Development of a novel AAK1 inhibitor via Kinobeads-based screening.

A chemical proteomics approach using Ca2+/calmodulin-dependent protein kinase kinase (CaMKK) inhibitor-immobilized sepharose (TIM-063-Kinobeads) identified main targets such as CaMKKα/1 and ß/2, and potential off-target kinases, including AP2-associated protein kinase 1 (AAK1), as TIM-063 interactants. Because TIM-063 interacted with the AAK1 catalytic domain and inhibited its enzymatic activity moderately (IC50 = 8.51 µM), we attempted to identify potential AAK1 inhibitors from TIM-063-derivatives and found a novel AAK1 inhibitor, TIM-098a (11-amino-2-hydroxy-7H-benzo[de]benzo[4,5]imidazo[2,1-a]isoquinolin-7-one) which is more potent (IC50 = 0.24 µM) than TIM-063 without any inhibitory activity against CaMKK isoforms and a relative AAK1-selectivity among the Numb-associated kinases family. TIM-098a could inhibit AAK1 activity in transfected cultured cells (IC50 = 0.87 µM), indicating cell-membrane permeability of the compound. Overexpression of AAK1 in HeLa cells significantly reduced the number of early endosomes, which was blocked by treatment with 10 µM TIM-098a. These results indicate TIM-063-Kinobeads-based chemical proteomics is efficient for identifying off-target kinases and re-evaluating the kinase inhibitor (TIM-063), leading to the successful development of a novel inhibitory compound (TIM-098a) for AAK1, which could be a molecular probe for AAK1. TIM-098a may be a promising lead compound for a more potent, selective and therapeutically useful AAK1 inhibitor.

Activation of Transient Receptor Potential Vanilloid 1 Is Involved in Both Pain and Tumor Growth in a Mouse Model of Cancer Pain.

Activation of calcitonin gene-related peptide (CGRP)-positive sensory neurons in the tumor microenvironment has been shown to be involved in tumor growth. However, how CGRP-positive sensory neurons are activated requires elucidation. In this study, we focused on transient receptor potential vanilloid 1 (TRPV1) and examined the contribution of TRPV1 to tumor growth and cancer pain in a mouse cancer model in which Lewis lung carcinoma was subcutaneously inoculated in the left plantar region. Tumor inoculation gradually increased the volumes of the hind paws of wild type (WT) mice over time, but those of both αCGRP knockout mice and TRPV1 knockout mice were significantly smaller than those of WT mice after tumor inoculation. Both TRPV1 and CGRP are therefore suggested to be involved in tumor growth. In an immunohistochemical study, the percentage of phosphorylated cyclic adenosine monophosphate response element-binding protein (p-CREB)-positive profiles in CGRP-positive dorsal root ganglion (DRG) neurons in WT mice was significantly increased after tumor inoculation. The percentage of p-CREB-positive profiles in CGRP-positive DRG neurons in TRPV1 knockout mice was also increased after tumor inoculation, but was significantly lower than that in WT mice, indicating the contribution of TRPV1 to activation of CGRP-positive DRG neurons. Cancer pain in TRPV1 knockout mice was significantly lower than that in WT mice. In conclusion, TRPV1 is involved in both tumor growth and cancer pain, potentially leading to a novel strategy for the treatment of cancer pain and cancer development. Cancer pain is also suggested to facilitate tumor growth.

Ibudilast Reduces IL-6 Levels and Ameliorates Symptoms in Lipopolysaccharide-Induced Sepsis Mice.

In Japan, ibudilast (IBD) is a therapeutic agent used to treat asthma, allergic conjunctivitis, and dizziness caused by cerebrovascular disease. Previously, we have reported that IBD could reduce the secretion of proinflammatory cytokines, including interleukin (IL)-6 and tumor necrosis factor (TNF)-α, in lipopolysaccharide (LPS)-treated RAW264.7 monocyte-linage cells in vitro. In the present study, we examined the anti-inflammatory effects of IBD in vivo. As IL-6 is a biomarker for sepsis and has been suggested to exacerbate symptoms, we determined whether IBD reduces IL-6 levels in vivo and improves sepsis symptoms in animal models. We observed that IBD treatment reduced IL-6 levels in the lungs of LPS-treated mice and improved LPS-induced hypothermia, one of the symptoms of sepsis. In addition, IBD reduced IL-6 and attenuated plasminogen activator inhibitor-1 (PAI-1) and alanine aminotransferase (ALT) levels in the serum of LPS-treated mice. Elevated PAI-1 levels exacerbate sepsis-induced disseminated intravascular coagulation (DIC), and ALT is a biomarker for liver dysfunction. IBD improved the survival of mice administered a lethal dose of LPS. IBD administration ameliorated kidney pathology of model mice. Overall, these results suggest that IBD exerts anti-inflammatory functions in vivo and could be a drug candidate for treating endotoxemia, including sepsis.

