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Introduction:The aim of the study was to explore the association between urate-lowering agents and reduced response to erythropoietin-stimulating agents in patients suffering from chronic kidney disease G5. Methods:We conducted a cross-sectional, multicenter study in Japan between April and June 2013, enrolling patients aged 20 years or older with an estimated glomerular filtration rate of ≤15 mL/min/1.73 m2. Exclusion criteria encompassed patients with a history of hemodialysis, peritoneal dialysis, or organ transplantation. The patients were categorized into four groups based on the use of urate-lowering drugs: high-dose allopurinol (>50 mg/day), low-dose allopurinol (≤50 mg/day), febuxostat, and no-treatment groups. We used a multivariable logistic regression model, adjusted for covariates, to determine the odds ratio (OR) for erythropoietin hyporesponsiveness, defined by an erythropoietin resistance index (ERI) of ≥10, associated with urate-lowering drugs. Results:A total of 542 patients were included in the analysis, with 105, 36, 165, and 236 patients in the high-dose allopurinol, low-dose allopurinol, febuxostat, and no-treatment groups, respectively. The median and quartiles of ERIs were 6.3 (0, 12.2), 3.8 (0, 11.2), 3.4 (0, 9.8), and 4.8 (0, 11.2) in the high-dose allopurinol, low-dose allopurinol, febuxostat, and no-treatment groups, respectively. The multivariate regression model showed a statistically significant association between the high-dose allopurinol group and erythropoietin hyporesponsiveness, compared to the no-treatment group (OR = 1.98, 95% confidence interval: 1.10–3.57). Conclusions:Our study suggests that the use of high-dose allopurinol exceeding the optimal dose may lead to hyporesponsiveness to erythropoiesis-stimulating agents. This study aimed to investigate the link between urate-lowering drugs and a reduced response to erythropoietin-stimulating agents in patients with chronic kidney disease. The study included 542 patients in Japan with an estimated glomerular filtration rate of ≤15 mL/min/1.73 m2, who were divided into four groups based on their use of urate-lowering drugs: high-dose allopurinol (>50 mg/day), low-dose allopurinol (≤50 mg/day), febuxostat, and no treatment. The researchers used a statistical model to analyze the odds ratio for erythropoietin hyporesponsiveness associated with the use of urate-lowering drugs. The study found a significant association between high-dose allopurinol use and erythropoietin hyporesponsiveness when compared to the no-treatment group. The results suggest that using high doses of allopurinol may lead to a decreased response to erythropoiesis-stimulating agents. The study was conducted between April and June 2013, and patients with a history of hemodialysis, peritoneal dialysis, or organ transplantation were excluded. The findings of this study may be useful for clinicians treating patients with chronic kidney disease who are taking urate-lowering drugs and need erythropoietin-stimulating agents.

ObjectivesThe COVID-19 pandemic has had variable effects on the rates of STIs reported across the globe. This study sought to assess how the number of STI reports changed during the pandemic in Japan.MethodsWe used national infectious disease surveillance data from the National Institute of Infectious Diseases (Tokyo, Japan) for the period between January 2013 and December 2021. We compared reported rates of chlamydia, gonorrhoea, condyloma acuminata and genital herpes, as well as total notifications for HIV/AIDS and syphilis during the pandemic versus previous years in Japan. We used a quasi-Poisson regression to determine whether any given week or month between January 2018 and December 2021 had a significant excess or deficit of STIs. Notification values above or below the 95% upper and lower prediction thresholds were considered as statistically significant. The start of the pandemic was defined as January 2020.ResultsChlamydia generally remained within predicted range during the pandemic period. Reporting of gonorrhoea was significantly higher than expected throughout early-to-mid 2021 but otherwise generally remained within predicted range prior to 2021. Condyloma, herpes and HIV/AIDS reporting were transiently significantly lower than expected throughout the pandemic period, but no significant periods of higher-than-expected reporting were detected. Syphilis showed widespread evidence of significantly lower-than-predicted reporting throughout 2020 but eventually reversed, showing significantly higher-than-predicted reporting in mid-to-late 2021.ConclusionsThe COVID-19 pandemic was associated with variable changes in the reporting of STIs in Japan. Higher-than-predicted reporting was more likely to be observed in the later phases of the pandemic. These changes may have been attributable to pandemic-related changes in sexual behaviour and decreased STI clinic attendance and testing, but further research on the long-term impact of the pandemic on STIs is necessary.

Study objective: Human T-lymphotropic virus type 1 (HTLV-1) is closely associated with the development of certain pulmonary diseases, such as bronchiolitis, although the pathologic mechanism remains unclear. To elucidate the [...]

To enhance CH4conversion values in oxidative coupling of methane (OCM) reactions under an O2-lean condition (CH4/O2= 6.0), a support vector regression (SVR) and one-hot encoding manner implemented machine learning (ML) is examined. From an open-source high-throughput screening (HTS) database of 300 OCM catalysts made by random sampling from a materials space, the top 10 three-element-supported catalysts with C2yield higher than 11.0% and C2selectivity higher than 80.0% at CH4/O2= 6.0 were selected as targets for modification. Then, ML-aided investigation of an additive fourth element as a promoter was performed at the SVR field based on the HTS database among 350 catalysts (40,330 data points). Application of one-hot encoding to ascertain positive elements for CH4conversion revealed that manganese (Mn) frequently appears at CH4conversion higher than 44.0%. After the 10 selected catalysts were prepared with the Mn additive, their OCM performance was compared with those of pristine three-element-supported catalysts. Results show that four catalysts represent positive features on C2yield in the presence of additive Mn working as a promoter. Consequently, 5 wt % Mn-loaded LiFeBa/La2O3and LiBaLa/La2O3, respectively, show attractive OCM performance of 16.3% C2yield with 88.4% selectivity and 13.8% C2yield with 71.9% selectivity, even under an O2-lean condition (CH4/O2= 6.0).

