Bilateral Prefrontal Cortex Blood Flow Dynamics during Silent and Oral Reading Using Near-Infrared Spectroscopy.

This study aimed to investigate blood flow dynamics in the bilateral prefrontal cortex during silent and oral reading using near-infrared spectroscopy (NIRS). The subjects were 40 right-handed university students (20.5±1.8 years old, 20 men and 20 women). After completing the NIRS measurements, the subjects were asked to rate their level of proficiency in silent and oral reading, using a 5-point Likert scale. During oral reading, the left lateral prefrontal cortex (Broca's area) was significantly more active than the right side. During silent reading, prefrontal cortex activity was lower than that during oral reading, and there was no significant difference between both sides of the brain. A significant negative correlation was found between the change in oxy-hemoglobin (oxy-Hb) concentration in the left and right lateral prefrontal cortex during silent reading and silent reading speed. In addition, students with lower self-reported reading proficiency had significantly greater changes in oxy-Hb concentrations in the left and right lateral prefrontal cortex during silent/oral reading than did students with higher self-reported reading proficiency. Reading task assessment using NIRS may be useful for identifying language lateralization and Broca's area. The results demonstrate that NIRS is useful for assessing effortful reading and may be used to diagnose developmental dyslexia in children. J. Med. Invest. 71 : 92-101, February, 2024.

Amide-to-chloroalkene substitution for overcoming intramolecular acyl transfer challenges in hexapeptidic neuromedin U receptor 2 agonists.

CPN-116 is a peptidic agonist that activates human neuromedin U receptor type 2 (NMUR2) but suffers from chemical instability due to inherent backbone isomerization on the Dap residue. To address this, a Leu-Dap-type (Z)-chloroalkene dipeptide isostere was synthesized diastereoselectively as a surrogate of the Leu-Dap peptide bond to develop a (Z)-chloroalkene analogue of CPN-116. The synthesized CPN-116 analogue is stable in 1.0 M phosphate buffer (pH 7.4) without backbone isomerization and can activate NMUR2 with similar potency to CPN-116 at nM concentrations (EC50 = 1.0 nM).

Enhanced Physical Stability of L-Ascorbic Acid in an Ionic Liquid.

Ionic liquid (IL) technology was used to enhance the stability of L-ascorbic acid (AA). Pyridoxine was selected as the counter cation for anionic AA in IL. After AA was dissolved in water at 40 °C, its ratio decreased to 3.2% after 7 d. In contrast, the IL formulation showed negligible degradation, with almost no loss of AA even after 28 d. These results suggest that the use of IL enhances the stability of AA.

Relationship between respiratory muscle strength and dynamic balance in older persons requiring care or support: Focusing on the maximal single step length test and maximal double step length test as dynamic balance indices.

BACKGROUND: Falls are a major health problem. The relationship between dynamic balance related to falls and respiratory muscle strength related to sarcopenia and frailty is poorly understood. RESEARCH QUESTION: How do dynamic balance measures, such as maximal single step length test (MSL) and maximal double step length test (MDST), and respiratory muscle strength measures, such as maximal inspiratory (PImax) and maximal expiratory (PEmax), related to the requirement for long-term care or support in older people who live in the community? METHODS: This was a cross-sectional study of 39 older people (17 men, 22 women) aged ≥ 65 years community-dwelling who were certified as requiring long-term care or support under the Japanese system. The participants' PImax, PEmax, MSL, and MDST results were recorded. The measurement data were evaluated using Pearson's correlation coefficients and multiple regression analysis. RESULTS: MDST showed a positive correlation with PImax (r = 0.430, p = 0.006) but no correlation with PEmax. MSL showed no correlation with PImax or PEmax. A positive correlation was found between MDST and MSL (r = 0.851, p < 0.001), and multiple regression analysis with MDST as the dependent variable and PImax and MST as independent variables showed significant differences for MSL (p < 0.001) and PImax (p = 0.027). SIGNIFICANCE: In older people requiring long-term care or support, MDST had a greater association with inspiratory muscle strength compared with MSL. These results suggest the importance of inspiratory muscle strength training and MDST assessment in the prevention of falls in older people requiring long-term care or support.

Design of Ionic Liquid Formulations with Azone-Mimic Structures for Enhanced Drug Skin Permeation.

