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This study aimed to investigate the linguistic factors involved in stuttering among Japanese-speaking preschool children. The participants included 10 Japanese children who stutter, with a mean age of 5 years and 9 months. Speech samples comprised spontaneous conversations of the participants with their parents for about 20 minutes. We compared the percentages of the occurrence of stuttering-like disfluencies (SLDs) at the word and sentence levels, using the Wilcoxon signed-rank test. The results showed no significant differences in SLDs based on syllable structure when comparing light and heavy syllables and comparing consonants and vowels in the initial position of each content word. SLDs occurred more frequently in the initial than non-initial position of words and in longer rather than shorter words. Additionally, SLDs occurred more frequently in sentences that contained more 'bunsetsu' (a kind of linguistic unit in Japanese). Our study is the first to show that both word and sentence-level factors could contribute to SLDs in preschool children who stutter in agglutinating languages, such as Japanese. This aspect is rarely reported in psycholinguistic studies based on stuttering occurrence in inflecting languages, such as English.

BACKGROUND Kawasaki disease (KD) is an acute febrile illness with systemic vasculitides, mostly affecting infants and young children. The etiology of KD is still unclear; however, altered gut microbiota have been recently implicated as a contributing factor for the development of vasculitis. METHODS We conducted an age- and gender-matched case-control study on 50 patients and 200 control subjects to search for potential factors leading to intestinal dysbiosis associated with KD. Data were analyzed using conditional multivariable logistic regression. RESULTS Previous antibiotic administration was associated with the patients who developed KD (odds ratio [OR] 11.7, 95% confidence interval [CI] 4.7-29.1, P < 0.0001), but not other variables, including breastfeeding and group nursery. In subgroup analyses, cesarean birth was indicated as an associated factor in addition to previous antibiotic administration in infants under 12 months of age (OR: 8.0, 95% CI: 1.8-34.4, P = 0.005), but not in older children. CONCLUSIONS The association between previous antibiotic administration and the onset of KD was demonstrated. Antibiotics may contribute to the development of KD by affecting the intestinal microbiota in infants and young children.

Background Maxacalcitol was approved in Taiwan in 2018 as the first active vitamin D3 injection for secondary hyperparathyroidism (SHPT) in patients on maintenance hemodialysis. However, no data from any clinical study with maxacalcitol in Taiwanese patients is available. Objectives This analysis aimed to evaluate the profiles of parathyroid hormone (PTH) and calcium (Ca) concentrations in Taiwanese SHPT patients on hemodialysis and maxacalcitol. Methods We developed population pharmacokinetic (PK) and pharmacodynamic (PD) models using a modeling and simulation approach. The data for these analyses were obtained from two studies: a clinical pharmacology study in Japanese patients and an ethnic comparison study in healthy Japanese and -Taiwanese volunteers. We then conducted a simulation study with a PK-PD model comprising the PK and PD models developed here. Results Serum maxacalcitol concentration profile was modeled using a two-compartment model that took into consideration the distribution of concentrations below the lower limit of quantification. An ethnic difference in clearance was included in the PK model as a covariate. A PD model that used a PTH/Ca feedback loop best described the observed data. There were no significant differences in Ca or PTH concentrations between Taiwanese and Japanese based on the simulation results from our PK-PD model, even though maxacalcitol exposure was approximately 40% higher in Taiwanese than in Japanese. Conclusions On the basis of these population PK and PD analyses and the clinical study conducted in Japan, there is no clinically relevant difference between Taiwanese and Japanese in terms of serum Ca or PTH levels.

Nicotine exerts its reinforcing actions by activating nicotinic acetylcholine receptors (nAChRs), but the detailed mechanisms remain unclear. Nicotine releases 3, 4-dihydroxyphenylalanine (DOPA), a neurotransmitter candidate in the central nervous system. Here, we investigated the distribution of GPR143, a receptor of DOPA, and nAChR subunits in the nigrostriatal and mesolimbic regions. We found GPR143 mRNA-positive cells in the striatum and nucleus accumbens. Some of them were surrounded by tyrosine hydroxylase (TH)-immunoreactive fibers. There were some GPR143 mRNA-positive cells coexpressing TH, and nAChR subunit α4 or α7 in the substantia nigra and ventral tegmental area. These findings suggest that DOPA-GPR143 signaling may be involved in the nicotine action in the nigrostriatal and mesolimbic dopaminergic systems.