Rapid and efficient isolation of intact lysosomes is necessary to study their functions and metabolites by proteomic analysis. We developed a swift and robust nanoparticle-based magnetic separation method in which magnetic–plasmonic hybrid nanoparticles (MPNPs) conjugated with amino dextran (aDxt) were targeted to the lumen of lysosomes viathe endocytosis pathway. For well-directed magnetic separation of the lysosomes, it is important to trace the intracellular trafficking of the aDxt-conjugated MPNPs (aDxt-MPNPs) in the endocytosis pathway. Therefore, we analyzed the intracellular transport process of the aDxt-MPNPs by investigating the time-dependent colocalization of plasmonic scattering of aDxt-MPNPs and immunostained marker proteins of organelles using the threshold Manders’ colocalization coefficient (Rt). Detailed analysis of time variations of Rtfor early and late endosomes and lysosomes allowed us to derive the transport kinetics of aDxt-MPNPs in a cell. After confirming the incubation time required for sufficient accumulation of aDxt-MPNPs in lysosomes, the lysosomes were magnetically isolated as intact as possible. By varying the elapsed time from homogenization to complete isolation of lysosomes (tdelay) and temperature (T), the influences of tdelayand Ton the protein composition of the lysosomes were investigated by polyacrylamide gel electrophoresis and amino acid analysis. We found that the intactness of lysosomes could become impaired quite quickly, and to isolate lysosomes as intact as possible with high purity, tdelay= 30 min and T= 4 °C were optimal settings.

Herein, multi-component La2O3-based catalysts for the oxidative coupling of methane (OCM) were designed based on high-throughput screening (HTS) and literature datasets with multi-output machine learning (ML) approaches including random forest regression (RFR), support vector regression (SVR), Gaussian process regression (Bayesian), and itemset mining (LCM). The combined use of HTS data and SVR successively assisted the search for 11 types of multi-component La2O3-based OCM catalysts in 20 validations with C2yields appearing at 450 °C based on indirect ML assistance. The appropriate multi-component predicted from ML contributed to the determination of a characteristic feature of the lower onset temperature for an La2O3-based OCM catalyst. The LCM application on the SVR extended HTS data area supported the observation of the effective elements in the HTS area. However, a challenging subject remains, i.e., 2 types of multi-component La2O3-based catalysts afforded an effective C2yield (>5.0%) at 450 °C, as inferred from the 20 selected types of catalyst validation. Thus, to predict unique multi-component La2O3-based OCM catalysts further, a combination of HTS and literature data was applied for four ML approaches. This was helpful to discover 17 additional combinations of multi-component La2O3-based catalysts affording effective C2yields (>5.0%) at 450 °C in the 38 selected types of predictions. In total, 30 new types of multi-component La2O3-based catalysts with a C2yield greater than 5.0% at 450 °C in CH4/O2= 2.0 condition were found based on the indirect ML assistance driven by HTS and literature data.

Background. The authors encountered six patients with Kaposi sarcoma in Okinawa; one was classic type, two were associated with adult T-cell leukemia (ATL), one was with multiple myeloma, and two were with acquired immune deficiency syndrome (AIDS). In the classic type, many nodular lesions were seen on the skin of the extremities and a few on the trunk, some of which were ulcerated. Most lesions regressed in 1.5 years. In four other patients (three without AIDS and one with AIDS), many plaques and a few nodular lesions were seen on the trunk, face, and extremities. The other patient with AIDS showed Kaposi sarcoma only in the lymph nodes and perineural tissues in the abdomen. Methods. Immunohistochemical and lectin histochemical studies were done on deparaffinized sections and on cells cultured from small pieces of tumor mass from the classic type Kaposi sarcoma. Isolation of viruses from tumor tissue was also attempted. Results. Large numbers of endothelial cells lining irregular vascular spaces, and some spindle cells showed positive reactions for Factor VIII-related antigen, Ulex europaeus 1 (UEA-1) (E.Y. Labs, Inc., San Mateo, CA), Griffonia simplicifolia (GS-1) (E.Y. Labs, Inc.) lectins, and epidermal growth factor (EGF) receptor antigen. Cytomegalovirus (CMV), hepatitis B, herpes simplex virus (HSV) 1 and 2, papillomavirus antigens, and human immunodeficiency virus (HIV) p24 core antigen were not seen in any patients, except in the patient with AIDS in whom CMV was demonstrated in tissues adjacent to the tumor (Patient 6). In cell culture, elongated spindle cells proliferated in plate and also in three-dimensional cultures. The cells were positive immunohistochemically for Factor VIII-related antigen and EGF receptor. They also stained lectin histochemically with UEA-1 and GS-1. Tube formations were demonstrated by electron microscopic study. Conclusions. Six cases of Kaposi sarcoma have been diagnosed within a short time span where this condition has previously been said to be rare. The studies suggest a vascular endothelial cell origin and growth factor regulated growth for this tumor. Cancer 1992; 70:861-868.