Although laurocapram (Azone) significantly enhances the skin permeation of drugs, its development was hindered by its skin irritation. We then developed an Azone-mimic ionic liquid (IL-Azone), composed of less irritating cationic ε-caprolactam and anionic myristic acid. IL-Azone dissociates to the original cation and anion in the presence of water in the formulation. We tried to select a formulation suitable for IL-Azone in the present study. Each formulation contained 5 % of either Azone or IL-Azone along with the model drug antipyrine, and skin permeation experiments of the drug were conducted. The results revealed that IL-Azone did not enhance skin permeation when combined with most formulations tested. However, a notable and rapid enhancement in skin permeation was observed when combined with white petrolatum. This effect could be attributed to the minimal water content in white petrolatum, which prevented IL-Azone degradation. Furthermore, its permeation-enhancing effects from IL-Azone in white petrolatum were more pronounced and rapid than Azone. The rapid onset observed with IL-Azone can be attributed to its degradation into its original components at the interface between the stratum corneum and the living epidermis, which results in a shorter lag time before achieving a steady-state concentration in the SC compared to Azone.

Transvenous Radiofrequency Catheter Ablation for an Aldosterone-Producing Tumor of the Left Adrenal Gland: A First in Human Case Report.

PURPOSE: To describe a novel technique of transvenous radiofrequency catheter ablation of an aldosterone-producing adenoma (APA) of the left adrenal gland using the GOS System (Japan Lifeline, Tokyo, Japan). Using the GOS system, a flexible radiofrequency tip catheter can be inserted into the adrenal central and tributary veins, the drainers for functional tumors. MATERIALS AND METHODS: An APA at the left adrenal gland, which was diagnosed by segmental adrenal venous sampling following administration of 0.25 mg cosyntropin, was ablated using the GOS catheter inserted into adrenal tributary veins via a right femoral vein 7-Fr sheath. The effect of radiofrequency ablation on APA was assessed using the international consensus on surgical outcomes for unilateral primary aldosteronism (PA). RESULTS: No device-related complications were observed. The patient was deeply sedated under blood pressure and heart rate control with continuous administration of ß-blockers. Then, the tumor and surrounding adrenal gland were cauterized at 7000 J two times each in sequence. The output time was 7-11 min for each ablation and 80 min in total. For blood pressure and pulse rate control, esmolol hydrochloride and phentolamine mesylate were used. The contrast enhancement of APA disappeared on dynamic CT immediately after the procedure. PA was biochemically cured until 12 months after the procedure. CONCLUSION: Using the radiofrequency device with the GOS catheter and system is a method for cauterizing adrenal tumors from blood vessels. This approach resulted in a marked reduction in aldosterone concentrations and a complete biochemical cure of PA over the observation period.

Comparison of the effect of respiratory muscle strength on dynamic and static balance assessment between sarcopenia and non-sarcopenia groups.

[Purpose] We compared differences in the association between respiratory muscle strength and static and dynamic balance in sarcopenia and non-sarcopenia groups, for fall risk assessment. [Participants and Methods] The study included 37 participants aged ≥65 years, who were certified to receive long-term care. Inspiratory and expiratory muscle strength, hand grip strength, Timed Up and Go Test scores, and one-leg standing task scores were recorded. Pearson's correlation coefficients and multiple regression analysis were used for data analysis. [Results] Only the expiratory muscle and hand grip strength were correlated in the sarcopenia group. Expiratory and inspiratory muscle strength was correlated with both one-leg standing task scores and hand grip strength, and inspiratory muscle strength was correlated with the Timed Up and Go Test scores in the non-sarcopenia group. Multiple regression analysis revealed that expiratory muscle strength was an explanatory variable for the one-leg standing task and inspiratory muscle strength for the Timed Up and Go Test in the non-sarcopenia group. [Conclusion] Combined evaluation of expiratory muscle strength and the Timed Up and Go Test scores may be useful to assess the fall risk.

The roles and competencies of welfare commissioners supporting children with developmental disorders and their families expected by Japan's public health nurses.