In mismatch repair (MMR) immunohistochemistry, four MMR proteins’ staining pattern reveals which particular gene may be defective. However, in the null phenotype, four MMR proteins are lost; consequently, it will be challenging to assume the target gene by immunohistochemistry and to determine whether deficient MMR was sporadic or germline. A 70-year-old man underwent right hemicolectomy with the diagnosis of ascending colon cancer. The postoperative histopathology revealed the diagnosis of medullary carcinoma and the loss of all four MMR expressions in immunohistochemistry. The mutation analysis using a peripheral blood sample showed no germline mutations in the four genes. This clinical case presents an unusual colon carcinoma that showed a MMR protein immunohistochemistry null phenotype. The cause of expression loss of MMR proteins can be explained by the loss of MLH1 and MSH2 functions associated with somatic loss of function mutations, functional loss in all four MMR proteins associated with somatic loss of function mutations, or Lynch-like syndrome. Correct interpretation and accumulation of relevant cases are necessary to unveil unusual cases in the era of universal screening.

Krabbe disease involves the accumulation of neurotoxic metabolites due to lysosomal galactocerebrosidase enzyme deficiency, which results in widespread demyelination of central and peripheral nerves. Generally, Krabbe disease presents as spastic paraplegia with a slow progressive course; however, some cases may show clinical symptoms similar to those of chronic inflammatory demyelinating polyneuropathy (CIDP). No previously reported studies have investigated the efficacy of intravenous immunoglobulin (IVIg) for treating Krabbe disease, and reporting a case involving IVIg treatment may be informative in the clinical setting. A 14-year-old girl who developed Guillain-Barré syndrome-like limb weakness was administered IVIg, and her limb weakness improved. At 16 years old, she developed abnormal sensory perception and weakness of both upper limbs. A nerve conduction study revealed demyelination, which led us to suspect CIDP. IVIg was administered, and her symptoms gradually improved. A nerve biopsy, enzyme activity, and genetic test results indicated adult Krabbe disease. In some cases, IVIg may be an effective treatment for Krabbe disease.

Background A comprehensive understanding of DNA adducts, one of the most plausible origins of cancer mutations, is still elusive, especially in human tissues in clinical settings. Recent technological developments have facilitated the identification of multiple DNA adducts in a single experiment. Only a few attempts toward this “DNA adductome approach” in human tissues have been reported. Geospatial information on DNA adducts in human organs has been scarce. Aim Mass spectrometry of human gastric mucosal DNA was performed to identify DNA adducts associated with environmental factors. Materials and methods From 59 subjects who had received gastrectomy for gastric cancer, 306 samples of nontumor tissues and 15 samples of tumors (14 cases) were taken for DNA adductome analysis. Gastric nontumor tissue from autopsies of 7 subjects without gastric cancer (urothelial cancer, hepatocellular carcinoma, lung cancer each; the other four cases were without any cancers) was also investigated. Briefly, DNA was extracted from each sample with antioxidants, digested into nucleosides, separated by liquid chromatography, and then electrospray-ionized. Specific DNA adducts were identified by mass/charge number and column retention time compared to standards. Information on lifestyle factors such as tobacco smoking and alcohol drinking was taken from the clinical records of each subject. Results Seven DNA adducts, including modified bases, C5-methyl-2′-deoxycytidine, 2′-deoxyinosine, C5-hydroxymethyl-2′-deoxycytidine, N6-methyl-2′-deoxyadenosine, 1,N6-etheno-2′-deoxyadenosine, N6-hydroxymethyl-2′-deoxyadenosine, and C8-oxo-2′-deoxyguanosine, were identified in the human stomach and characterized. Intraindividual differences according to the multiple sites of these adducts were noted but were less substantial than interindividual differences. N6-hydroxymethyl-2′-deoxyadenosine was identified in the human stomach for the first time. The amount of C5-hydroxymethyl-2′-deoxycytidine was higher in the stomachs of subjects without gastric cancer than in the nontumor and tumor portions of the stomach in gastric cancer patients. Higher levels of 1,N6-etheno-2′-deoxyadenosine were detected in the subjects who reported both smoking and drinking than in those without these habits. These DNA adducts showed considerable correlations with each other. Conclusions We characterized 7 DNA adducts in the nontumor portion of the human stomach in both gastric cancer subjects and nongastric cancer subjects. A reduction in C5-hydroxymethyl-dC even in the nontumor mucosa of patients with gastric cancer was observed. Smoking and drinking habits significantly influenced the quantity of one of the lipid peroxidation-derived adducts, etheno-dA. A more expansive DNA adductome profile would provide a comprehensive understanding of the origin of human cancer in the future.

