Fucosylation inhibitor 6-alkynylfucose enhances the ATRA-induced differentiation effect on acute promyelocytic leukemia cells.

For acute promyelocytic leukemia (APL), differentiation therapy with all-trans retinoic acid (ATRA) is well established. However, the narrow application and tolerance development of ATRA remain to be improved. In this study, we investigated the effects of combinations of glycosylation inhibitors with ATRA to achieve better efficiency than ATRA alone. We found that the combination of fucosylation inhibitor 6-alkynylfucose (6AF) and ATRA had an additional effect on cell differentiation, as revealed by expression changes in two differentiation markers, CD11b and CD11c, and significant morphological changes in NB4 APL and HL-60 acute myeloid leukemia (AML) cells. In AAL lectin blot analyses, ATRA or 6AF alone could decrease fucosylation, while their combination decreased fucosylation more efficiently. To clarify the molecular mechanism for the 6AF effect on ATRA-induced differentiation, we performed microarray analyses using NB4 cells. In a pathway analysis using DAVID software, we found that the C-type lectin receptor (CLR) signaling pathway was enriched with high significance. In real-time PCR analyses using NB4 and HL-60 cells, FcεRIγ, CLEC6A, CLEC7A, CASP1, IL-1ß, and EGR3, as components of the CLR pathway, as well as CD45 and AKT3 were upregulated by 6AF in ATRA-induced differentiation. Taken together, the present findings suggest that the CLR signaling pathway is involved in the 6AF effect on ATRA-induced differentiation.

Prevalence and risk factors for onychomycosis in acute care dermatology wards.

We conducted a cross-sectional study on the clinical and mycological features of onychomycosis in patients in the dermatology ward of Iwate Medical University Hospital, an acute care hospital. Of the 226 hospitalized patients, 73 (32.3%) had onychomycosis and 61 (26.9%) were diagnosed after admission. The toenail was the most common site of onychomycosis (94.5%), while toenail plus fingernail and fingernail only sites were 4.1% and 1.4%, respectively. The most common clinical form of onychomycosis was distal and lateral subungual onychomycosis (79%) with Trichophyton rubrum (66.7%) and T. interdigitale (27.8%) as the main causative species. Patients who were older, or had neurological diseases, or needed stretcher transfer had onychomycosis significantly more frequently than those who were obese, had diabetes, cancer, needed an escort for moving, or could move independently. Our study suggests that there is likely to be a significant number of untreated and undiagnosed patients with onychomycosis in acute care hospitals. Therefore, it is necessary to increase awareness of onychomycosis in hospitals.

Population Pharmacokinetics of Ozoralizumab in Patients with Rheumatoid Arthritis.

Ozoralizumab is a bispecific NANOBODY compound that binds tumor necrosis factor alpha (TNFα) and human serum albumin. Ozoralizumab inhibits the TNFα physiological activity while maintaining long-term plasma retention owing to its human serum albumin-binding ability. A population pharmacokinetic (PK) model was developed using data from 494 Japanese patients with rheumatoid arthritis in Phase II/III and Phase III trials to assess the effects of potential PK covariates. The ozoralizumab PK after subcutaneous administration was described using a 1-compartment model with first-order absorption and first-order elimination processes. A proportional error model was used for inter- and intra-individual variabilities, with covariance set between inter-individual variabilities of the apparent clearance and apparent distribution volume. Body weight, sex, antidrug antibody status, estimated glomerular filtration rate, and concomitant methotrexate use were identified as covariates for apparent clearance, while body weight and sex were covariates for apparent distribution volume in the final model. Body weight had the greatest effect on the PK of ozoralizumab, while the other covariates had minor effects. When administered at 30 mg every 4 weeks, the predicted steady-state plasma trough concentration in a patient weighing 83.2 kg exceeded the trough concentration required to maintain efficacy of ozoralizumab, and the estimated exposure in a patient weighing 42.5 kg did not exceed the mean exposure at 80 mg, a well-tolerated dose, throughout 52 weeks. We developed a population PK model that adequately described the ozoralizumab PK in Japanese patients with rheumatoid arthritis, and none of the evaluated covariates showed clinically relevant effects on the PK of ozoralizumab.