Background: Public Health Nurses (PHNs) collaborate with community volunteer welfare commissioners to support children with developmental disorders and their families lead a life without isolation. Objective: This study aims to clarify the roles and competencies that PHNs expect of welfare commissioners in supporting children with developmental disorders and their families. Methods: An online survey was administered through Survey Monkey© to 220 PHNs working in Japanese municipalities using an independently developed questionnaire regarding the roles and competencies of welfare commissioners supporting children with developmental disorders and their families expected by PHNs. Exploratory Factor Analysis (EFA) was performed to simplify the data structure and enhance understanding. The reliability of the scale was confirmed using Cronbach's α. Differences due to PHN attributes (e.g., experience collaborating with welfare commissioners) were analyzed using Welch's t-test. This study was conducted between April and September 2021. Results: The highest scoring items were, for the role, "a welfare commissioner's role is to pass on accurate information to their successor," and for competencies, "a necessary competency for a welfare commissioner is to protect the information about children with developmental disorders, and their families learned during one's work." The EFA results revealed a two-factor structure for role items: Factor 1, "Supporting children with developmental disorders and their families and preventing abuse," and Factor 2, "Connecting to social resources." Competency items were also found to have a two-factor structure: Factor 1, "Understanding the position of children with developmental disorders and their families and connecting with local residents," and Factor 2, "Understanding developmental disorders and supporting them based on assessment." A comparison of the attributes of PHNs showed no significant differences. Conclusion: PHNs feel welfare commissioners should pass on the information and protect confidentiality when supporting children with developmental disorders and their families. Furthermore, PHNs expect welfare commissioners to connect children with developmental disorders and their families to the community, prevent abuse, and provide support based on assessment. PHNs had the same expectations regarding the roles and competencies of welfare commissioners regardless of their own attributes.

Design of an Ante-enhancer with an Azone-Mimic Structure using Ionic Liquid.

PURPOSE: Laurocapram (Azone) was broadly examined as a representative enhancer of skin penetration in the 1980s. However, it was not approved for treatment because it caused skin irritation following its penetration into the epidermis through the stratum corneum. In the present study, a so-called ante-enhancer with an Azone-mimic structure was designed based on an ante-drug with negligible systemic toxic effects following its permeation through the skin. METHODS: The ante-enhancer was designed using ionic liquid technology: an ionic liquid-type ante-enhancer (IL-Azone) with an Azone-mimic structure was prepared from ε-caprolactam and myristic acid as cationic and anionic substances, respectively. The enhancing effects of IL-Azone on the permeation by the following model drugs through pig skin were examined: isosorbide 5-mononitrate (ISMN), antipyrine (ANP), and fluorescein isothiocyanate dextran (FD-4). Skin irritation by IL-Azone was assessed using the Draize method. RESULTS: The primary irritation index (P.I.I.) of IL-Azone by the Draize method was markedly lower than that of Azone (6.9). Although the ability of IL-Azone to enhance skin penetration was not as high as Azone, IL-Azone moderately increased skin permeation by the model compounds tested (ISMN: 4.7 fold, ANP: 4.5 fold, FD-4: 4.0 fold). CONCLUSIONS: These results suggest the usefulness of designing a skin penetration enhancer using ionic liquid technology. Further trials on the ionic liquid design with an Azone-mimic structure using other cations and anions may lead to the development of better ante-enhancers.

Remote-controllable dosage management through a wearable iontophoretic patch utilizing a cell phone.

With regard to medical treatment through operations, remote control is possible, however, the area of remote-controllable drug treatment is yet to be established. In this study, a prototyped remote-controllable dosage management system that allows patients and caregivers to administer therapeutic drugs via an internet line without touching the dosage device or formulation was developed. This system consists of a transmitter (System A) located away from the patient, and a dosage device (System B) equipped with a receiver (B1), dosage management unit (B2), and a drug treatment unit (B3) that can be installed on the patient. Additionally, Bluetooth® is adopted to communicate from System A to System B. In the present study, System A was incorporated into a cell phone, and System B was a constant-current iontophoresis (IP) device, which was applied on excised pig skin. Sodium salt of betamethasone phosphate (BP-Na+) was selected as a model drug, and the in vitro skin permeation of BP- was evaluated. As a result, by transmitting the administration information incorporated in System A through B1 to B2, the optimal current was passed between the IP electrodes in B3, and the skin permeation of BP- was obtained by remote control. That is, the skin permeation of BP- was obtained by the current flowing from the IP device. The permeation amount decreased when the voltage load was stopped. These results suggested that remote control from System A enables dosing management of bioactive substances from dosage devices applied on the skin, intracutaneously, or subcutaneously without being near the patient. Although various trials are still required to complete the remote-controlled system, the patient does not have to go to the hospital except to take injections. Such drug administrations would lead to decreased medical expenses and increased quality of life for patients.

