Spontaneous differentiation of human induced pluripotent stem cells to odorant-responsive olfactory sensory neurons.

Pluripotent stem cells, such as embryonic stem cells and induced pluripotent stem cells (iPSCs), can differentiate into almost all cell types and are anticipated to have significant applications in the field of regenerative medicine. However, there are no reports of successfully directing iPSCs to become functional olfactory sensory neurons (OSNs) capable of selectively receiving odorant compounds. In this study, we employed dual SMAD inhibition and fibroblast growth factor 8 (FGF-8, reported to dictate olfactory fates) along with N-2 and B-27 supplements in the culture medium to efficiently induce the differentiation of iPSCs into neuronal cells with olfactory function through olfactory placode. Temporal gene expression and expression of OSN-specific markers during differentiation indicated that the expression of olfactory marker proteins and various olfactory receptors (ORs), which are markers of mature OSNs, was observed after approximately one month of differentiation culture, irrespective of the differentiation cues, suggesting differentiation into OSNs. Cells that exhibited specific responses to odorant compounds were identified after administering odorant compounds to differentiated iPSC-derived OSNs. This suggests the spontaneous generation of functional OSNs expressing diverse ORs that respond to odorant compounds from iPSCs.

Rapid and simple quantification of belimumab in human plasma using ultra-high performance liquid chromatography with tandem mass spectrometry.

OBJECTIVE: Belimumab is a monoclonal antibody against the B-lymphocyte stimulating factor and is approved for the treatment of patients with systemic lupus erythematosus (SLE) not responding adequately to existing therapies. In this study, we established and validated an assay for quantifying belimumab in human plasma. METHODS: From the peptides generated by trypsin digestion of belimumab, in silico analysis was used to search for unique peptides to determine the surrogate peptides. Samples were trypsin digested, pretreated with solid phase extraction, and analyzed by ultra-high performance liquid chromatography with tandem mass spectrometry (UHPLC-MS/MS) to quantify the surrogate peptide in the samples. The assay was validated according to the Food and Drug Administration (FDA) bioanalytical method validation guidance. We used the established assay to quantify plasma belimumab concentrations in two SLE patients treated with belimumab. RESULTS: Among the unique peptides identified by the in silico analysis, the peptide with the best peak shape when measured by UHPLC-MS/MS was selected as the surrogate peptide. The validation results of this assay met the acceptable criteria recommended by the FDA guidance. The lower limit of quantification (LLOQ) for belimumab was 2 µg/mL. Recovery rates and matrix effects when corrected for internal standards were 91.5-114.3 % and 96.9-108.4 %, respectively. Plasma concentrations of belimumab were measured in 12 samples from two belimumab-treated SLE patients. All concentrations were within the calibration range. CONCLUSIONS: We have established and validated a method for measuring plasma belimumab concentrations using UHPLC/MS-MS. By measuring plasma belimumab concentrations in more patients, this method is expected to contribute to appropriate use of belimumab.

Case Report: Solid variant of papillary thyroid carcinoma in a young adult with Turner syndrome with chronic thyroiditis.

Turner syndrome is associated with an increased risk of developing several neoplasms. In particular, a clinical feature of Turner syndrome with chronic thyroiditis implies a relationship with thyroid malignancies. We report a very rare case of a solid variant of papillary thyroid carcinoma that was identified during a follow-up of chronic thyroiditis in a 22-year-old woman with Turner syndrome. The patient had no notable history of radiation exposure. No genetic mutations relating to the occurrence of the solid variant of papillary thyroid carcinoma, including RET/PTC rearrangements and mutations in the BRAF or RAS, were detected by a gene panel test, namely, the Oncomine™ Dx Target test. To the best of our knowledge, this is the first report of a solid variant of papillary thyroid carcinoma in a young adult with Turner syndrome with chronic thyroiditis. Our case suggests that in patients with Turner syndrome, there may be different pathogeneses from those previously reported, including exposure to radiation or known genetic mutations for the development of a solid variant of papillary thyroid carcinoma.

Neurobiological correlation between phosphorylated tau and mood symptoms in memory clinic patients.