Direct design of low temperature oxidative coupling of methane (OCM) catalysts is proposed viamachine learning and data mining. 58 OCM catalysts are experimentally synthesized and evaluated. The collected 58 sets of data are then classified by unsupervised machine learning in a multi-dimensional space where an active catalyst group for low temperature OCM is identified. Data mining then identifies the physical rule within the group. Catalysts satisfying such a physical rule are designed where 2 undiscovered low temperature OCM catalysts are found and experimentally validated. Thus, machine learning and data mining reveal the hidden physical rule behind the catalysis leading to the direct design of catalysts. Hence, machine learning and data mining open up the insight on a powerful strategy for designing catalysts.

Expectations for industrial implementation of direct conversion of CH4to CH3OH are growing with the increasing demand for energy-efficient chemical processes. In this study, catalytic production of CH3OH by direct oxidation of CH4with O2was performed using Cu zeolite catalysts in a CH4/O2/H2O flow reaction. Among the various Cu zeolites investigated, the Cu-MOR catalyst exhibited relatively high CH3OH production with a turnover number of 7.4 molCH3OHmolCu−1over 24 h (CH4conversion: 0.011%). The catalytically active Cu species and catalytic cycle were investigated by in situsimultaneous X-ray absorption and infrared spectroscopy. The results suggest that the key to the catalytic cycle over Cu-MOR is the redox of Cu(i)/Cu(ii) species. Furthermore, H2O-adsorption-included dynamic Cu species are revealed to be catalytically active.

The lack of theoretical understanding of X-ray absorption near-edge structure (XANES) spectroscopy necessitates the development of analysis tools for its study. Here, an algorithm for judicious choice of local minima and maxima points of the XANES spectrum (experimental or simulated) is proposed, without any loss of information neither on the peak location nor on the peak strength. The method is named the Rising Sun Envelope Method and is based on successive regularizations of the spectral measurement that, according to parameter choices that are intrinsic to the measurements, keep the peak location and strength as invariants. This is the first method that finds peaks in XANES automatically, without depending on first derivative information. Nevertheless, a direct computation of the absorption edge is provided, overcoming the low quality and poor information given by inflection point computations based on the XANES second derivative: computations of inflection points from a higher quality cubic spline approximation are used instead. To illustrate its use, the algorithm is applied to XANES, electron energy-loss spectroscopy, and Raman spectra.

Supplemental Digital Content is available in the text.

Obesity and metabolic syndrome are threats to the health of large population worldwide as they are associated with high mortality, mainly linked to cardiovascular diseases. Recently, CPN-116 (CPN), which is an agonist peptide specific to neuromedin-U receptor 2 (NMUR2) that is expressed predominantly in the brain, has been developed as a new therapeutic candidate for the treatment of obesity and metabolic syndrome. However, treatment with CPN poses a challenge due to the limited delivery of CPN to the brain. Recent studies have clarified that the direct anatomical connection of the nasal cavity with brain allows delivery of several drugs to the brain. In this study, we confirm the nasal cavity as a promising CPN delivery route to the brain for the treatment of obesity and metabolic syndrome. According to the pharmacokinetic study, the clearance of CPN from the blood was very rapid with a half-life of 3 min. In vitrostudy on its stability in the serum and cerebrospinal fluid (CSF) indicates that CPN was more stable in the CSF than in the blood. The concentration of CPN in the brain was higher after nasal administration, despite its lower concentrations in the plasma than that after intravenous administration. The study on its pharmacological potency suggests the effective suppression of increased body weight in mice in a dose-dependent manner due to the direct activation of NMUR2 by CPN. This results from the higher concentration of corticosterone in blood after nasal administration of CPN as compared to nasal application of saline. In conclusion, the above findings indicate that the nasal cavity is a promising CPN delivery route to the brain to treat obesity and metabolic syndrome.

Whether polycystic ovary syndrome (PCOS) affects bone health during a woman's lifespan remains controversial. An androgenized rodent model replicated many metabolic and reproductive features of women with PCOS, and we aimed to use it to investigate the impact of androgens on microarchitecture (by micro-CT), bone mechanical strength, bone formation and resorption markers in rats with intact ovaries (SHAM) who underwent oophorectomy.

Countries in the Southeast Asia region have a high prevalence of soil-transmitted helminth, such as roundworm, whipworm, and hookworms [Ancylostoma duodenale, Necator americanus, Ancylostoma ceylanicum]. Recent molecular-based surveys have revealed that A. ceylanicum, a zoonotic hookworm, is likely the second most prevalent hookworm species infecting humans in that part of the world, while others have noted that this infection is an emerging public health risk not only for indigenous people but also for visitors from other countries. We recently encountered four cases of A. ceylanicuminfection in Japanese individuals who returned from Southeast Asia and Papua New Guinea. Case 1 was a 25-year-old male who stayed in a rainforest in Malaysia for 4 weeks, where he developed abdominal pain and diarrhea in the third week. Eleven adult worms (five males, six females) were expelled after treatment with pyrantel pamoate and identified as A. ceylanicumbased on morphological characteristics and DNA sequences of the mitochondrial cytochrome c oxidase subunit 1 (cox1) gene. Case 2 was a 26-year-old male who spent 2 years as an overseas cooperation volunteer for agriculture in Papua New Guinea. He did not note any symptoms at that time, though eggs were detected in feces samples at a medical check-up examination after returning. Although collection of adult worms was unsuccessful, DNA analysis of the eggs for cox1 and the ribosomal internal transcribed spacer (ITS)-1 and ITS-2 genes demonstrated that they were A. ceylanicum.Case 3 was a 47-year-old male who spent 1 month in a rural village in Lao People’s Democratic Republic and began suffering from watery diarrhea from the third week. A total of nine adult worms (three males, six females) were collected by endoscopic procedures and following treatment with pyrantel pamoate. Morphological examination and molecular analyses of the cox1 gene showed that they were A. ceylanicum.Case 4 was a 27-year-old male who participated in group travel to India for 5 days. Three weeks after returning, he developed abdominal pain and diarrhea. Hookworm eggs were found in feces samples and developed into larvae in culture, which were identified as A. ceylanicumbased on molecular analysis of the cox1 gene.Eosinophilia was observed in all of the cases prior to treatment. A. ceylanicumshould be recognized as an important etiologic pathogen of hookworm diseases in travelers to countries in the Southeast Asia and West Pacific Ocean regions.