This study aimed to identify factors that influence the decision to take safety regulatory actions in routine signal management based on spontaneous reports. For this purpose, we analyzed the safety signals identified from the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) and related information. From the signals that the FDA identified in the FAERS between 2008 1Q and 2014 4Q, we selected 216 signals for which regulatory action was or was not taken. Characteristics of the signals were extracted from the FAERS quarterly reports that give information about what signals were identified from the FAERS and what actions were taken for them, and the FAERS data released in the same quarter when the signal was published. Univariate and multivariable logistic regression analysis was used to assess the relationship between the characteristics of each of the signals and the decision on regulatory action. As a result of the univariate logistic regression analysis, we selected 5 factors (positive rechallenge, number of cases accumulated in the last one-year period before the signal indication, previous awareness, serious outcome, risk for special populations) to include in the multivariable logistic regression model (p

Objective To study the efficacy of phosphodiesterase-5 inhibitor tadalafil in attenuating adverse events after low-dose-rate brachytherapy for prostate cancer. Methods This was a randomized open-label trial, conducted at two institutions. Prostate cancer patients undergoing low-dose-rate brachytherapy were randomly assigned to receive tadalafil (study group) or tamsulosin (control group). The primary endpoint was International Prostate Symptom Score for subjective evaluation of lower urinary tract symptoms. Uroflowmetry, postvoid residual urine volume, and Sexual Health Inventory for Men score were the secondary endpoints. Each clinical variable was evaluated during a follow-up period of 1 year after low-dose-rate brachytherapy. Results A total of 107 patients were enrolled in this study, with a final total of 96 patients analyzed. The mean total International Prostate Symptom Score changes at 1, 3, 6, 9, and 12 months after low-dose-rate brachytherapy were +7.4, +7.1, +4.7, +1.5, and +0.8, respectively, in the tamsulosin group, and +8.5, +9.2, +6.4, +4.1, and +1.6, respectively, in the tadalafil group. There were no statistically significant differences in International Prostate Symptom Score with the exception of the score at 9-month follow-up. Moreover, there were no statistically significant differences in any of the uroflowmetry or postvoid residual urine volume findings. The Sexual Health Inventory for Men score in the tadalafil group was significantly higher than that in the tamsulosin group at 6, 9, and 12 months after low-dose-rate brachytherapy. Conclusions Tadalafil could be an effective option for the management of lower urinary tract symptoms after low-dose-rate brachytherapy.

Endurance exercise training enhances muscle fat oxidation while concomitantly reducing carbohydrate (glycogen) utilization during exercise, thereby delaying the onset of fatigue. This study examined the effects of dietary fat restriction on endurance training-induced metabolic adaptations in rat skeletal muscle. Male Sprague-Dawley rats were placed on either a control diet (CON: 19.2% protein, 21.6% fat, and 59.2% carbohydrate as a percentage of total energy) or a fat-restricted diet (FR: 21.5% protein, 2.4% fat, and 76.1% carbohydrate as a percentage of total energy) for 4 wks. Half the rats in each dietary group performed daily 6-h swimming exercise (two 3-h sessions separated by 45 min of rest) on 5 days each wk. Endurance training significantly increased the expression of β-hydroxyacyl CoA dehydrogenase (βHAD), a key enzyme of fat oxidation, and pyruvate dehydrogenase kinase 4 (PDK4), an inhibitory regulator of glycolytic flux, in the skeletal muscle of rats fed the CON diet. However, such endurance training-induced increases in muscle βHAD and PDK4 were partially suppressed by the FR diet, suggesting that a FR diet may diminish the endurance training-induced enhancement of fat oxidation and reduction in glycogen utilization during exercise. We then assessed the muscle glycogen utilization rate during an acute bout of swimming exercise in the trained rats fed either the CON or the FR diet and consequently found that rats fed the FR diet had a significantly higher muscle glycogen utilization rate during exercise compared with rats fed the CON diet. In conclusion, dietary fat restriction may attenuate the endurance training-induced metabolic adaptations in skeletal muscle.

Purpose Bioelectrical impedance analysis (BIA) has been used recently to measure the body water of patients with acute heart failure. We used BIA in this study to better understand, and possibly identify a predictive marker for, perioperative water behavior in cardiac surgery patients. Methods We measured body water and studied its behavior in 44 patients undergoing surgery for cardiac valvular disease at our hospital. Measurements included the levels of extracellular water (ECW), intracellular water (ICW), and total body water, the edema index (EI), and the ratio of ECW to total body water. The first measured EI was defined as the “preoperative EI” and the maximum as the “peak EI”. Results A negative correlation was found between the preoperative EI and the preoperative estimated glomerular filtration rate (eGFR) (R = 0.644, p R = 0.625, p R = 0.366, p R = 0.464, p = 0.026). Conclusion The EI is possibly a predictive marker for perioperative water management in cardiac surgery.