Experience with transesophageal echocardiography for mitral valve plasty in the remote stage after esophagectomy with gastric tube reconstruction via the retrosternal route.

A 69-year-old male patient with mitral valve prolapse was scheduled for mitral valve plasty. Sixteen years earlier, he had undergone right open thoracotomy for esophageal cancer with subtotal esophagectomy, cervicothoraco-abdominal three-region dissection, posterior mediastinal tube reconstruction, and cervical anastomosis. Postoperatively, the patient had a treatment- and recurrence-free course, and an upper gastrointestinal endoscopy performed 2 years prior revealed no abnormality. We scheduled a transesophageal echocardiography for mitral valve surgery. We attempted to insert the probe but felt resistance at the height of the mid-thoracic region, and the image quality was poor, so we abandoned the intraoperative diagnosis. The surgery was performed as planned, and when the probe was manipulated again at the time of cardiopulmonary withdrawal, the mitral valve could be observed. The mitral valve was judged to be sufficiently repaired, and the surgery was terminated. There were no complications associated with transesophageal echocardiography.

Efficacy and pharmacokinetics of ozoralizumab, an anti-TNFα NANOBODY® compound, in patients with rheumatoid arthritis: 52-week results from the OHZORA and NATSUZORA trials.

INTRODUCTION: Ozoralizumab (OZR), a tumor necrosis factor alpha (TNFα) inhibitor, is a NANOBODY® compound that binds to TNFα and human serum albumin. The main objective of this study was to analyze the pharmacokinetics (PK) of the drug and its correlation with clinical efficacy in patients with rheumatoid arthritis (RA). METHODS: Efficacy data were analyzed from the OHZORA trial, in which OZR 30 or 80 mg was administered to Japanese patients with RA at 4-week intervals for 52 weeks in combination with methotrexate (MTX; n = 381), and the NATSUZORA trial, in which OZR 30 or 80 mg was administered without concomitant MTX (n = 140). Effects of patient baseline characteristics and anti-drug antibodies (ADAs) on the PK and efficacy of OZR were investigated, and a post hoc analysis of PK effects on drug efficacy was performed. RESULTS: The maximum plasma concentration (Cmax) was reached in 6 days in both the 30 and 80 mg groups, with an elimination half-life of 18 days. The Cmax and area under the plasma concentration-time curve increased in a dose-dependent manner, and the trough concentration reached steady state by week 16. The exposure of OZR correlated negatively with patient body weight and was not affected by other patient baseline characteristics. Effects of ADAs on the exposure and efficacy of OZR were limited in both trials. However, antibodies that neutralize the binding to TNFα had some effect on the exposure and efficacy of OZR in the NATSUZORA trial. The receiver operating characteristic analysis of the effect of trough concentration on the American College of Rheumatology 20% and 50% improvement rates was retrospectively performed, and a cutoff trough concentration of approximately 1 µg/mL at week 16 was obtained in both trials. The efficacy indicators in the subgroup with trough concentration ≥ 1 µg/mL were higher than those in the < 1 µg/mL subgroup at week 16, while no clear cutoff was obtained at week 52 in both trials. CONCLUSIONS: OZR showed a long half-life and favorable PK properties. A post hoc analysis suggested sustained efficacy independent of trough concentration by subcutaneous administration of OZR 30 mg at 4-week intervals for 52 weeks. TRIAL REGISTRATION: JapicCTI, OHZORA trial: JapicCTI-184029, registration date July 9, 2018; NATSUZORA trial: JapicCTI-184031, registration date July 9, 2018.

Identification of C-C motif chemokine ligand 5 as a heat-dependent myokine.