Materials and catalyst informatics are emerging fields that are a result of shifts in terms of how materials and catalysts are discovered in the fields of materials science and catalysis. However, these fields are not reaching their full potential due to issues related to database creation and curation. Issues such as lack of uniformity, data selectivity, and the presence of bias affect the quality and usefuless of materials databases, especially when attempting to search for materials descriptors. Without uniform rules and frameworks, databases are limited in use outside of the intent of the creators of the database. Ontologies are therefore investigated as a means of redesigning the way materials and catalysts databases are designed and created. In particular, an ontology consisting of information found within the periodic table as well as commonly used related data is constructed and applied toward the search for materials descriptors. Additional ontologies are also developed for two databases—a database consisting of computational data related to perovskites and a database consisting of experimental data related to oxidative coupling of methane (OCM) catalysts—in order to investigate the impact of merging ontologies.

AbstractGas chromatographic analysis of Citrus tachibana(Makino) Tanaka peel essential oil showed that the volatile composition contained 111 components including monoterpenes, sesquiterpenes and oxygenated compounds. Limonene (69.1 %), γ-terpinene (10.5 %) and β-pinene (5.07 %) were the major components. Linalool (0.95 %) and linalyl acetate (1.01 %) were the major oxygenated compounds. We first analysed the key aroma compounds by aroma extract dilution analysis. Among 33 compounds with flavour dilution (FD) factors that were >4, α-pinene (pine, FD = 2048), β-pinene (pungent, FD = 1024) and linalool (floral, FD = 1024) were the predominant odorants. Vinyl ketones and unsaturated aliphatic aldehydes were also determined, even though they were present at very low concentrations: (Z)-1,5-octadien-3-one (pungent, metallic), 1-nonen-3-one (mushroom, metallic), 7-methyl-1,6-octadien-3-one (mushroom, metallic), (Z)-2-nonenal (tallowy), (E)-2-nonenal (fatty, rice), (Z)-4-decenal (spicy, waxy), (Z)-2-decenal (fatty), (E,Z)-2,4-decadienal (fatty, rice), (E,Z)-2,7-decadienal (cucumber), (E,E,Z)-2,4,7-decatrienal (green, orange), trans-4,5-epoxy-(E)-2-decenal (albedo) and trans-4,5-epoxy-(E,Z)-2,7-decadienal (albedo). These compounds may be important to the Tachibana aroma.

To clarify the role of serotonin (5-HT) in the prevention of stress urinary incontinence (SUI) during sneezing, we investigated the effect of intraperitoneal application of p-chlorophenylalanine (PCPA; a serotonin synthesis inhibitor) and intravenous application of CP-809101 (a 5-HT2Cagonist) or LP44 (a 5-HT7agonist) using female rats, in which the neurally evoked continence reflex during sneezing was examined. Amplitudes of urethral pressure response during sneezing (A-URS), urethral baseline pressure (UBP) at the middle urethra, and sneeze-induced leak point pressure (S-LPP) were measured in normal female adult rats with or without drug administration. PCPA decreased A-URS by 35.1 cmH2O and UBP by 13.3 cmH2O compared with normal rats. In PCPA-administrated rats, CP-809101 increased A-URS by 24.1 cmH2O and UBP by 15.1 cmH2O, and LP44 also increased A-URS by 20.6 cmH2O and UBP by 11.4 cmH2O compared with rats treated with PCPA alone. SUI was observed with S-LPP of 40.1 cmH2O in PCPA-administrated rats, in which CP-809101 and LP44 increased S-LPP by 28.0 and 15.2 cmH2O, respectively, compared with rats treated with PCPA alone. The effects of CP-809101 and LP44 were antagonized by SB-242084 (a selective 5-HT2Cantagonist) and SB-269970 (a selective 5-HT7antagonist), respectively. These results indicate that activation of 5-HT receptors enhances the active urethral closure reflex during sneezing, at least in part via 5-HT2Cand 5-HT7receptors.

Multiple vaginal parities have been reported to be an important risk factor for stress urinary incontinence (SUI). Simulated birth trauma with single vaginal distention (VD) has been used to induce the SUI condition in animals; however, the effect of multiple simulated birth traumas on the urethral continence function has not been well characterized. Therefore, we examined the effects of multiple VDs on urethral functions in vivo and the changes in gene expressions of several molecules in the urethra using female SD rats, which were divided into three groups; sham, VD-1 (single VD), and VD-3 groups (3 times of VDs every 2 wk). Two weeks after the final VD, leak point pressure (LPP) and urethral responses during sneezing were evaluated. Also, changes in mRNA levels of urethral molecules were quantified with RT-PCR.　The VD-1 group did not show any change in LPP with only a tendency of decrease in amplitudes of the urethral responses during sneezing (A-URS); however, the VD-3 group showed a significant decrease in LPP and urethral responses such as baseline urethral pressure and A-URS accompanied with SUI episodes during sneezing. Nicotinic receptor subtypes and transforming growth factor (TGF)-β1 were significantly increased in both VD-1 and VD-3 groups while TNF receptor (TNFR)-1, IL-6, collagens, and matrix metalloproteinases-9 were significantly increased only in the VD-3 group.　These data indicate that rats with multiple simulated birth traumas exhibit profound impairment of the urethral continence function and that these functional changes are associated with those in cytokines, extracellular matrix molecules, and nicotinic receptor subtypes in the urethra.

