autophagy and cellular senescence. Autophagy and cellular senescence share a number of stimuli including telomere shortening, DNA damage, oncogenic stress and oxidative stress, suggesting their intimate relationship. Autophagy is originally thought to suppress cellular senescence by removing damaged macromolecules or organelles, yet recent studies also indicated that autophagy promotes cellular senescence by facilitating the synthesis of senescence-associated secretory proteins. These seemingly opposite roles of autophagy may reflect a complex picture of autophagic regulation on cellular senescence, including different types of autophagy or a unique spatiotemporal activation of autophagy. Thus, a better understanding of autophagy process will lead us to not only elucidate the conundrum how autophagy plays dual roles in the regulation of cellular senescence but also helps the development of new therapeutic strategies for many human diseases associated with cellular senescence. We address the pro-senescence and anti-senescence roles of autophagy while focusing on the potential mechanistic aspects of this complex relationship between autophagy and cellular senescence.

Airborne particulate matter increases MUC5AC expression by downregulating Claudin-1 expression in human airway cells.

CLB2.0, a constituent of PM, induces secretion of multiple cytokines and chemokines that regulate airway inflammation. Specifically, IL-6 upregulates CLB2.0-induced MUC5AC and MUC1 expression. Interestingly, of the tight junction proteins examined, claudin-1 expression was inhibited by CLB2.0. While the overexpression of claudin-1 decreased CLB2.0-induced MUC5AC expression, it increased the expression of the anti-inflammatory mucin, MUC1. CLB2.0-induced IL-6 secretion was mediated by ROS. The ROS scavenger N-acetylcysteine inhibited CLB2.0-induced IL-6 secretion, thereby decreasing the CLB2.0-induced MUC5AC expression, whereas CLB2.0-induced MUC1 expression increased. CLB2.0 activated the ERK1/2 MAPK via a ROS-dependent pathway. ERK1/2 downregulated the claudin-1 and MUC1 expressions, whereas it dramatically increased CLB2.0-induced MUC5AC expression. These findings suggest that CLB2.0-induced ERK1/2 activation acts as a switch for regulating inflammatory conditions though a ROS-dependent pathway. Our data also suggest that secreted IL-6 regulates CLB2.0-induced MUC5AC and MUC1 expression via ROS-mediated downregulation of claudin-1 expression to maintain mucus homeostasis in the airway. [BMB Reports 2017; 50(10): 516-521].

Single-cell mechanogenetics using monovalent magnetoplasmonic nanoparticles.

Spatiotemporal interrogation of signal transduction at the single-cell level is necessary to answer a host of important biological questions. This protocol describes a nanotechnology-based single-cell and single-molecule perturbation tool, termed mechanogenetics, that enables precise spatial and mechanical control over genetically encoded cell-surface receptors in live cells. The key components of this tool are a magnetoplasmonic nanoparticle (MPN) actuator that delivers defined spatial and mechanical cues to receptors through target-specific one-to-one engagement and a micromagnetic tweezers (µMT) that remotely controls the magnitude of force exerted on a single MPN. In our approach, a SNAP-tagged cell-surface receptor of interest is conjugated with a single-stranded DNA oligonucleotide, which hybridizes to its complementary oligonucleotide on the MPN. This protocol consists of four major stages: (i) chemical synthesis of MPNs, (ii) conjugation with DNA and purification of monovalent MPNs, (iii) modular targeting of MPNs to cell-surface receptors, and (iv) control of spatial and mechanical properties of targeted mechanosensitive receptors in live cells by adjusting the µMT-to-MPN distance. Using benzylguanine (BG)-functionalized MPNs and model cell lines expressing either SNAP-tagged Notch or vascular endothelial cadherin (VE-cadherin), we provide stepwise instructions for mechanogenetic control of receptor clustering and for mechanical receptor activation. The ability of this method to differentially control spatial and mechanical inputs to targeted receptors makes it particularly useful for interrogating the differential contributions of each individual cue to cell signaling. The entire procedure takes up to 1 week.