The skeletal muscle is an endocrine organ that produces proteins and peptides, collectively termed as myokines. The temperature of skeletal muscles varies during exercise and/or with changes in ambient temperature. However, whether myokine secretion is regulated by heat stimulation is unclear. Thus, we aimed to explore the effects of environmental heat stimulation on myokine secretion. We initially investigated the secretome of C2C12 myotubes and identified several novel heat-responsive myokines. The concentration of C-C motif chemokine ligand 5 (CCL5) dramatically decreased by 0.3-fold in response to heat stress. After 3 h heat stimulation of C2C12 cells, the expression of heat shock protein 70 was induced, and the gene expression and secretion of CCL5 was significantly attenuated in C2C12 cells. We then examined the effects of acute heat stress on serum CCL5 levels in mice and Ccl5 gene expression in skeletal muscles. Mice were maintained at 23°C, exposed to 45°C for 30 min, and then returned to the 23°C chamber for recovery. The expression of Ccl5 in the skeletal muscle significantly decreased after 3 h of recovery. Serum CCL5 levels increased by approximately 1.9-fold after 30 min of heat exposure and then significantly decreased by approximately 0.7-fold after 23 h of recovery. This study suggests that heat stimulation decreases CCL5 secretion from the skeletal muscle in vitro and in vivo. Given its fundamental role in inflammation by recruiting several immune cells, CCL5 has a potential role in controlling inflammatory responses in the body after heat stimulation.

Can Negation Be Depicted? Comparing Human and Machine Understanding of Visual Representations.

There is a widely held view that visual representations (images) do not depict negation, for example, as expressed by the sentence, "the train is not coming." The present study focuses on the real-world visual representations of photographs and comic (manga) illustrations and empirically challenges the question of whether humans and machines, that is, modern deep neural networks, can recognize visual representations as expressing negation. By collecting data on the captions humans gave to images and analyzing the occurrences of negation phrases, we show some evidence that humans recognize certain images as expressing negation. Furthermore, based on this finding, we examined whether or not humans and machines can classify novel images as expressing negation. The humans were able to correctly classify images to some extent, as expected from the analysis of the image captions. On the other hand, the machine learning model of image processing was only able to perform this classification at about the chance level, not at the same level of performance as the human. Based on these results, we discuss what makes humans capable of recognizing negation in visual representations, highlighting the role of the background commonsense knowledge that humans can exploit. Comparing human and machine learning performances suggests new ways to understand human cognitive abilities and to build artificial intelligence systems with more human-like abilities to understand logical concepts.

Validation study on definition of cause of death in Japanese claims data.

Identifying the cause of death is important for the study of end-of-life patients using claims data in Japan. However, the validity of how cause of death is identified using claims data remains unknown. Therefore, this study aimed to verify the validity of the method used to identify the cause of death based on Japanese claims data. Our study population included patients who died at two institutions between January 1, 2018 and December 31, 2019. Claims data consisted of medical data and Diagnosis Procedure Combination (DPC) data, and five definitions developed from disease classification in each dataset were compared with death certificates. Nine causes of death, including cancer, were included in the study. The definition with the highest positive predictive values (PPVs) and sensitivities in this study was the combination of "main disease" in both medical and DPC data. For cancer, these definitions had PPVs and sensitivities of > 90%. For heart disease, these definitions had PPVs of > 50% and sensitivities of > 70%. For cerebrovascular disease, these definitions had PPVs of > 80% and sensitivities of> 70%. For other causes of death, PPVs and sensitivities were < 50% for most definitions. Based on these results, we recommend definitions with a combination of "main disease" in both medical and DPC data for cancer and cerebrovascular disease. However, a clear argument cannot be made for other causes of death because of the small sample size. Therefore, the results of this study can be used with confidence for cancer and cerebrovascular disease but should be used with caution for other causes of death.

Factors Associated With Placebo Treatment Response in Functional Dyspepsia Clinical Trials.

INTRODUCTION: Controlling for potential placebo effects is an important aspect of gaining an accurate estimate of how much the therapy alone changes patient symptoms or other end points. When the placebo effect is large, this can lead to only a small fraction of changes seen in the active therapy group being attributed to the therapy itself. This problem has been well studied in some disorders of brain-gut interaction but not in functional dyspepsia where placebo response rates of 40% and higher have been reported. Understanding risk factors for placebo response might lead to changes in trial design that could reduce the magnitude of the problem. This study sought to identify risk factors for the placebo effect in a functional dyspepsia clinical trial with a longer-term aim of suggesting trial design changes that might minimize the problem. METHODS: A secondary analysis of the clinical trial data was undertaken using 2 arms deemed to involve placebo therapy. Potential predictors were drawn from a wide range of patient characteristics including psychological, clinical, and physiological features. RESULTS: Predictors of a stronger placebo effect on the gastrointestinal symptom rating scale included higher functional dyspepsia symptom burden at baseline ( b = -0.101), coexisting irritable bowel syndrome ( b = -0.436), and higher scores on the Nepean Dyspepsia Index eat/drink domain (-0.005). Baseline symptom burden and coexisting irritable bowel syndrome were found to be independent placebo predictors, explaining 13% of the variance in change in gastrointestinal symptom rating scale. Anxiety, childhood sexual abuse, sleep amount, and frequent abdominal pain were also found to be predictors of change in individual symptom scores. DISCUSSION: The findings of this study yield actionable insights into trial methodology that may help to reduce the magnitude of the placebo effect in future functional dyspepsia treatment trials.