The lower urinary tract’s main functions are storage and elimination. The micturition reflex pathway is modulated by the spinobulbospinal reflex pathway as well as higher brain centers involved in the voluntary micturition control. Micturition is sensitive to numerous injuries, resulting in various types of dysfunction. Animal studies indicate that lower urinary tract dysfunction partly depends on plasticity of the neural pathways. Reflex plasticity is associated with changes in ion channels, receptors, and numerous mediators. Animal models may aid in understanding the mechanisms leading to pathologic conditions and the plasticity in reflex pathways to the lower urinary tract after neurogenic lesions.

Application of highly N-doped buffer layers or a (N+B)-doped buffer layer to PiN diodes to suppress the expansion of Shockley stacking faults (SSFs) from the epilayer/substrate interface was studied. These buffer layers showed very short minority carrier lifetimes of 30–200 ns at 250°C. The PiN diodes were fabricated with buffer layers of various thicknesses and were then tested under high current injection conditions of 600A/cm2. The thicker buffer layers with shorter minority carrier lifetimes demonstrated the suppression of SSFs expansion and thus that of diode degradation.

We investigated the expansion of stacking faults (SFs) under a high current pulse stress in detail. In situ observations showed bar-shaped SFs and two types of triangle SFs with different nucleation sites. The calculated partial dislocation velocity of the bar-shaped SFs was four times faster than that of the triangle SFs. The temperature dependence of the partial dislocation velocity was used to estimate activation energies of 0.23±0.02 eV for bar-shaped SFs and 0.27±0.05 eV for triangle SFs. We also compared the electrical characteristics before and after the stress. The forward voltage drop slightly increased by 0.05 V, and the leakage current did not increase.

Background:Bone morphogenetic protein-3b (BMP-3b) is a member of the transforming growth factor-β superfamily and has several activities that differ from those of other BMPs. We previously found that BMP-3b is highly expressed in adipocytes, its level is increased during obesity, and it inhibits adipogenesis by suppressing peroxisome proliferator-activated receptor γ (PPARγ) in vitro. However, the function of BMP-3b in adipose tissues in vivo remains unknown.Methods:To determine the role of BMP-3b overexpression in adipose tissues in vivo, we generated transgenic mice (BMP-3b Tg) by using a conditional overexpression approach in fatty acid-binding protein 4-expressing adipocytes. We examined BMP-3b Tg mice fed a high-fat diet to elucidate the effects of BMP-3b on obesity. Adipocyte function was evaluated as expression of adipogenic and lipogenic markers in adipose tissue. We also performed glucose and insulin tolerance tests (GTT and ITT, respectively), and biochemical analysis of serum and measured energy expenditure by indirect calorimetry.Results:BMP-3b Tg mice fed a high-fat diet showed decreases in weight gain, fat-pad mass and adipocyte area, compared with wild-type mice. The adipose tissues of BMP-3b Tg mice showed downregulated expression of PPARγ and its target gene encoding fatty acid translocase/CD36. In addition, BMP-3b Tg mice had decreased blood glucose levels on GTT and ITT, and their serum leptin levels were decreased and adiponectin concentrations were increased. These changes in BMP-3b Tg mice were accompanied by increased energy expenditure, indicated as increased locomotor activity and oxygen consumption.Conclusions:These results provide in vivo evidence that BMP-3b regulates adipocyte function to cause an anti-obesity effect.

An inability to proliferate at high temperatures typically gives viruses an attenuated phenotype. Here, we present a protocol to obtain and isolate temperature-sensitive (TS) SARS-CoV-2 strains via 5-fluorouracile-induced mutagenesis. We describe steps for the induction of mutations in the wild-type virus and selection of TS clones. We then show how to identify the mutations associated with the TS phenotype, following forward and reverse genetics strategies.

For patients with unstable abdominal trauma unresponsive to initial transfusion, the damage control strategy includes prompt hemostasis by open surgery and packing. Recently, a hybrid treatment that combines packing and transcatheter arterial embolization as a damage control strategy was reported to be effective; however, the indications and techniques are yet to be established. A 25-year-old male patient who was in shock due to severe liver injury after a traffic accident was brought to our emergency room by emergency services. After initial resuscitation, including resuscitative endovascular balloon occlusion of the aorta and blood transfusion, preoperative contrast-enhanced computed tomography indicated grade IV liver injury with active bleeding from the right hepatic artery. Damage control strategy with packing and subsequent transcatheter arterial embolization was determined to be useful. During treatment, bile leakage was observed. An endoscopic nasobiliary drainage tube was inserted, and the patient was treated conservatively. He was discharged on day 83 of hospitalization. Although using preoperative contrast-enhanced computed tomography before damage control surgery remains controversial, it can provide useful information to determine damage control strategy, including morphological evaluation of the injured area and the presence of active bleeding.