Significance Glucagon-like peptide-1 receptor agonists have become established as a leading class of diabetes medications. However, these peptide-based drugs are administered by subcutaneous injection or, in one case, by a complex oral dosing regimen. We now report the discovery of LY3502970, a potent and selective small-molecule GLP-1R agonist. LY3502970 exhibits preclinical pharmacology equivalent to a marketed injectable GLP-1R agonist and possesses pharmacokinetic properties compatible with oral dosing in humans. Cryoelectron microscopy (cryo-EM) studies reveal an ECD-driven receptor binding mode for LY3502970 that provides a favorable pharmacological profile., Glucagon-like peptide-1 receptor (GLP-1R) agonists are efficacious antidiabetic medications that work by enhancing glucose-dependent insulin secretion and improving energy balance. Currently approved GLP-1R agonists are peptide based, and it has proven difficult to obtain small-molecule activators possessing optimal pharmaceutical properties. We report the discovery and mechanism of action of LY3502970 (OWL833), a nonpeptide GLP-1R agonist. LY3502970 is a partial agonist, biased toward G protein activation over β-arrestin recruitment at the GLP-1R. The molecule is highly potent and selective against other class B G protein–coupled receptors (GPCRs) with a pharmacokinetic profile favorable for oral administration. A high-resolution structure of LY3502970 in complex with active-state GLP-1R revealed a unique binding pocket in the upper helical bundle where the compound is bound by the extracellular domain (ECD), extracellular loop 2, and transmembrane helices 1, 2, 3, and 7. This mechanism creates a distinct receptor conformation that may explain the partial agonism and biased signaling of the compound. Further, interaction between LY3502970 and the primate-specific Trp33 of the ECD informs species selective activity for the molecule. In efficacy studies, oral administration of LY3502970 resulted in glucose lowering in humanized GLP-1R transgenic mice and insulinotropic and hypophagic effects in nonhuman primates, demonstrating an effect size in both models comparable to injectable exenatide. Together, this work determined the molecular basis for the activity of an oral agent being developed for the treatment of type 2 diabetes mellitus, offering insights into the activation of class B GPCRs by nonpeptide ligands.

The origin and life-long fate of quiescent neural stem cells (NSCs) in the adult mammalian brain remain largely unknown. A few neural precursor cells in the embryonic brain elongate their cell cycle time and subsequently become quiescent postnatally, suggesting the possibility that life-long NSCs are selected at an early embryonic stage. Here, we utilized a GFP-expressing lentivirus to investigate the fate of progeny from individual lentivirus-infected NSCs by identifying the lentiviral integration site. Our data suggest that NSCs become specified to two or more lineages prior to embryonic day 13.5 in mice: one NSC lineage produces cells only for the cortex and another provides neurons to the olfactory bulb. The majority of neurosphere-forming NSCs in the adult brain are relatively dormant and generate very few cells, if any, in the olfactory bulb or cortex, and this NSC population could serve as a reservoir that is occasionally reactivated later in life.

TAS-102 improved the overall survival of metastatic colorectal cancer (CRC) patients with a median progression-free survival (PFS) in the RECOURSE trial. Subsequently, the combination of TAS-102 and bevacizumab was shown to extend the median PFS (C-TASK FORCE study). However, the study included patients who received second- and third-line treatment. Our study exclusively examined patients receiving this combination as a third-line treatment to investigate the clinical impact beyond cytotoxic doublets. This investigator-initiated, open-label, single-arm, multi-centered phase II study was conducted in Japan. Eligible CRC patients were refractory or intolerant to fluoropyrimidine, irinotecan, and oxaliplatin in first- and second-line therapy. TAS-102 (35 mg/m2) was given orally twice daily on days 1–5 and 8–12 in a 4-week cycle, and bevacizumab (5 mg/kg) was administered by intravenous infusion every 2 weeks. The primary endpoint was PFS and the secondary endpoints were time-to-treatment failure, response rate, overall survival (OS), and safety. Between June 2016 and August 2017, 32 patients were enrolled. All patients previously received bevacizumab. The median PFS was 4.5 months; the median overall survival was 9.3 months. Partial response was observed in two patients. The most common adverse events above grade 3 were neutropenia followed by thrombocytopenia. There were no non-hematological adverse events above grade 3 and no treatment-related deaths occurred. This study met its primary endpoint of PFS, which is comparable to the results of the C-TASK FORCE study. The TAS-102 and bevacizumab combination has the potential to be a therapeutic option for third-line treatment of metastatic CRC.

Lipocalins are very important proteins for stress resistance in plants. To better understand the function of tomato lipocalins, we observed responses to oxidative stress using over-expressed SlTIL1, SlTIL2, SlCHL, and silenced-plants. Significant differences in reactive oxygen species accumulation (oxidative damage) were observed in all tested plants under heat stress. Plants with over-expressed SlTIL1, SlTIL2, and SlCHL showed less oxidative damage compared with wild-type plants under heat stress. The expression of SlSODs was induced in over-expressed SlTIL1, SlTIL2, and SlCHL plants under normal and heat stress conditions. Furthermore, silenced PDS, SlTILs, and SlCHL plants showed slightly increasing oxidative damage under heat stress alongside with lower SlSODs under normal and stress conditions. These results suggest that SlTIL1, SlTIL2, and SlCHL were involved in antioxidant defense by eliminating ROS in tomato plants.