Efficacy of Preoperative Bilateral Thoracic Paravertebral Block in Cardiac Surgery Requiring Full Heparinization: A Propensity-Matched Study.

OBJECTIVES: To assess the efficacy of preoperative bilateral paravertebral block (PVB) with general anesthesia (GA) in contributing to early extubation and decreasing opioid consumption in cardiac surgery. DESIGN: A propensity score-matched retrospective study. SETTING: A single tertiary medical center between January 2018 and December 2020. PARTICIPANTS: Adult patients undergoing isolated first-time aortic valve replacement and coronary artery bypass grafting with full sternotomy. INTERVENTIONS: A cohort of 44 patients who received PVB with GA (PVB group) was matched with 44 patients who underwent similar surgery with GA only (GA only group). MEASUREMENTS AND MAIN RESULTS: The completion rate of extubation in the operating room was significantly greater in the PVB group (65.9%) than in the GA only group (43.2%; p = 0.032). The completion rate of extubation within eight hours after surgery also was significantly greater in the PVB group (86.4%) than in the GA only group (68.2%; p = 0.042). The median amount of intraoperative fentanyl administered was significantly less in the PVB group (4.8 µg/kg; interquartile range [IQR], 3.3-7.2) than in the GA only group (8.4 µg/kg; IQR, 5.4-12.7; p < 0.001). The median amount of postoperative fentanyl administered was significantly less in the PVB group (6.8 µg/kg; IQR, 3.9-10.6) than in the GA only group (8.1 µg/kg; IQR, 6.2-15.9; p = 0.012). CONCLUSIONS: This study demonstrated that preoperative bilateral PVB combined with GA contributed to early extubation in isolated first-time aortic valve replacement and coronary artery bypass grafting and in the reduction of intraoperative and postoperative fentanyl consumption.

Possible involvement of CXC motif chemokine ligand 10 in exercise-induced collagen production of mouse dermal fibroblasts.

Evidence suggests that exercise can regulate skin functions such as promoting wound healing and inhibiting aging. Physical exercise modulates the secretion of proteins and peptides from skeletal muscles, called myokines, which play a role in transmitting exercise signals throughout the body. Therefore, exercise-regulated myokines may play a role in controlling skin functions; however, the precise mechanisms remain elusive. In this study, we focused on the recently identified CXC motif chemokine ligand 10 (CXCL10), an exercise-reduced myokine, and attempted to elucidate its role in regulating collagen synthesis in dermal fibroblasts. Mouse C2C12 myotubes were stimulated with or without electrical pulse stimulation (EPS) to induce contraction for 24 h, and conditioned medium was collected (EPS-CM or Ctrl-CM, respectively). The reduction in CXCL10 concentration by EPS was confirmed using ELISA. Next, mouse dermal fibroblasts were isolated from the dorsal skin of C57BL6/J mice (2 weeks old) and were stimulated with Ctrl-CM or EPS-CM for 24 h. EPS-CM treatment significantly increased collagen production compared to Ctrl-CM treatment. Even in the Ctrl-CM condition, the addition of an antagonist for CXCR3 (CXCL10 receptor) increased collagen production. In contrast, recombinant CXCL10 abolished EPS-CM-dependent collagen induction. Overall, this study raises the possibility that CXCL10 secretion from skeletal muscles may control collagen production in mouse dermal fibroblasts.

Infant with right hemiplegia due to acute encephalopathy with biphasic seizures and late reduced diffusion (AESD): A case report.