Mechanochemical subcellular-element model of crawling cells.

Constructing physical models of living cells and tissues is an extremely challenging task because of the high complexities of both intra- and intercellular processes. In addition, the force that a single cell generates vanishes in total due to the law of action and reaction. The typical mechanics of cell crawling involve periodic changes in the cell shape and in the adhesion characteristics of the cell to the substrate. However, the basic physical mechanisms by which a single cell coordinates these processes cooperatively to achieve autonomous migration are not yet well understood. To obtain a clearer grasp of how the intracellular force is converted to directional motion, we develop a basic mechanochemical model of a crawling cell based on subcellular elements with the focus on the dependence of the protrusion and contraction as well as the adhesion and de-adhesion processes on intracellular biochemical signals. By introducing reaction-diffusion equations that reproduce traveling waves of local chemical concentrations, we clarify that the chemical dependence of the cell-substrate adhesion dynamics determines the crawling direction and distance with one chemical wave. Finally, we also perform multipole analysis of the traction force to compare it with the experimental results. Our present work sheds light on how intracellular chemical reactions are converted to a directional cell migration under the force-free condition. Although the detailed mechanisms of actual cells are far more complicated than our simple model, we believe that this mechanochemical model is a good prototype for more realistic models.

Chitosan-coated PLGA nanoparticles for transcutaneous immunization: Skin distribution in lysozyme-sensitized mice.

The effect of transcutaneous immunization was studied using a combined system of poly(DL-lactide-co-glycolide) (PLGA) nanoparticles and iontophoresis (IP). Both hen egg-white lysozyme (HEL)-loaded PLGA nanoparticles coated with chitosan hydroxypropyltrimonium chloride and their fluorescent nanoparticles were prepared using an antisolvent diffusion method. Their mean volume diameters were 87.6 ± 38.9 nm and 84.9 ± 27.6 nm, respectively. It was suggested from the results of the ex vivo skin accumulation study using fluorescent nanoparticles that the HEL released from the nanoparticles to the skin surface was efficiently delivered to antigen-presenting cells. HEL-specific IgG1 and IgG2a titers were determined in an in vivo percutaneous immunoreactivity study using lysozyme-sensitized mice. As results, the group using nanoparticles and IP showed 1.33 times higher HEL-specific IgG1 titer than a sham treatment group. The HEL-specific IgG2a titer was 1.36 times higher in the nanoparticles and IP group than in the HEL solution and IP group. It was suggested from the quantification results of total IgE in serum that the combined use of PLGA nanoparticles and IP reduced the total IgE concentration. The level of cytokines may have decreased due to Th1 cell activation and relative suppression of Th2 cells. The cytokine level is presumed to be reduced by activation of Th1 cells and relative suppression of Th2 cells. The histamine amount in plasma and rectal temperature after the induction of anaphylactic shock using lysozyme-sensitized mice were also studied, which indicates that the combined use of PLGA nanoparticles and IP may provide the same therapeutic effect as an injection.

Effects of Physicochemical Properties of Constituent Ions of Ionic Liquid on Its Permeation through a Silicone Membrane.

Ionic liquids (ILs), defined as liquid salts composed of anions and cations, have the advantage of allowing constituent ions to be stably absorbed through biological membranes, such as skin. However, limited information is currently available on the effects of the physicochemical properties of constituent ions on the membrane permeation of ILs. Therefore, we herein investigated the effects of the polarity of constituent cations on the membrane permeation of each constituent ion from IL. Various ILs were prepared by selecting lidocaine (LID) as a cation and a series of p-alkylbenzoic acids with different n-octanol/water partition coefficients (Ko/w) as anions. These ILs were applied to a skin model, a silicone membrane, and membrane permeability was investigated. The membrane permeabilities of p-alkylbenzoic acids from their single aqueous suspensions were also measured for comparison. The membrane permeability of p-alkylbenzoic acid from the aqueous suspension increased at higher Ko/w. However, the membrane permeability of ILs was similar regardless of the Ko/w of the constituent p-alkylbenzoic acid. Furthermore, the membrane permeability of the counterion LID remained unchanged regardless of the constituent p-alkylbenzoic acid. These results suggest that even when the Ko/w of IL constituents markedly differs, the resulting IL does not affect membrane permeability.