The 79 years old man was referred to our department due to high value of serum prostate specific antigen (39.54 ng/ml). The magnetic resonance imaging demonstrated diffuse low signal at his prostate. Bone scintigraphy revealed multiple metastatic lesion. Needle biopsy was performed for definite diagnosis. Systemic purpura showed after prostate needle biopsy although he had noticed local purpura at his back before the examination. He was diagnosed as disseminated intravascular coagulation (DIC) syndrome due to advanced prostate cancer. Treatment with anti-DIC therapy, blood transfusion, subcutaneous injection of degarelix acetate settled the DIC. Abiraterone hydrochloride and prednisolone was added as we confirmed Gleason score5+4 in the pathological examination. He has been alive for 15 months after diagnosis without desease progression.

Aim Ample evidence indicates that gastrin‐releasing peptide receptor (GRPR)–expressing neurons play a critical role in the transmission of acute itch. However, the pathophysiology of spinal mechanisms underlying intractable itch such as psoriasis remains unclear. In this study, we aimed to determine whether itch‐responsive GRPR+ neurons contribute to the spinal transmission of imiquimod (IMQ)‐induced psoriatic itch. Methods To generate a psoriasis model, C57BL/6J mice received a daily topical application of 5% IMQ cream on their shaved back skin for 7‐10 consecutive days. GRP+ neurons were inhibited using Cre‐dependent expression of Gi‐designer receptors exclusively activated by designer drugs (DREADDs), while GRPR+ neurons were ablated by intrathecal administration of bombesin‐saporin. Results Repeated topical application of IMQ elicited psoriasis‐like dermatitis and scratching behaviors. The mRNA expression levels of GRP and GRPR were upregulated in the cervical spinal dorsal horn (SDH) on days 7 and 10 after IMQ application. Either chemogenetic silencing of GRP+ neurons by Gi‐DREADD or ablation of GRPR+ neurons significantly attenuated IMQ‐induced scratching behaviors. Conclusion The GRP‐GRPR system might be enhanced in the SDH, and itch‐responsive GRPR+ neurons largely contribute to intractable itch in a mouse model of psoriasis., The aim of this study was to determine whether itch‐responsive gastrin‐releasing peptide receptor (GRPR)–expressing neurons contribute to the spinal transmission of imiquimod (IMQ)‐induced psoriatic itch. We found that mRNA expression of GRP and GRPR was upregulated in the cervical spinal dorsal horn after IMQ application, and IMQ‐induced psoriatic itch was suppressed by either chemogenetic inhibition of GRP+ neurons or ablation of GRPR+ neurons.

Na,K‐ATPase is a ubiquitous molecule contributing to the asymmetrical distribution of Na+ and K+ ions across the plasma membrane and maintenance of the membrane potential, a prerequisite of neuronal activity. Na,K‐ATPase comprises three subunits (α, β, and FXYD). The α subunit has four isoforms in mice, with three of them (α1, α2, and α3) expressed in the brain. However, the functional and biological significances of the different brain isoforms remain to be fully elucidated. Recent studies have revealed the association of Atp1a3, a gene encoding α3 subunit, with neurological disorders. To map the cellular distributions of the α subunit isoforms and their coexpression patterns, we evaluated the mRNA expression of Atp1a1, Atp1a2, and Atp1a3 by in situ hybridization in the mouse brain. Atp1a1 and Atp1a3 were expressed in neurons, whereas Atp1a2 was almost exclusively expressed in glial cells. Most neurons coexpressed Atp1a1 and Atp1a3, with highly heterogeneous expression levels across the brain regions and neuronal subtypes. We identified parvalbumin (PV)‐expressing GABAergic neurons in the hippocampus, somatosensory cortex, and retrosplenial cortex as an example of a neuronal subtype expressing low Atp1a1 and high Atp1a3. The expression of Atp1b isoforms was also heterogeneous across brain regions and cellular subtypes. The PV‐expressing neurons expressed a high level of Atp1b1 and a low level of Atp1b2 and Atp1b3. These findings provide basic information on the region‐ and neuronal‐subtype‐dependent expression of Na,K‐ATPase α and β subunit isoforms, as well as a rationale for the selective involvement of neurons expressing high levels of Atp1a3 in neurological disorders., Na,K‐ATPase comprises α (Atp1a), β (Atp1b), and FXYD subunits, and each subunit has isoforms. In situ hybridization for α and β subunit isoforms revealed regional‐ and neuronal‐subtype‐specific expression of the isoforms in the mouse brain. The photograph shows Atp1a1 (red) and Atp1a3 (green) expression in the hippocampal dentate gyrus (stained with DAPI, blue).