BACKGROUND: Alzheimer's disease (AD) dementia and mild cognitive impairment are characterised by impaired cognition accompanied by neuropsychiatric symptoms (NPS) relating to mood, including depression, anxiety, and apathy. However, the utility of AD biomarkers for predicting mood symptoms of NPS remains controversial. Herein, we analyzed the relationship between phosphorylated tau (p-tau) and depression, anxiety, and apathy of NPS. We also examined the influence of genetic factors such as apolipoprotein E (APOE) ε4 on these relationships. METHODS: We conducted a cross-sectional survey in older patients (n = 122) with normal cognition (n = 12), mild cognitive impairment (n = 46), and AD (n = 64) strictly diagnosed by the board of psychiatrists and neurologists of Hokkaido University. NPS of the patients were assessed using the Neuropsychiatric Inventory Questionnaire (NPI). All patients also received a lumbar puncture to obtain cerebral spinal fluid for assessment of p-tau. The inverse probability weighting method was used to adjust for demographic differences between the p-tau present group and the p-tau absent group. RESULTS: There was an association between p-tau accumulation and decreased incidence of depression and apathy. APOE ε4 non-carriers also showed a trend toward a negative association between p-tau and depression, which was not evident in APOE ε4 carriers. CONCLUSIONS: We provide new evidence for a negative correlation between p-tau and depression and apathy of NPS, which may be influenced by APOE ε4. Future longitudinal studies are required to confirm the utility of p-tau for predicting the course of mood symptoms in patients with cognitive decline.

Assessment of electroencephalography modification by antipsychotic drugs in patients with schizophrenia spectrum disorders using frontier orbital theory: A preliminary study.

AIM: Schizophrenia is characterized by an abnormality in electroencephalography (EEG), which can be affected by antipsychotic drugs. Recently, the mechanism underlying these EEG alterations in schizophrenia patients was reframed from the perspective of redox abnormalities. The highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) can be calculated using a computational method and may be useful for evaluating the antioxidant/prooxidant effect of antipsychotic drugs. Thus, we examined the association between the effects of antipsychotic monotherapy on quantitative EEG and HOMO/LUMO energy. METHODS: We used medical report data including EEG results of psychiatric patients admitted to Hokkaido University Hospital. We extracted the EEG records of patients diagnosed with a schizophrenia spectrum disorder undergoing antipsychotic monotherapy during the natural course of treatment (n = 37). We evaluated the HOMO/LUMO energy of all antipsychotic drugs using computational methods. Multiple regression analyses were used to examine the relationship between the HOMO/LUMO energy of all antipsychotic drugs and spectral band power in all patients. Statistical significance was set at p < 6.25 × 10-4 adjusted with Bonferroni correction. RESULTS: We showed that the HOMO energy of all antipsychotic drugs had weak positive correlations with delta- and gamma-band power (e.g., standardized ß = 0.617 for delta in the F3 channel, p = 6.6 × 10-5 ; standardized ß = 0.563 for gamma in the O1 channel, p = 5.0 × 10-4 ). CONCLUSION: Although there may be unexpected bias and confounding factors, our findings suggest that the effect of antipsychotic drugs on EEG may be related to their antioxidant actions.

Prevalence and factors related to hypouricemia and hyperuricemia in schoolchildren: results of a large-scale cross-sectional population-based study conducted in Japan.

Hypouricemia in children including renal hypouricemia, which is a major cause of exercise-induced acute renal injury (EIAKI), is an important clinical problem, in addition to hyperuricemia. However, no large-scale studies of serum uric acid (UA) concentrations in the general pre-adolescent population have been carried out. We conducted a population-based cross-sectional study to measure the prevalences of hypouricemia and hyperuricemia and identify the associated factors. We analyzed 31,822 (16,205 boys and 15,617 girls) 9-10-year-old children who underwent pediatric health check-ups in Kagawa prefecture between 2014 and 2018. Hypouricemia and hyperuricemia were defined using serum UA concentrations of ≤ 2.0 mg/dL and ≥ 6.0 mg/dL, respectively. The prevalence of hypouricemia was 0.38% in both 9- and 10-year-old boys and girls, and was not significantly associated with age, sex, or environmental factors, including overweight. The prevalence of hyperuricemia was significantly higher in boys (2.7%) than in girls (1.9%), and was significantly associated with age, overweight, future diabetes risk, hypertriglyceridemia, low high-density lipoprotein-cholesterol, and liver damage, but not with high low-density lipoprotein cholesterol. Therefore, some pre-adolescent children in the general population in Japan showed hypouricemia. A means of identifying children with hypouricemia and lifestyle guidance measures for the prevention of EIAKI should be established.