RATIONALE: Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is a condition characterized by biphasic convulsions and disturbance of consciousness. In Japan, the most common pediatric cases of acute encephalopathy are associated with infection. AESD usually occurs in early childhood, with the characteristic magnetic resonance imaging (MRI) appearance called "bright tree appearance." The disease often has neurological sequelae and interferes with the schooling of children and their activities of daily living; however, there are few clinical case reports of hemiplegia caused by AESD. PATIENT CONCERNS: A case with right-sided hemiplegia due to AESD in an 11-month-old girl who was followed up to 30 mo of age. DIAGNOSES: The patient was diagnosed with overlap AESD and hemiconvulsion-hemiplegia-epilepsy syndrome (HHE syndrome), based on the clinical course and imaging findings. DNA tests of her blood and cerebrospinal fluid revealed the presence of human herpesvirus 6. INTERVENTIONS: Pharmacotherapy and rehabilitation therapy. OUTCOME: Gross motor function has recovered considerably, but she had a mild developmental delay at 30 mo old. LESSONS: Hemiplegia due to AESD was extremely rare, and appropriate rehabilitation treatment resulted in recovery of physical function. However, as mild developmental delay was observed, the patient was referred to a specialized facility before entering school.

The effects of glucose and fatty acids on CXCL10 expression in skeletal muscle cells.

Skeletal muscles produce secretory factors termed as myokines, which alter physiological functions of target tissues. We recently identified C-X-C chemokine ligand 10 (CXCL10) as a novel myokine, which is downregulated in response to exercise. In the present study, we investigated whether the nutritional changes affect CXCL10 expression in mouse skeletal muscle. Expression of CXCL10 was evaluated in mice fed a normal diet or a high fat diet for 10 weeks. In animals fed on HFD, Cxcl10 expression was significantly induced in fast-twitched muscles, and was accompanied by increased blood glucose and free fatty acid levels. In vitro experiments using C2C12 myotubes suggested that the increased levels of glucose and palmitic acids directly enhanced CXCL10 expression. Interestingly, the effect of palmitic acids was attenuated by palmitoleic acids. Considering its potent angiostatic activity, induction of CXCL10 by nutritional changes may contribute to the impairment of microvascular networks in skeletal muscles.

[A Case of Interstitial Pneumonitis Induced by Palbociclib].

An 89-year-old woman with recurrent hormone receptor-positive and HER2-negative breast cancer was treated with fulvestrant-palbociclib combination therapy. However, 3 months after therapy initiation, she presented to our emergency room with dyspnea and fever and was admitted to our hospital because of respiratory failure. After radiological and microbiological evaluation, she was diagnosed with palbociclib-related pneumonitis. Accordingly, corticosteroids were administered, and the patient exhibited initial clinical and radiological improvement. However, pneumonitis recurred following corticosteroid tapering; her condition did not improve with high-dose intravenous corticosteroid administration, leading to death. Palbociclib- related pneumonitis is rare, but clinicians need to pay attention to this potentially lethal adverse event.

Bacterial Contamination of Hemodialysis Devices in Hospital Dialysis Wards.

Chronic care patients undergoing hemodialysis for treatment of end-stage renal failure experience higher rates of bloodstream-associated infection due to the patients' compromised immune system and management of the bloodstream through catheters. Staphylococcus species are acommon cause of hemodialysis catheterrelated bloodstream infections. We investigated environmental bacterial contamination of dialysis wards and contamination of hemodialysis devices to determine the source of bacteria for these infections. All bacterial samples were collected by the swab method and the agarose stamp method. And which bacterium were identified by BBL CRYSTAL Kit or 16s rRNA sequences. In our data, bacterial cell number of hemodialysis device was lower than environment of patient surrounds. But Staphylococcus spp. were found predominantly on the hemodialysis device (46.8%), especially on areas frequently touched by healthcare-workers (such as Touch screen). Among Staphylococcus spp., Staphylococcus epidermidis was most frequently observed (42.1% of Staphylococcus spp.), and more surprising, 48.2% of the Staphylococcus spp. indicated high resistance for methicillin. Our finding suggests that hemodialysis device highly contaminated with bloodstream infection associated bacteria. This study can be used as a source to assess the risk of contamination-related infection and to develop the cleaning system for the better prevention for bloodstream infections in patients with hemodialysis. J. Med. Invest. 66 : 148-152, February, 2019.