Physical disuse could lead to a state of chronic pain typified by complex regional pain syndrome type I due to fear of pain through movement (kinesiophobia) or inappropriate resting procedures. However, the mechanisms by which physical disuse is associated with acute/chronic pain and other pathological signs remain unresolved. We have previously reported that inflammatory signs, contractures, disuse muscle atrophy, spontaneous pain-like behaviors, and chronic widespread mechanical hyperalgesia based on central plasticity occurred after 2-weeks of cast immobilization in chronic post-cast pain (CPCP) rat model. In the present study, we also demonstrated dystrophy-like changes, both peripheral nociceptive signals and activation of the central pain pathway in CPCP rats. This was done by the following methods: (1) vascular permeability (Evans blue dye) and inflammatory- and oxidative stress-related messenger RNA (mRNA) changes (real-time quantitative polymerase chain reaction); (2) immunofluorescence of pERK and/or c-Fos expression in the spino-parabrachio-amygdaloid pathway; and (3) blockade of nociceptive-related signals using sciatic nerve block (SNB). Furthermore, we demonstrated tactile allodynia using an optogenetic method in a transgenic rat line (W-TChR2V4), cold allodynia using the acetone test, and activation of dorsal horn neurons in the chronic phase associated with chronic mechanical hyperalgesia using c-Fos immunofluorescence. In addition, we showed that nociceptive signals in the acute phase are involved in chronic pathological pain-like behaviors by studying the effects of SNB. Thus, we conclude that physical disuse contributes to dystrophy-like changes, spontaneous pain-like behavior, and chronic widespread pathological pain-like behaviors in CPCP rats after 2 weeks of cast immobilization.

BACKGROUND Intraoperative cardiac arrest (ICA) has a reported frequency of 1 in 10,000 anesthetics but has a much higher estimated incidence in orthotopic liver transplantation (OLT). Single-center studies of ICA in OLT are limited by small sample size that prohibits multivariable regression analysis of risks. METHODS Utilizing data from 7 academic medical centers, we performed a retrospective, observational study of 5296 adult liver transplant recipients (18-80 years old) between 2000 and 2017 to identify the rate of ICA, associated risk factors, and outcomes. RESULTS ICA occurred in 196 cases (3.7% 95% confidence interval [CI], 3.2-4.2) and mortality occurred in 62 patients (1.2%). The intraoperative mortality rate was 31.6% in patients who experienced ICA. In a multivariable generalized linear mixed model, ICA was associated with body mass index (BMI)

Endovascular therapy is developing, but not all aneurysms are completely obliterated even by using the techniques such as stent-assisted coiling or a flow diverter. To predict the aneurysm-occlusion status after stent-assisted coiling, the authors applied computational fluid dynamics (CFD) using porous media modeling to propose a new technique with the double porous media settings, one of which is a porous media setting for a coiled aneurysm and another of which is that for an intracranial stent. CFD with double porous media settings using preoperative aneurysm geometry may be useful for simulating the hemodynamic changes in intracranial aneurysms after stent-assisted coiling.

We previously demonstrated that expression of a Krüppel-like zinc finger transcription factor, GLIS1, dramatically increases under hypoxic conditions via a transcriptional mechanism induced by HIF-2α cooperating with AP-1 members. In this study, we focused on the functional roles of GLIS1 in breast cancer. To uncover its biological function, the effects of altered levels of GLIS1 in breast cancer cell lines on cellular growth, wound-healing and invasion capacities were assessed. Knockdown of GLIS1 using siRNA in BT-474 cells resulted in significant growth stimulation under normoxia, while attenuation was found in the cell invasion assay under hypoxic conditions. In MDA-MB-231 cells expressing exogenous 3xFLAG-tagged GLIS1, GLIS1 attenuated cell proliferation and enhanced cell mobility and invasion capacities under normoxia. In addition, breast cancer cells expressing GLIS1 acquired resistance to irradiation. Whole transcriptome analysis clearly demonstrated that downstream signals of GLIS1 are related to various cellular functions. Among the genes with increased expression, we focused on WNT5A. Knockdown of WNT5A indicated that enhancement of acquired cell motility in the MDA-MB-231 cells expressing GLIS1 was mediated, at least in part, by WNT5A. In an analysis of publicly available data, patients with estrogen receptor-negative breast cancer showing high levels of GLIS1 expression showed much worse prognosis than those with low levels. In summary, hypoxia-induced GLIS1 plays significant roles in breast cancer cells via regulation of gene expression related to cell migration and invasion capacities, resulting in poorer prognosis in patients with advanced breast cancer.