Saireito, a Japanese herbal medicine, alleviates leaky gut associated with antibiotic-induced dysbiosis in mice.

Antibiotics disrupt normal gut microbiota and cause dysbiosis, leading to a reduction in intestinal epithelial barrier function. Disruption of the intestinal epithelial barrier, which is known as "leaky gut", results in increased intestinal permeability and contributes to the development or exacerbation of gastrointestinal diseases such as inflammatory bowel disease and irritable bowel syndrome. We have previously reported on a murine model of intestinal epithelial barrier dysfunction associated with dysbiosis induced by the administration of ampicillin and vancomycin. Saireito, a traditional Japanese herbal medicine, is often used to treat autoimmune disorders including ulcerative colitis; the possible mechanism of action and its efficacy, however, remains unclear. In this study, we examined the efficacy of Saireito in our animal model for leaky gut associated with dysbiosis. C57BL/6 mice were fed a Saireito diet for the entirety of the protocol (day1-28). To induce colitis, ampicillin and vancomycin were administered in drinking water for the last seven consecutive days (day22-28). As previously demonstrated, treatment with antibiotics caused fecal occult bleeding, cecum enlargement with black discoloration, colon inflammation with epithelial cell apoptosis, and upregulation of pro-inflammatory cytokines. Oral administration of Saireito significantly improved antibiotics-induced fecal occult bleeding and cecum enlargement by suppressing inflammation in the colon. Furthermore, Saireito treatment ensured the integrity of the intestinal epithelial barrier by suppressing apoptosis and inducing cell adhesion proteins including ZO-1, occludin, and E-cadherin in intestinal epithelial cells, which in turn decreased intestinal epithelial permeability. Moreover, the reduced microbial diversity seen in the gut of mice treated with antibiotics was remarkably improved with the administration of Saireito. In addition, Saireito altered the composition of gut microbiota in these mice. These results suggest that Saireito alleviates leaky gut caused by antibiotic-induced dysbiosis. Our findings provide a potentially new therapeutic strategy for antibiotic-related gastrointestinal disorders.

Highly Linear and Wide Non-Resonant Two-Degree-of-Freedom Piezoelectric Laser Scanner.

Laser scanners with mechanically driven mirrors have exhibited increasing potential for various applications, such as displays and laser radar. Resonant scanners are the predominantly used scanners; however, non-resonant scanners are required for applications where point-to-point driving is desirable. Because a non-resonant drive cannot amplify the drive angle owing to the resonance phenomenon, high values are difficult to achieve for the main performance metrics of the scanners: mirror area, drive angle, and operating frequency. In this paper, we present a two-axis scanner with a piezoelectric actuator made of a piezoelectric single-crystal Pb(In1/2Nb1/2)O3-Pb(Mg1/3Nb2/3)O3-PbTiO3 as the actuation force source. The scanner contains a circular mirror with a diameter of 7 mm and achieves an average static mechanical deflection angle amplitude of 20.8° in two axes with a resonant frequency of 559 Hz. It is equipped with a transmission mechanism that can decouple each axis to achieve high linearity; in our study, the nonlinearity error was less than 1°.

Comprehensive lipidomics of lupus-prone mice using LC-MS/MS identifies the reduction of palmitoylethanolamide that suppresses TLR9-mediated inflammation.