Prevalence of urinary retention after vaginal delivery: a systematic review and meta- analysis.

INTRODUCTION AND HYPOTHESIS: Postpartum urinary retention requires timely detection and intervention as late detection can lead to long-term voiding dysfunction; however, trends in the prevalence of urinary retention during the postpartum period remain unclear. This systematic review and meta-analysis aimed to estimate the pooled overall prevalence of overt and covert urinary retention in women after vaginal delivery and the difference in prevalence within 4 days after delivery. METHODS: MEDLINE, CINAHL, Ichu-shi web, and J-stage databases were searched up until October 2020. Two researchers screened and included observational studies reporting the prevalence of urinary retention up to 4 days postpartum based on inclusion criteria. The overall prevalence of overt and covert urinary retention was calculated. RESULTS: From 24 studies, the overall overt and covert urinary retention prevalence rates were estimated to be 1% and 13%, respectively. The prevalence of overt urinary retention over time was 2% at 6 h postpartum, 1% at 6-12 h, and 3% from postpartum to 24 h postpartum. The prevalence of covert urinary retention over time was 19% (6 h postpartum), 15% (24 h postpartum), 11% (1 day postpartum), 7% (2 days postpartum), 8% (3 days postpartum), and 0.1% (4 days postpartum). CONCLUSIONS: By postpartum day 4 after vaginal delivery, 14% of women were found to have experienced urinary retention. The highest prevalence was observed at 6 h postpartum, suggesting that urinary retention could be identified at 6 h postpartum.

Relationship between low back pain and stress urinary incontinence at 3 months postpartum.

Previous studies have proposed that pelvic misalignment may be associated with stress urinary incontinence through a decrease in the contractile function of the pelvic floor muscles; however, this relationship remains unclear. This study aimed to clarify the relationship between low back pain, an indication of pelvic misalignment, and stress urinary incontinence at 3 months postpartum. We conducted a cross-sectional study of women who gave birth to full-term babies between July 2008 and July 2009. Stress urinary incontinence was defined as urinary leakage when coughing, sneezing, or exercising. Low back pain was defined as pain between the ribs and gluteal sulcus in the preceding 2 months. Of the 228 subjects included in the study, the prevalence of stress urinary incontinence was 22.8% (n = 52). The prevalence of low back pain in the stress urinary incontinence group was significantly higher than that in the non-stress urinary incontinence group (78.8% [n = 41] vs. 57.4% [n = 101]; p = 0.005). Stress urinary incontinence was associated with older age, primiparity, vaginal delivery, and low back pain at 3 months. In conclusion, low back pain was associated with stress urinary incontinence after adjusting for pregnancy and delivery factors, suggesting pelvic misalignment contributes to the development of stress urinary incontinence. We propose that including care for pelvic misalignment in pelvic floor muscle training, the treatment of choice for stress urinary incontinence, could be beneficial.

Prevention of trigeminocardiac reflex-induced severe bradycardia during cerebral aneurysm clipping surgery by topical anesthesia of the dura surface and atropine administration: a case report.

BACKGROUND: Trigeminocardiac reflex (TCR) by stimulation of the sensory branch of the trigeminal nerve induces transient bradycardia and hypotension. We report a case in which light mechanical stimulation to the dura mater during brain surgery induced severe bradycardia. CASE PRESENTATION: A 77-year-old woman with bradycardia-tachycardia syndrome was scheduled for clipping of an unruptured left middle cerebral artery aneurysm. General anesthesia was performed with propofol, remifentanil, and rocuronium. Before starting surgery, the function of the pyramidal tract was examined by motor evoked potential. Transcranial electric stimulation for motor evoked potential induced atrial fibrillation and tachycardia. Continuous administration of landiolol was started and verapamil was used for tachycardia. During detachment of the dura mater from the bone, an electrocardiogram suddenly showed sinus arrest for 6 s. Immediately after the manipulation was interrupted, a junctional rhythm appeared. However, light touch to the dura mater induced severe bradycardia again, and atropine was therefore administered. In addition, the dura surface was anesthetized with topical lidocaine infiltration. After that, light touch-induced bradycardia was prevented. CONCLUSIONS: We experienced a case of severe bradycardia during surgery due to TCR caused by light mechanical stimulation to the dura mater. Topical anesthesia of the dura surface and atropine administration were effective for preventing TCR-induced bradycardia.

Dietary supplementation with monosodium glutamate with dietary balance such as protein, salt and sugar intake with increasing T1R3 taste receptor gene expression in healthy females.