Transvenous Radiofrequency Ablation of Adrenal Gland: Experimental Study.

PURPOSE: The aim was to evaluate a flexible device for transvenous adrenal gland radiofrequency ablation in vitro and in an in vivo animal model. MATERIALS AND METHODS: A flexible radiofrequency-tip catheter with an inner-cooling mechanism and a guidewire lumen was made. Then, using a polyvinyl alcohol gel model, the ablation diameter was evaluated and how much energy to deliver in vivo was determined. Finally, transvenous radiofrequency ablation of the left adrenal glands of two pigs was performed, delivering 5000 or 7000 J in a single dose to each. The ablation effects were also assessed by histological examination of hematoxylin-eosin-stained sections. RESULTS: The mean ablation diameters in the gel model were 20.2 and 21.9 mm in the short axis and 15 and 20 mm in the long axis for 5000 or 7000 J, respectively. The device was inserted into porcine left adrenal vein with no complications. The mean ablation diameters were 10 mm in the shorter axis (whole thickness of porcine left adrenal gland) in the porcine model for 7000 J. Transient increases in blood pressure and heart rate occurred during ablation. Histologically, the adrenal gland showed severe necrosis at ablated area. There was venous congestion upstream in a non-ablated area, and thermal damage to surrounding organs was not observed. CONCLUSIONS: A flexible radiofrequency-tip catheter could be inserted successfully into the left adrenal vein. The left adrenal gland was entirely ablated without any thermal damage to surrounding organs. We suggest transvenous adrenal ablation has potential as a therapeutic option for primary aldosteronism.

Magnetic Field-Responsive Pulsatile Drug Release Using A Magnetic Fluid.

Ferrofluids are colloidal liquids with fine magnetic particles. They change shape and fluidity depending on the magnitude and direction of the external magnetic field. The magnetic field-responsive pulsatile release of a model drug, lidocaine hydrochloride (LID·HCl), was determined using a depot-type injection containing white petrolatum and/or hydrophilic cream with a magnetic fluid in various proportions. Drug release was confirmed using a self-made diffusion cell and the application of a moving magnet at the bottom of the preparation. Magnetic field-responsive LID release was observed only when using the white petrolatum preparation and depended on the concentration of the magnetic fluid. Magnetic field responsiveness was not observed in the preparation with only the hydrophilic cream. A greater magnetic field-responsive release was observed with a combination of white petrolatum and hydrophilic cream than with white petrolatum alone. These results may lead to the development of an injectable formulation that enables pulsatile administration of macromolecular drugs.

Brain abnormalities in children with attention-deficit/hyperactivity disorder assessed by multi-delay arterial spin labeling perfusion and voxel-based morphometry.

PURPOSE: To obtain an understanding of the correlation between hemodynamic differences and morphological changes as well as potential sex differences in children with ADHD using multi-delay pseudo-continuous arterial spin labeling (pCASL) imaging and voxel-based morphometry (VBM), especially given that previous findings are limited for girls. MATERIALS AND METHODS: We recruited 23 children with ADHD (mean age, 8.3 years; 19 boys; 4 girls) and 24 children without ADHD (mean age, 9.1 years; 13 boys; 11 girls) as controls. All participants underwent 3D multi-delay pCASL and T1-weighted imaging. The voxel-based statistical parameter mapping (SPM) method was used for group-wise comparisons. RESULTS: Compared with controls, children with ADHD exhibited decreased regional cerebral blood flow (rCBF) and gray matter volume (GMV) in the left middle frontal gyrus and left postcentral gyrus. Analysis by sex revealed reduced rCBF and GMV in the left lingual gyrus and left inferior occipital gyrus in boys with ADHD versus controls and increased rCBF and GMV in the left superior frontal gyrus in girls with ADHD. CONCLUSION: Although our results are preliminary because of small sample sizes, several brain regions exhibit changes in both cerebral perfusion and GMV in the same direction in patients with ADHD, with boys with ADHD showing decreased activity and girls with ADHD displaying increased activity in the fronto-parietal cortices.