Lipid mediators are known to play crucial roles not only in the onset of the inflammatory response but also in the induction of resolution of inflammation. Here, we report that palmitoylethanolamide (PEA), an endogenous N-acylethanolamine, can suppress the inflammation induced by Toll-like receptor (TLR) signaling both in vitro and in vivo. PEA was found to be significantly reduced in the serum and spleen of lupus-prone MRL/lpr mice analyzed by lipidomics. PEA suppressed pro-inflammatory cytokine production in a mouse macrophage cell line stimulated with TLR ligands such as lipopolysaccharide, peptidoglycan, poly (I:C), imiquimod, and CpG-ODN. PEA also inhibited both mRNA and protein levels of IL-6 in bone marrow-derived dendritic cells (BMDCs) and B cells stimulated with CpG-ODN. Augmentation of cell surface CD86 and CD40 on BMDCs and B cells, IgM production, and cell proliferation of B cells in response to CpG-ODN were attenuated by PEA. Moreover, PEA treatment significantly reduced mortality and serum IL-6 levels in mice injected with CpG-ODN plus D-galactosamine. Taken together, PEA ameliorates inflammation induced by TLR signaling, which could be a novel therapeutic target for inflammatory disorders.

Wide Two-Degree-of-Freedom Static Laser Scanner with Miniaturized Transmission Mechanism and Piezoelectric Actuation.

In recent years, laser scanners have attracted significant attention for applications such as laser radars. However, the establishment of a two-degree-of-freedom scanner that can quasi-statically drive a large mirror with a large deflection angle has proven to be challenging. In this paper, we propose a laser scanner design and fabrication method by combining two unimorph piezoelectric actuators composed of piezoelectric single-crystal Pb(In1/2Nb1/2)O3-Pb(Mg1/3Nb2/3)O3-PbTiO3 and a miniature translation-rotation conversion mechanism with flexible polyimide hinges. The size of the entire scanner was 32 mm × 12 mm × 10 mm. We successfully demonstrated that the scanner could achieve a large quasi-static mechanical deflection angle amplitude of 20.5° in two axes with a 6-mm-square mirror.

Hot lamination and origami assembly fabrication of miniaturized compliant mechanism.

We developed a process for fabricating a miniaturized hinged mechanism for microrobots by customizing our previously reported flapping-wing method to fabricate microscopic wing structures resembling insects. Flexible hinges were realized by removing the titanium layers of the structure, which were previously sandwiched between thin polyimide layers. A three-dimensional structure can also be realized via origami-like assembly owing to the hinge structure, where the hinge is made to work as a crease. Details of our method and a reference design are reported through a demonstration of a translation-to-rotation conversion mechanism for a piezoelectric actuator. • Simple fabrication using a single hot lamination and origami-like assembly. • Method based on FPC manufacturing technologies would be easy to implement in a variety of research. • Transmission mechanism for piezoelectric actuators was demonstrated, verifying that the structures fabricated by this process function appropriately.

Factors Influencing Plasma Coproporphyrin-I Concentration as Biomarker of OATP1B Activity in Patients With Rheumatoid Arthritis.

Organic anion transporting polypeptides (OATPs) 1B are drug transporters mainly expressed in the sinusoidal membrane. In previous reports, genetic factor, 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF), which is one of the uremic toxins, inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) decreased OATP1B1 activity in vitro, but in vivo effects of these factors have not been elucidated. Plasma coproporphyrin-I (CP-I) is spotlighted as a highly accurate endogenous substrate of OATP1B. This study focused on patients with rheumatoid arthritis (RA) and evaluated the influence of several factors comprising gene polymorphisms, uremic toxins, and inflammatory cytokines on OATP1B activity using plasma CP-I concentration. Thirty-seven outpatients with RA who satisfied the selection criteria were analyzed at the time of recruitment (baseline) and at the next visit. OATP1B1*15 carriers tended to have higher CP-I concentration compared with noncarriers. Plasma CP-I correlated positively with CMPF concentration, but did not correlate with IL-6 or TNF-α concentration. Multiple logistic regression analysis by stepwise selection identified plasma CMPF concentration and OATP1B1*15 allele as significant factors independently affecting plasma CP-I concentration at baseline and at the next visit, respectively. In conclusion, the present results suggest that inflammatory cytokines do not have clinically significant effects on OATP1B activity, whereas the effects of genetic polymorphisms and uremic toxins should be considered.

Quantitative Resting State Electroencephalography in Patients with Schizophrenia Spectrum Disorders Treated with Strict Monotherapy Using Atypical Antipsychotics.