Background Coronary artery evaluation by virtual histological intravascular ultrasonography (VH-IVUS) late in Kawasaki disease (KD) shows intimal thickening, calcification, fatty components, and necrosis of regressed coronary artery lesions (CALs). However, it is not clear when these VH-IVUS findings start to occur. Therefore, we evaluated coronary arteries using VH-IVUS in patients with early-stage KD and tried to determine whether these atherosclerotic findings on VH-IVUS were different from that in patients with late-stage KD. Methods Eighteen patients with KD aged between 1 and 32 years who had CALs and underwent cardiac catheterization between January 1, 2008 and December 31, 2014 were included. They were divided into 2 groups—those with the disease for 10 years (group B). VH-IVUS findings were compared between the groups. The coronary arteries were divided based on coronary angiography findings into normal, regressed (dilated CALs regressed to a normal size), and aneurysmal lesions. The Wilcoxon signed-rank test was used in the statistical analysis. Results In both regressed and aneurysmal lesions, marked intimal proliferation and atherosclerotic findings (fibro-fatty and necrotic core lesions) were observed. In addition, there was no difference in the area percentage of atherosclerosis between the groups. Conclusions VH-IVUS revealed that atherosclerotic-like findings exist in CALs in patients with KD, even within a year of onset. The findings were almost the same in those with the disease for >10 years. Because there is no histological evidence of atherosclerosis in KD, these VH-IVUS findings may indicate complex histological findings of KD. Nevertheless, early interventions to help reduce the risk factors of atherosclerosis may be required in these patients.

Increasing game meat consumption in Japan requires the dissemination of safety information regarding the presence of human pathogens in game animals. Health information regarding the suitability of these animals as a meat source is not widely available. In this study, we aimed to evaluate the safety of game meat and detect potential human pathogens in wild deer (Cervus nippon) and boar (Sus scrofa) in Japan. Fecal samples from 305 wild deer and 248 boars of Yamaguchi, Kagoshima, and Tochigi prefectures collected monthly for 2 years were examined for the prevalence of Shiga toxin-producing Escherichia coli (STEC) and Campylobacter spp. STEC was isolated from 51 deer consistently throughout the year and from three boars; O-antigen genotype O146, the expression of stx2b, and eaeA absence (n=33) were the major characteristics of our STEC isolates. Other serotypes included the medically important O157, stx2b or stx2c, and eaeA-positive (n=4) and O26, stx1a, and eaeA-positive strains (n=1). Campylobacter spp. were isolated from 17 deer and 31 boars. Campylobacter hyointestinalis was the most common species isolated from 17 deer and 25 boars, whereas Campylobacter lanienae and Campylobacter coli were isolated from three and two boars, respectively. Seasonal trends for the isolation of these bacteria were not significant. This study demonstrates that wild game animals carry human pathogens; therefore, detailed knowledge of the safe handling of game meat is needed to prevent foodborne infections.

BACKGROUND Kawasaki disease (KD) is a systemic inflammatory disease resulting in an acute febrile syndrome commonly affecting children younger than 5 years. Coronary arteritis in KD is occasionally non-responsive to several treatments. Recently, adipose tissue-derived stem cells (ADSCs) have been shown to have anti-inflammatory, immunosuppressive, and tissue-repair characteristics and are considered a useful treatment for inflammatory disease. The present study aimed to elucidate whether the administration of ADSCs can suppress KD-associated vasculitis in vivo. METHODS Candida albicans water-soluble fraction is often used to model KD via the induction of severe coronary arteritis. Kawasaki disease model mice were intravenously administered ADSCs and phosphate-buffered saline (PBS). On day 29, the mice were sacrificed and hearts from mice in each group were dissected. This was followed by serum collection. Cardiac tissue sections were subjected to histopathological examination to evaluate the inflammatory area. The levels of pro-inflammatory cytokines in the serum were analyzed at days 15 and 29. The survival rates of both groups were compared. RESULTS The mean inflammatory area in coronary arteritis was significantly lower in the ADSC group compared to the PBS group (P < 0.01). Furthermore, the levels of pro-inflammatory cytokines, such as IL-1β, IL-12, IL-17, RANTES, INF-γ, and TNF-α, in the ADSC group were significantly lower than those in the PBS group. Moreover, the ADSC group had a significantly higher survival rate than the PBS group. CONCLUSIONS These findings highlight that ADSCs have anti-inflammatory and immune regulatory functions that could provide novel cell-based therapeutic strategies for severe KD.