We investigated the effects of geranium essential oil (GEO) on anaphylaxis. GEO can exert antioxidant and anti-inflammatory effects, but its roles in allergic reactions are incompletely understood. Here, we used mouse cells to show that GEO inhibited the degranulation of cultured mast cells (CMCs). Citronellol is the major component of GEO and inhibited CMC degranulation. The l-enantiomer of citronellol more effectively suppressed CMC degranulation than did d-citronellol. We also examined whether citronellol could inhibit the immunoglobulin (Ig) E-induced production of tumor necrosis factor (TNF)-α. Treatment with various concentrations of citronellol before CMC activation with IgE significantly inhibited the induction of TNF-α in a dose-dependent manner. Mechanistically, citronellol suppressed the phosphorylation of mitogen-activated protein kinase (ERK), which is critical for ERK activation and the production of inflammatory cytokines in mast cells. These findings suggest that citronellol may represent a candidate compound for the effective treatment of allergic diseases.

Plant leaves administered with systemic insecticides as agricultural chemicals were analyzed using imaging mass spectrometry (IMS). Matrix-assisted laser desorption/ionization (MALDI) is inadequate for the detection of insecticides on leaves because of the charge-up effect that occurs on the non-conductive surface of the leaves. In this study, surfaceassisted laser desorption/ionization with a sputter-deposited platinum film (Pt-SALDI) was used for direct analysis of chemicals in plant leaves. Sputter-deposited platinum (Pt) films were prepared on leaves administered with the insecticides. A sputter-deposited Pt film with porous structure was used as the matrix for Pt-SALDI. Acephate and acetamiprid contained in the insecticides on the leaves could be detected using Pt-SALDI-MS, but these chemical components could not be adequately detected using MALDI-MS because of the charge-up effect. Enhancement of ion yields for the insecticides was achieved using Pt-SALDI, accompanied by prevention of the charge-up effect by the conductive Pt film. The movement of systemic insecticides in plants could be observed clearly using Pt-SALDI-IMS. The distribution and movement of components of systemic insecticides on leaves could be analyzed directly using Pt-SALDI-IMS. Additionally, changes in the properties of the chemicals with time, as an indicator of the permeability of the insecticides, could be evaluated.

A tetracopper(II) complex containing two oxalate anions in the metal-based host cavity, [Cu4(Lpy)(µ-ox)2](PF6)2·2(2-PrOH), where ox2−: oxalato (C2O42−), was prepared by reacting H2Lpy, a phenol-based tetranucleating macrocyclic ligand with four pyridylmethyl pendant arms, Cu(ClO4)2·6H2O, and sodium oxalate (1:4:2 stoichiometry, respectively) in methanol, followed by exchange of the counteranion with excess of NH4PF6. Single-crystal X-ray diffraction of 1revealed that two {Cu(II)Cu(II)} units, bridged by a phenolato group of Lpy2−, were connected by two oxalato anions, to construct a rectangular “{CuCu}(µ-ox)2{CuCu}” tetranuclear framework. This rectangular framework was maintained in DMF solution. The magnetic measurement of 1in the 2–300 K range revealed antiferromagnetic behavior. The antiferromagnetic interaction in this complex occurs between the Cu(II) centers bridged by an oxalate (J= −140 cm−1).

Background:: We prospectively examined influence of androgen deprivation therapy (ADT) on lipid and glucose metabolisms in Japanese patients with prostate cancer. Methods:: Patients with prostate cancer who were hormone-naive and scheduled to receive long-term ADT were recruited between 2011 and 2013. Body weight, abdominal circumference and blood testing associated with lipid and glucose metabolism were recorded every 3 months during 1 year of ADT. Computed tomography (CT) was performed to measure areas of subcutaneous and visceral fat before and after 1 year of ADT. ADT was limited to a luteinizing hormone-releasing hormone (LHRH) agonist with or without bicalutamide. Results:: Of 218 patients registered, data were available from 177 patients who completed 1 year of ADT. Of these, CT was performed before and after 1 year of ADT in 88 patients. Median age was 75 years (range, 49–85 years). Median PSA before ADT was 16.7 ng ml−1(range, 0.3–3316). Clinical stage was B (54.2%), C (23.2%) and D (20.9%). Mean increases in body weight and abdominal circumference after 1 year of ADT were 2.9 and 3.0%, respectively. Mean increases in total, low-density lipoprotein and high-density lipoprotein cholesterol and triglycerides were 10.6, 14.3, 7.8 and 16.2%, respectively. Mean increases in fasting blood sugar and hemoglobin A1c (HbA1c) were 3.9 and 2.7%, respectively. Lipid alterations were noted in patients without comorbidities, whereas changes in HbA1c were noted in patients with diabetes mellitus at baseline. These lipid and glucose alterations were prominent in the early ADT period. Both visceral and subcutaneous fat, as measured by CT, increased by >20%. The increase in subcutaneous fat was significantly greater than that in visceral fat (P=0.028). Conclusions:: One year of ADT significantly changed lipid and glucose metabolism in Japanese patients with prostate cancer. Patient characteristics or comorbidities at baseline may be associated with ADT-induced metabolic changes.

The rainbow schlieren deflectometry has been combined with the computed tomography to obtain three-dimensional density fields of shock containing free jets and we call the method the schlieren CT. Experiments on the schlieren CT have been performed at a nozzle pressure ratio of 4.0 by using an axisymmetric convergent nozzle with an inner diameter of 10 mm at the exit where the nozzle was operated at an underexpanded condition. Multidirectional rainbow schlieren pictures of an underexpanded sonic jet can be acquired by rotating the nozzle about its longitudinal axis in equal angular intervals and the three-dimensional density fields are reconstructed by the schlieren CT. The validity of the schlieren CT is verified by a comparison with the density fields reconstructed by the Abel inversion method. As a result, it is found that excellent quantitative agreement is reached between the three-dimensional jet density fields reconstructed from both methods.

Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) bind to the receptor guanylyl cyclase (GC)-A, leading to diuresis, natriuresis, and blood vessel dilation. In addition, ANP and BNP have various angiogenic properties in ischemic tissue. When breeding mice devoid of GC-A, we noted significant skewing of the Mendelian ratio in the offspring, suggesting embryonic lethality due to knockout of GC-A. Consequently, we here investigated the roles of endogenous ANP and BNP in embryonic neovascularization and organ morphogenesis. Embryos resulting from GC-A−/−× GC-A+/−crosses developed hydrops fetalis (HF) beginning at embryonic day (E)14.5. All embryos with HF had the genotype GC-A−/−. At E17.5, 33.3% (12 of 36) of GC-A−/−embryos had HF, and all GC-A−/−embryos with HF were dead. Beginning at E16.0, HF-GC-A−/−embryos demonstrated poorly developed superficial vascular vessels and sc hemorrhage, the fetal side of the placenta appeared ischemic, and vitelline vessels on the yolk sac were poorly developed. Furthermore, HF-GC-A−/−embryos also showed abnormal constriction of umbilical cord vascular vessels, few cardiac trabeculae and a thin compact zone, hepatic hemorrhage, and poor bone development. Electron microscopy of E16.5 HF-GC-A−/−embryos revealed severe vacuolar degeneration in endothelial cells, and the expected 3-layer structure of the smooth muscle wall of the umbilical artery was indistinct. These data demonstrate the importance of the endogenous ANP/BNP-GC-A system not only in the neovascularization of ischemic tissues but also in embryonic vascular development and organ morphogenesis.

The [{Fe(Me3tacn)}2(µ-P2O7)(µ-HPO4)]·12H2O dinuclear Fe2(III, III) complex was prepared. The HPO42-bridge in the complex arises from hydrolysis of the pyrophosphate bound to the Fe(III) centers in the trinuclear [{Fe(Me3tacn)}3(P2O7)2]+intermediate. Electrochemical reduction of this complex at pH <3.2 results in dissociation of the H2PO4-bridge.The [{Fe(Me3tacn)}2(µ-P2O7)(µ-HPO4)]·12H2O dinuclear Fe2(III, III) complex was prepared. The HPO42-bridge in the complex arises from hydrolysis of the pyrophosphate bound to the Fe(III) centers in the trinuclear [{Fe(Me3tacn)}3(P2O7)2]+intermediate. Electrochemical reduction of this complex at pH <3.2 results in dissociation of the H2PO4-bridge.

Platinum complexes with 1,4,7-triazacyclononane (tacn) as facial ligands, [PtIVCl3(tacn)](ClO4), [PtIVCl(bpy)(tacn)](ClO4)3([1](ClO4), and [2](ClO4)3, bpy: 2,2′-bipyridine) were prepared, and their hexa-coordinated octahedral structures were determined via single-crystal X-ray analysis. In aqueous solutions containing NaCl as the electrolyte, [2]3+exhibited a quasi-reversible two-electron redox wave at +0.22 V (vs. SCE) with a large peak separation (ΔE= Epc− Epa= 0.28 V). In addition, controlled-potential reduction of [2]3+at −0.30 V in aqueous solutions containing NaCl afforded [PtII(bpy)(tacn)]2+([3]2+), which was then re-oxidized to regenerate [2]3+. X-ray analysis of [3]2+revealed a tetra-coordinated square-planar structure in which both tacn and bpy were bound to the central Pt as bidentate ligands. The redox potential of this reaction is coupled with dissociation/association of Cl−from/to Pt in the solution. MO/DFT calculations indicate that structural changes in tacn promote the reversible two-electron redox reaction between the octahedral Pt(IV) and square planar Pt(II) complexes.

Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia-lymphoma (ATL) and inflammatory diseases in a small percentage of infected individuals. Host immune responses, in particular cytotoxic T lymphocytes (CTLs), influence the proliferation and survival of ATL cells and HTLV-1–infected cells. We generated recombinant vaccinia viruses (rVVs) expressing HTLV-1 basic leucine zipper (bZIP) factor (HBZ) or Tax to study the immunogenic potential of these viral proteins. Vaccination with rVV expressing Tax or HBZ induced specific T-cell responses, although multiple boosters were needed for HBZ. HBZ-stimulated T cells killed HBZ peptide-pulsed T cells and CD4+ T cells from HBZ transgenic (HBZ-Tg) mice. The anti-lymphoma effect of the CTLs targeting HBZ was tested in mice inoculated with a lymphoma cell line derived from an HBZ-Tg mouse. Transfer of splenocytes from HBZ-immunized mice increased the survival of the lymphoma cell–inoculated mice, suggesting that the anti-HBZ CTLs have a protective effect. The rVV could also induce specific T-cell responses to HBZ and Tax in HTLV-1–infected rhesus monkeys. On the basis of the results of rVV-vaccinated mice and macaques, we identified a candidate peptide (HBZ157-176) for vaccine development. Dendritic cells pulsed with this peptide could generate HBZ-specific CTLs from human CD8+ T cells. This study demonstrates that HBZ could be a target for immunotherapy of patients with ATL.