Human inference beyond syllogisms: an approach using external graphical representations.

Research in psychology about reasoning has often been restricted to relatively inexpressive statements involving quantifiers (e.g. syllogisms). This is limited to situations that typically do not arise in practical settings, like ontology engineering. In order to provide an analysis of inference, we focus on reasoning tasks presented in external graphic representations where statements correspond to those involving multiple quantifiers and unary and binary relations. Our experiment measured participants' performance when reasoning with two notations. The first notation used topological constraints to convey information via node-link diagrams (i.e. graphs). The second used topological and spatial constraints to convey information (Euler diagrams with additional graph-like syntax). We found that topo-spatial representations were more effective for inferences than topological representations alone. Reasoning with statements involving multiple quantifiers was harder than reasoning with single quantifiers in topological representations, but not in topo-spatial representations. These findings are compared to those in sentential reasoning tasks.

The Nepean Dyspepsia Index is a valid instrument for measuring quality-of-life in functional dyspepsia.

BACKGROUND: The Nepean Dyspepsia Index (NDI) has been in widespread use since its publication in 1999 and the addition of a short form in 2001. The NDI was one of the first disease-specific quality-of-life instruments created for functional dyspepsia (FD). However, its psychometric properties have never been validated in an independent sample. AIM: This study aimed to evaluate the validity and reliability of the NDI in an a-priori driven approach in an independent population. PATIENTS AND METHODS: In 289 individuals who fulfilled the Rome criteria for FD enrolled in a randomized placebo-controlled trial (FD treatment trial), we examined construct validity, convergent validity, and internal consistency. RESULTS: Construct validity was supported in its 25-item unweighted and weighted forms as well as the 10-item short form. All items in the 25-item form yielded considerable (>0.5) standardized loadings on their respective latent variables and all reached statistical significance (P<0.0001), supporting their relationships with the hypothesized domains. Convergent validity was strongly supported, with every domain being correlated with multiple external instruments; the majority of correlations were in the range 0.3-0.5 (in absolute values). The items comprising each domain showed good internal consistency, with the lowest value of Chronbach α at 0.80. Scores based on the short form (10-item) version of the NDI correlated strongly with the full 25-item form (tension ρ=0.88, interference ρ=0.94, eat/drink ρ=0.95, knowledge ρ=0.84 and work/study ρ=0.97; all P<0.0001). CONCLUSION: The NDI is a valid instrument that can be used to measure the disease-specific impact of FD on quality of life.

Pharmacokinetics and Pharmacodynamics of Luseogliflozin, a Selective SGLT2 Inhibitor, in Japanese Patients With Type 2 Diabetes With Mild to Severe Renal Impairment.

This open-label, parallel-group, multicenter study aimed to assess the effects of renal impairment on the pharmacokinetics, pharmacodynamics, and safety of luseogliflozin. A single 5-mg dose of luseogliflozin was administered to Japanese patients with type 2 diabetes mellitus in the following groups: G1, normal renal function; G2, mild renal impairment; G3a, mild to moderate impairment; G3b, moderate to severe impairment; G4, severe impairment, based on estimated glomerular filtration rate (eGFR; ≥90, 60-89, 45-59, 30-44, 15-29 mL/min/1.73 m2 , respectively). While luseogliflozin pharmacokinetics were similar for patients across all renal function groups, the increase in plasma concentration was slightly slower and maximum concentration was slightly reduced in the lower eGFR groups compared with the other groups. However, luseogliflozin pharmacodynamics were affected by the severity of renal impairment. Urinary glucose excretion (UGE) increased in all groups relative to baseline levels, but the degree of UGE increase was smaller in the lower eGFR groups. Moreover, plasma glucose AUC changes from baseline tended to be smaller in the lower eGFR groups. No clear trends were observed between eGFR and incidence, type, or severity of adverse events. Thus, luseogliflozin administration should be carefully considered, as patients with renal impairment may show an insufficient response to treatment.