OBJECTIVE: The effect of antipsychotic drugs on quantitative electroencephalography (EEG) has been mainly examined by the administration of a single test dose or among patients using combinations of other psychotropic drugs. We therefore investigated the effects of strict monotherapy with antipsychotic drugs on quantitative EEG among schizophrenia patients. METHODS: Data from 2,364 medical reports with EEG results from psychiatric patients admitted to the Hokkaido University Hospital were used. We extracted EEG records of patients who were diagnosed with schizophrenia spectrum disorders and who were either undergoing strict antipsychotic monotherapy or were completely free of psychotropic drugs. The spectral power was compared between drug-free patients and patients using antipsychotic drugs. We also performed multiple regression analysis to evaluate the relationship between spectral power and the chlorpromazine equivalent daily dose of antipsychotics in all the patients. RESULTS: We included 31 monotherapy and 20 drug-free patients. Compared with drug-free patients, patients receiving antipsychotic drugs demonstrated significant increases in theta, alpha and beta power. When patients taking different types of antipsychotics were compared with drug-free patients, we found no significant change in any spectrum power for the aripiprazole or blonanserin groups. Patients taking risperidone demonstrated significant increases in alpha and beta power. Patients taking clozapine and olanzapine demonstrated significant slow wave increases. Multiple regression analysis revealed that the chlorpromazine equivalent dose was positively associated with theta power. CONCLUSION: Use of any antipsychotic drug by patients was associated with a dose-dependent increase in theta power. However, each type of antipsychotic demonstrated different spectral power changes.

Effectiveness of subcutaneous tocilizumab in refractory adult Still's disease: report of three cases and a review of the literature.

Adult Still's disease (ASD) is a systemic inflammatory disorder characterised by spiking fever, skin rash, arthritis, hepatosplenomegaly, and elevated inflammatory markers. Several proinflammatory cytokines, including interleukin (IL)-6, contribute to its pathogenesis. There have been some recent reports on the efficacy of tocilizumab (TCZ), a humanised anti-IL-6 receptor antibody, in the treatment of ASD refractory to conventional therapy. However, most of the evidence is for intravenous administration of TCZ, whereas subcutaneous injection is often preferred in terms of efficiency in cost and labour. We have experienced three patients whose ASD was refractory to corticosteroid and immunosuppressant therapy but showed a marked response to off-label use of subcutaneous TCZ (TCZ-SC). Patient 1 received TCZ-SC 162 mg on days 0 and 14 and every week thereafter. Patients 2 and 3 received TCZ-SC every 2 weeks. At the time of initiation of TCZ-SC, all three patients had elevated inflammatory markers and two had fever despite previous therapy. After the first TCZ-SC injection, the patients became afebrile within one day and inflammatory parameters (i.e. C-reactive protein and erythrocyte sedimentation rate) returned to normal within 2 weeks. None of the patients developed severe infection or other serious side effects during 104 weeks of follow-up. There have been only a limited number of case reports showing that TCZ-SC significantly improves refractory ASD during its active phase. Our experience with these patients suggests that TCZ-SC could, as well as offering cost efficiency in clinical practice, be a potent treatment option for refractory ASD.

Analysis of the Prevalence and Species of Anisakis nematode in Sekisaba, Scomber japonicus Caught in Coastal Waters off Saganoseki, Oita in Japan.

Anisakidosis is developed by ingesting Anisakis in marine fish, including the chub mackerel, Scomber japonicus, without proper pre-treatment such as cooking or freezing. Two sibling species of Anisakis are found in S. japonicus from Japanese waters, and the prevalence and species of Anisakis in the fish depend on the sea area. For example, Anisakis simplex sensu stricto (s.s.) is found in the Pacific stock of S. japonicus, whereas A. pegreffii is found in the Tsushima Warm Current stock. S.japonicus caught in the Bungo Channel, off the coast of Saganoseki in Oita Prefecture, which is branded as Sekisaba, inhabits a very limited area; however, the infection states of Anisakis found in Sekisaba remain unclear. In this study, we compared the infection states of Anisakis in Sekisaba with those in S. japonicus caught in the South Oita area and Nagasaki Prefecture. All Anisakis from the Nagasaki Prefecture were A. pegreffii, while most of them found in Sekisaba and fish from the South Oita area were A. simplex s.s. Interestingly, the prevalence of Anisakis in Sekisaba was significantly lower than that in the other two areas. This may reflect the fact that Sekisaba might belong to a distinct stock of S. japonicus, varying from other stocks.