Objective Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is overexpressed in a subset of malignant cells. However, it remains unknown whether ROR1 is targetable in malignant mesothelioma (MM). Therefore, in this study, we investigated the effects of ROR1 inhibition in mesothelioma cells. Materials and methods Growth inhibition, colony formation, apoptosis, and mRNA/protein levels using siRNA-transfected MM cells were evaluated. Cluster analysis using Gene Expression Omnibus repository of transcriptomic information was also performed. Results Our results indicated that in three (H2052, H2452, and MESO-1) among four MM cell lines, ROR1 inhibition had anti-proliferative and apoptotic effects and suppressed the activation of AKT and STAT3. Although growth inhibition by siROR1 was minimal in another mesothelioma cell line (H28), colony formation was significantly suppressed. Microarray, quantitative polymerase chain reaction, and Western blot analyses showed that there were differences in the suppression of mRNA and proteins between H2452 and H28 cells transfected with siROR1 compared with those transfected with control siRNA. Cluster analysis further showed that MM tumors had relatively high ROR1 expression, although the cluster in them was different from that in MM cell lines. Thymidylate synthase, a target of pemetrexed, was downregulated in H2452 cells transfected with siROR1. Accordingly, a combination of pemetrexed with siROR1 was found to be effective in the three MM cell lines we studied. Conclusion Our findings may provide novel therapeutic insight into the treatment of advanced MM.

An 84-year-old woman was referred for lower abdominal pain lasting more than six months. Computed tomography showed a left ovarian varicose vein and a peri-uterine venous plexus. Due to suspected pelvic congestion syndrome, left ovarian venography and left ovarian embolization were performed. Blood flowed back through the dilated left ovarian vein and through the uterine venous plexus to the right ovarian vein. Embolization of the left ovarian vein with a sclerosing agent resulted in the disappearance of the venous congestion. Preoperative Visual Analogue Scale was 7, which decreased to 3 after the operation. As a result, improvements in QOL were recognized. Although pelvic congestion syndrome is a treatable disease, its recognition as a urological disease is low. Here, we have reported a case of pelvic congestion syndrome in which symptoms improved with treatment and have discussed its pathophysiology and treatment.

The aging population problem is growing worldwide and physical therapists must be able to care for the elderly and injured efficiently. One burden facing physical therapists is determining the Functional Independence Measure (FIM), which measures the level of independence in activities of daily living for the elderly and injured. This measure is used in designing rehabilitation programs. Determining the FIM is a time-consuming task for both physical therapists and rehabilitation patients because it requires an interview. Some researchers have explored estimating FIM using wearable devices; however, it is burdensome for patients to wear such devices continuously. Therefore, we propose a method to estimate FIM motor items automatically using machine learning and sleep sensors. The proposed method classifies patients into three levels of FIM values that are referred to as s-FIM using vital data acquired through sleep sensors, personal data (age, gender, and Body Mass Index), and s-FIM values from the previous day. The results of a one-week study based on 19 patients showed that the proposed method had a mean accuracy of 0.87 for s-FIM motor items. The results were more accurate than continuing to use the s-FIM values determined by the physical therapist without updating them for one week.

Primary hepatic neuroendocrine tumors (PHNETs) are rare in dogs, and limited information exists about the treatment of these tumors. A 12-year-old castrated male French bulldog was presented to our clinic with gastrointestinal signs. Diagnostic tests revealed increased hepatic enzyme levels, a mass in the hepatic quadrate lobe, multiple intrahepatic nodules, and enlarged hepatic hilar lymph nodes. The liver mass was diagnosed cytologically as a malignant epithelial tumor suspected to be of neuroendocrine origin. The dog was treated with single-agent toceranib phosphate (TOC) and survived 25.1 months after the initial presentation. On necropsy, a liver mass was found and was subsequently diagnosed as a PHNET on histopathology. To the best of our knowledge, this is the first report of long-term survival in a dog with PHNET treated with TOC.

Since understanding molecular mechanisms of SARS-CoV-2 infection is extremely important for developing effective therapies against COVID-19, we focused on the internalization mechanism of SARS-CoV-2 via ACE2. Although cigarette smoke is generally believed to be harmful to the pathogenesis of COVID-19, cigarette smoke extract (CSE) treatments were surprisingly found to suppress the expression of ACE2 in HepG2 cells. We thus tried to clarify the mechanism of CSE effects on expression of ACE2 in mammalian cells. Because RNA-seq analysis suggested that suppressive effects on ACE2 might be inversely correlated with induction of the genes regulated by aryl hydrocarbon receptor (AHR), the AHR agonists 6-formylindolo(3,2-b)carbazole (FICZ) and omeprazole (OMP) were tested to assess whether those treatments affected ACE2 expression. Both FICZ and OMP clearly suppressed ACE2 expression in a dose-dependent manner along with inducing CYP1A1. Knock-down experiments indicated a reduction of ACE2 by FICZ treatment in an AHR-dependent manner. Finally, treatments of AHR agonists inhibited SARS-CoV-2 infection into Vero E6 cells as determined with immunoblotting analyses detecting SARS-CoV-2 specific nucleocapsid protein. We here demonstrate that treatment with AHR agonists, including FICZ, and OMP, decreases expression of ACE2 via AHR activation, resulting in suppression of SARS-CoV-2 infection in mammalian cells.