Use of Silicone Membrane Permeation to Assess Thermodynamic Activities of Ionic Liquids and Their Component Cation and Anion.

Ionic liquid (IL) was prepared by mixing lidocaine and ibuprofen as a cation and anion, respectively, at various ratios. We determined the permeation of both compounds from the IL through a silicone membrane selected as a model biological membrane, and mathematically analyzed the permeation data from the viewpoint of the thermodynamic activities of lidocaine, ibuprofen, and the IL. As a result, IL and ibuprofen diffusely permeated through the membrane in the case of applying IL preparations with a molar fraction of ibuprofen of 0.5 or higher. The IL was thought to separate into lidocaine and ibuprofen in the receiver. On the other hand, when applying IL preparations with a molar fraction of lidocaine of 0.5 or higher, IL and lidocaine permeated. The permeation rate of IL itself was maximized when the applied IL was prepared using equimolar amounts of lidocaine and ibuprofen, and it decreased when the fraction of lidocaine or ibuprofen increased by more than 0.5. Their membrane permeation rates increased with an increase in their activity, and no more increase was found when the drugs were saturated in the IL. These membrane permeation profiles reflected well the mathematically calculated ones according to the concept of activity.

Usefulness of Near-Infrared Spectroscopy (NIRS) for evaluating drug effects and improvements in medication adherence in children with Attention Deficit Hyperactivity Disorder (ADHD).

The symptoms of attention deficit hyperactivity disorder (ADHD) are inattention, hyperactivity, and impulsiveness. Physicians often prescribe methylphenidate (MPH) for children with ADHD for long periods of time. The purpose of the present study was to investigate the usefulness of near-infrared spectroscopy (NIRS) for evaluating drug effects and improvements in medication adherence in children with ADHD. Subjects were 10 male children diagnosed with ADHD : average age, 9.3 years, and 10 boys with typical development : average age 9.5 years. Children with intellectual disability, autism, and obvious depressive symptoms were excluded. The present study revealed that in the ADHD group, oxy-Hb concentrations in the left and right lateral prefrontal cortex significantly increased during the execution of the Stroop color-word test in both channels when taking MPH. This method was considered to be useful for assessing drug effects on ADHD because NIRS is an objective indicator for evaluating ADHD executive dysfunction and visualizes the activation of frontal lobe function by MPH. A pediatric neurologist explained the results of NIRS while presenting images to the ADHD group, and medication adherence and the drug-taking ratio both markedly improved. Therefore, this therapeutic explanation is an effective strategy for improving medication compliance and adherence among patients. J. Med. Invest. 68 : 53--58, February, 2021.

Comparison of physiological functions between neuromedin U-related peptide and neuromedin S-related peptide in the rat central nervous system.

Two novel peptides, neuromedin U precursor-related peptide (NURP) and neuromedin S precursor-related peptide (NSRP), are produced from neuromedin U (NMU) and neuromedin S (NMS) precursors, respectively, as these precursors have multiple consensus sequences for proteolytic processing. Our group has shown previously that one of these two novel peptides, NURP, stimulates body temperature and locomotor activity, but not food intake. However, the physiological function of the other peptide, NSRP, has remained unclear. Therefore, the aim of this study was to characterize differences in the regions of the rat brain targeted by the NMU/NMS peptide family, including NURP and NSRP, and their physiological functions. First, we explored the regions of c-Fos expression after intracerebroventricular (i.c.v.) injection of NURP and NSRP and found that these were fewer than after i.c.v. injection of NMU and NMS in the hypothalamus, possibly because NURP and NSRP cannot activate NMU/NMS receptors. In the ventral subiculum, which is one region of the hippocampus, c-Fos expression was evident only after i.c.v. injection of NURP. We also examined the effects of NSRP on food intake, body temperature and locomotor activity. Like NURP, NSRP increased both body temperature and locomotor activity, but not food intake, indicating that NSRP is also a functional peptide. However, these effects of NSRP were distinctly weaker than those of NURP. These findings suggest differences in the affinity of NURP and/or NSRP for specific receptors, or in their respective biological activities.