Influence of social interaction on behavioral and psychological symptoms of dementia over 1 year among long-term care facility residents.

This study investigated the effect of social interaction including activity participation, relationships with residents, and communication with family/relatives and friends at baseline on the behavioral and psychological symptoms of dementia (BPSD) among long-term care facility residents over 1 year. This follow-up study was conducted among older adult residents with dementia or similar symptoms. Generalized linear mixed effect models were used to examine associations between social interaction and changes in the number and severity of BPSD symptoms over 1 year. Among 220 participants, rare participation in activities and poor relationships with other residents at baseline were associated with greater baseline BPSD. Less communication with family/relatives at baseline was associated with increased severity of BPSD over 1 year. Active interaction with family and relatives may prevent progression of BPSD severity among long-term care facility residents for at least 1 year.

Batch fabrication process of biomimetic wing with high flexibility of stiffness design for flapping-wing micro aerial vehicles.

A lamination-based batch-fabrication process of biomimetic wing for flapping-wing micro aerial vehicles is presented. The key benefits of this process are:•One of the advantages of the process is high productivity; eight wings were successfully fabricated simultaneously in our experiment.•The wing fabricated with the reported process is made of soft polyimide and partially reinforced by a titanium layer. This configuration enables the flexible design of the bending stiffness distribution on the wing, which is the key specification for generating lift force.•The reinforcing material can be replaced with other metals or heat-resistant polymers, and the number of layers and layer thicknesses are also variable. This indicates that the reported process can be customized considerably to suit individual needs.

Undifferentiated pleomorphic sarcoma of the prostate in a young man.

INTRODUCTION: Prostate sarcoma is an extremely rare disease with a poor prognosis. Undifferentiated pleomorphic sarcoma has never been described in the prostate.Case presentation: A 27-year-old man complained of frequent urination and dysuria for several years. Various examinations were suggestive of prostate sarcoma. The pathological diagnosis was confirmed as prostate sarcoma via ultrasound-guided transrectal needle biopsy. Because the location of the tumor in the prostate was confirmed by magnetic resonance imaging, we performed robot-assisted radical prostatectomy. The final pathological diagnosis was undifferentiated pleomorphic sarcoma. Local recurrence occurred at the front of the rectum 2 months after surgery. Although chemotherapy and radiotherapy were initially effective, he died 18 months after surgery. CONCLUSION: Undifferentiated pleomorphic sarcoma of the prostate is believed to have a poor prognosis. When selecting the surgical procedure, functionality should be considered for individual cases with complete resection.

Effects of Sleeve Gastrectomy on Blood Pressure and the Renal Renin-Angiotensin System in Rats with Diet-Induced Obesity.

OBJECTIVE: Sleeve gastrectomy (SG) has been reported to decrease blood pressure (BP), although the reason has not been revealed. The present study aimed to establish the reason why SG decreases BP. METHODS: Male Sprague-Dawley rats were subjected to surgical (sham operation or SG) and dietary interventions (fed a normal diet or high-fat diet ad libitum or fed by pair-feeding [PF]). Systolic BP (SBP), urinary sodium excretion, and endocrine parameters were examined 4 weeks after surgery. RESULTS: Both SG and PF rats had reduced body weight compared with SO rats fed normal diet or high-fat diet ad libitum. SG rats exhibited a reduction in SBP compared with PF, which was associated with a reduction in renal renin, angiotensin II, and catechol-O-methyltransferase levels (P < 0.01 for each). SG increased plasma cholecystokinin (CCK) levels compared with PF (P < 0.0001 for each), whereas glucagon-like peptide 1 and peptide YY were not changed in fasting. Exogenous administration of CCK reduced renal catechol-O-methyltransferase (P = 0.0233), renin (P < 0.0001), and angiotensin II (P < 0.0001) levels and SBP (P = 0.0053). CONCLUSIONS: SG reduced SBP, at least in part, through suppression of sympathetic nerve action by elevation of CCK, which was followed by suppression of the intrarenal renin-angiotensin system.