We previously showed that chemotherapy-induced dysgeusia was associated with lingual taste receptor gene expression, and monosodium glutamate (MSG) improved dysgeusia by upregulating taste 1 receptor 3(T1R3) gene expression. In recent years, decreased taste sensitivity has also been reported in some young people, and these are partly due to their disordered eating habits. From these background, we investigated the effects of MSG supplementation on taste receptor expression and dietary intake in healthy females. Fifteen young healthy volunteers were enrolled for the present crossover study and divided in two groups (dietary supplementation with MSG at 2.7 g / day or 0.27 g / day). The relative expression of T1R3, a subunit of both umami and sweet taste receptors, in the tongue was assessed by quantitative PCR analysis. Food intake was assessed by food frequency questionnaire (FFQg), and body composition was measured using Omron HBF-701. T1R3 expression levels in the tongue and taste sensitivity increased significantly in participants who consumed <10 g of MSG daily, whereas no alteration was observed in participants who consumed >10 g of MSG daily. Furthermore, protein, fat, and carbohydrate (PFC) balance and salt and sugar intake improved by MSG supplementation. In conclusion, MSG supplementation increased T1R3 expression in the tongue and improved dietary balance. J. Med. Invest. 68 : 315-320, August, 2021.

Changes in Japanese Pharmacists' Recognition of Their Role in Community Public Health before and after the Spread of COVID-19.

BACKGROUND: In our previous study regarding infection prevention after COVID-19, many Japanese citizen respondents had not received education/training on infection prevention. However, a total of 47.7% (n = 143) of these respondents wanted to receive education from healthcare professionals regarding the methods and effects of infection prevention. Therefore, changes in recognition of the roles of Japanese pharmacists before and after COVID-19 were investigated. METHODS: We conducted a survey to determine whether recognition of Japanese pharmacists' roles, especially their role in public health in the community, changed after COVID-19. RESULTS: A total of 93.9% (n = 307) of the pharmacist respondents showed an increased awareness of infection prevention. Before COVID-19, the hospital pharmacists (67.2%; n = 80) were more aware of infection prevention than were pharmacy pharmacists (51.7%; n = 74) and drugstore pharmacists (47.7%; n = 31). The number of pharmacists who felt that the role of pharmacists in the community had changed after the pandemic increased, but the numbers of community pharmacy pharmacists (51.8%; n = 74) and drugstore pharmacists (55.4%; n = 36) were found to be slightly higher than those of hospital pharmacists (47.9%; n = 57). CONCLUSIONS: In a society in which swift responses and changes are required, for individuals to work as medical personnel their ability to respond while always being aware of the needs of society is required now more than ever.

Factors associated with quality of dreams during general anesthesia: a prospective observational study.

Patients frequently report having dreams during general anesthesia, and the dreams are often reported to be pleasant dreams. However, factors associated with the quality of dreams during general anesthesia have not been clarified. The aim of this study was to determine the relationships between the quality of dreams during general anesthesia and perioperative factors. This prospective observational study included patients scheduled for elective surgery under general anesthesia. Preoperative mental status was assessed by the Hospital Anxiety and Depression Scale (HADS). A postoperative interview was carried out in the operating room after recovery from general anesthesia. Dreams and awareness during general anesthesia were assessed by a modified Brice interview. The quality of dreams was classified in accordance with the patient's own opinion as pleasant, indifferent, or unpleasant. A total of 1100 patients were included in the study, and 293 (25.4%) of the patients reported having dreams during anesthesia. Half of the patients who experienced dreams during anesthesia (50.2%, 147/293 patients) reported having a pleasant dream. Multivariate logistic regression analysis revealed that only HADS-depression score of less than 11 was related to pleasant dreams (OR: 3.3 [95% CI 1.3-10.0]).

Microalgae cultivation using undiluted anaerobic digestate by introducing aerobic nitrification-desulfurization treatment.

A novel coupling process using an aerobic bacterial reactor with nitrification and sulfur-oxidization functions followed by a microalgal reactor was proposed for simultaneous biogas desulfurization and anaerobic digestion effluent (ADE) treatment. ADE nitrified by bacteria has a potential to be directly used as a culture medium for microalgae because ammonium nitrogen, including inhibitory free ammonia (NH3), has been converted to harmless NO3 -. To demonstrate this hypothesis, Chlorella sorokiniana NIES-2173, which has ordinary NH3 tolerance; that is, 1.6 mM of EC50 compared with other species, was cultivated using untreated/treated ADE. Compared with the use of a synthetic medium, when using ADE with 1-10-fold dilutions, the specific growth rate and growth yield maximally decreased by 44% and 88%, respectively. In contrast, the algal growth using undiluted ADE treated by nitrification-desulfurization was almost the same as with using synthetic medium. It was also revealed that 50% of PO4 3- and most metal concentrations of ADE decreased following nitrification-desulfurization treatment. Moreover, upon NaOH addition for pH adjustment, the salinity increased to 0.66%. The decrease in metals mitigates the bioconcentration of toxic heavy metals from wastewater in microalgal biomass. Meanwhile, salt stress in microalgae and limiting nutrient supplementation, particularly for continuous cultivation, should be of concern.

Validation of noninvasive continuous arterial pressure measurement by ClearSight System™ during induction of anesthesia for cardiovascular surgery.

BACKGROUND: Since blood pressure tends to be unstable during induction of anesthesia in patients undergoing cardiovascular surgery, an artery catheter is often inserted before induction to continuously monitor arterial pressure during induction of anesthesia. ClearSight System™ enables noninvasive continuous measurement of beat-to-beat arterial pressure via a single finger cuff without pain using photoplethysmographic technology. If ClearSight System™ can replace intra-arterial pressure measurement, blood pressure could be easily and noninvasively assessed. However, the validity of ClearSight System™ during induction of anesthesia in patients undergoing cardiovascular surgery has not been evaluated. The aim of this study was to compare blood pressure measured by ClearSight System™ with intra-arterial pressure during induction of anesthesia for cardiovascular surgery. METHODS: This study was registered retrospectively. Data during induction of anesthesia for elective cardiovascular surgery were obtained for patients in whom noninvasive arterial pressure was measured by ClearSight System™ (APcs) and invasive radial arterial pressure (APrad) was measured simultaneously. According to the widely used criteria formulated by international standards from the Association for the Advancement of Medical Instrumentation, the acceptable bias and precision for arterial pressure measurements were fixed at < 5 mmHg and 8 mmHg, respectively. RESULTS: Data for 18 patients were analyzed. For 3068 analyzed paired measurements, values of APcs vs APrad bias (precision) were 13.2 (17.5), - 9.1 (7.3) and - 3.9 (7.8) mmHg for systolic, diastolic, and mean arterial pressures, respectively. CONCLUSIONS: Mean arterial pressure measured by ClearSight System™ could be considered as an alternative for mean radial arterial pressure during induction of anesthesia for elective cardiovascular surgery.

Solving the Thermoelectric Trade-Off Problem with Metallic Carbon Nanotubes.

Semiconductors are generally considered far superior to metals as thermoelectric materials because of their much larger Seebeck coefficients (S). However, a maximum value of S in a semiconductor is normally accompanied by a minuscule electrical conductivity (σ), and hence, the thermoelectric power factor (P = S2σ) remains small. An attempt to increase σ by increasing the Fermi energy (EF), on the other hand, decreases S. This trade-off between S and σ is a well-known dilemma in developing high-performance thermoelectric devices based on semiconductors. Here, we show that the use of metallic carbon nanotubes (CNTs) with tunable EF solves this long-standing problem, demonstrating a higher thermoelectric performance than semiconducting CNTs. We studied the EF dependence of S, σ, and P in a series of CNT films with systematically varied metallic CNT contents. In purely metallic CNT films, both S and σ monotonically increased with EF, continuously boosting P while increasing EF. Particularly, in an aligned metallic CNT film, the maximum of P was ∼5 times larger than that in the highest-purity (>99%) single-chirality semiconducting CNT film. We attribute these superior thermoelectric properties of metallic CNTs to the simultaneously enhanced S and σ of one-dimensional conduction electrons near the first van Hove singularity.

Anesthetic management of a patient with factor VII deficiency undergoing laparoscopic colectomy: a case report.

BACKGROUND: Congenital factor VII (FVII) deficiency is a rare autosomal recessive coagulation disorder that is characterized by prolongation of prothrombin time. Recombinant activated FVII (rFVIIa) is widely used in the management of bleeding in patients with congenital FVII deficiency. We experienced anesthetic management of a patient with congenital FVII deficiency who was scheduled for laparoscopic colectomy using rFVIIa. CASE PRESENTATION: We report a 67-year-old man with rectal cancer who was diagnosed with congenital FVII deficiency. He was scheduled for laparoscopic colectomy. General anesthesia was performed with propofol, remifentanil, and rocuronium without epidural anesthesia. For coagulation management, 1 mg of rFVIIa was intravenously administered before starting surgery. During surgery, FVII activity and prothrombin time-international normalized ratio (PT-INR) were maintained to be above 10 % and within the normal range (0.8-1.2), respectively. The surgery was uneventfully completed. CONCLUSIONS: We reported successful management of a patient with congenital FVII deficiency undergoing laparoscopic colectomy with monitoring of FVII activity and/or PT-INR.