4H-SiC(000-1) C-face was oxidized in H2O and H2 mixture gas (H2 rich wet ambient) for the first time. H2 rich wet ambient was formed by the catalytic water vapor generator (WVG) system, where the catalytic action instantaneously enhances the reactivity between H2 and O2 to produce H2O. The dependence of SiC oxidation rate on the H2O partial pressure was investigated. We fabricated 4H-SiC C-face MOS capacitor and MOSFET by the H2 rich wet re-oxidation following the dry O2 oxidation. The density of interface traps was reduced and the channel mobility was improved in comparison with the conventional O2 rich wet oxidation.

Mesenchymal stem cell (MSC) transplantation has been pursued as a new method to repair damaged myocardium. We focused on the fetal membrane (FM) as an alternative source to bone marrow (BM)–derived MSCs. In this study, we investigated whether transplantation of allogeneic FM-MSC sheets could attenuate myocardial dysfunction in a rat chronic myocardial infarction (MI) model.

A high-fat diet (HFD) is a well-known contributing factor in the development of obesity. Most rats fed HFDs become obese. Those that avoid obesity when fed HFDs are considered diet resistant (DR). We performed a microarray screen to identify genes specific to the mesenteric fat of DR rats and revealed high expression of guanylin and guanylyl cyclase C (GC-C) in some subjects. Our histologic studies revealed that the cellular source of guanylin and GC-C is macrophages. Therefore, we developed double-transgenic (Tg) rats overexpressing guanylin and GC-C in macrophages and found that they were resistant to the effects of HFDs. In the mesenteric fat of HFD-fed Tg rats, Fas and perilipin mRNAs were downregulated, and those of genes involved in fatty acid oxidation were upregulated, compared with the levels in HFD-fed wild-type rats. In vitro studies demonstrated that lipid accumulation was markedly inhibited in adipocytes cocultured with macrophages expressing guanylin and GC-C and that this inhibition was reduced after treatment with guanylin- and GC-C-specific siRNAs. Our results suggest that the macrophagic guanylin-GC-C system contributes to the altered expression of genes involved in lipid metabolism, leading to resistance to obesity.

A tetranucleating macrocyclic ligand bearing four acetate pendants, L6-, was newly yielded by a stepwise synthesis from [Zn4(L')(AcO)2(OH)2](ClO4)2·H2O (1), which was prepared from [2 + 2] Schiff-base condensation of 2,6-diformyl-4-methylphenol and 1,2-bis(2-aminoethoxy)ethane in the presence of Zn(ClO4)2·6H2O, sodium acetate, and triethylamine. A µ4-oxo tetracopper(II) complex [Cu4(L)(µ4-O)]·H2O (2) was obtained from the reaction of Cu(ClO4)2·6H2O and Na2H4Lin methanol under basic conditions, and characterized by X-ray crystallography. Two adjacent copper centers were bridged by the phenoxo oxygen of L6-to form [Cu2(µ-OPh)] unit, two pairs of which were further linked by an oxo anion with a distorted tetrahedral geometry, finally creating a tetracopper core [{Cu2(µ-OPh)}2(µ4-O)]. Cryomagnetic measurements of 2in the range of 2–300 K exhibited antiferromagentic behavior. Magnetic analysis of 2was carried out by the four spin-exchange interactions model based on the bridging mode and the Cu–(µ4-O)–Cu angles, JA: Cu1/Cu4, JB: Cu2/Cu3, JC: Cu1/Cu2 and Cu3/Cu4, and JD: Cu1/Cu3 and Cu2/Cu4 pairs. The estimated four magnetic exchange interactions (JA, JB, JC, and JD) were -17, -161, -108, and -109 cm-1, respectively.

Cryptococcus neoformans is an opportunistic fungal pathogen that causes meningoencephalitis in immunocompromised patients. Recently, we reported that Toll-like receptor 9 (TLR9) is involved in host defense against C. neoformans: specifically, it detects the pathogen's DNA. In the present study, we aimed to elucidate the mechanisms underlying TLR9-mediated activation of innate immune responses by using the URA5 gene, which encodes a virulent component of this fungal pathogen. A PCR-amplified 345-bp URA5 gene fragment induced interleukin-12 p40 (IL-12p40) production by bone marrow-derived dendritic cells (BM-DCs) in a TLR9-dependent manner. Similar activity was detected in the 5' 129-bp DNA fragment of URA5 and in a synthesized oligodeoxynucleotide (ODN) with the same sequence. Shorter ODN fragments, which contained GTCGGT or GACGAT but had only 24 or 21 bases, induced IL-12p40 production and CD40 expression by BM-DCs, but this activity vanished when the CG sequence was replaced by GC or when a phosphorothioate modification was introduced. IL-12p40 production caused by active ODN was strikingly enhanced by treatment with DOTAP, a cationic lipid that increases the uptake of DNA by BM-DCs, though DOTAP failed to induce IL-12p40 production by inactive ODN and did not affect the activity of an ODN-containing canonical CpG motif. There was no apparent difference in intracellular trafficking between active and inactive ODNs. Finally, an extremely high dose of inactive ODN suppressed IL-12p40 production by BM-DCs that had been stimulated with active ODN. These results suggest that the C. neoformans URA5 gene activates BM-DCs through a TLR9-mediated signaling pathway, using a mechanism possibly independent of the canonical CpG motif.

ABSTRACTCryptococcus neoformansis an opportunistic fungal pathogen that causes meningoencephalitis in immunocompromised patients. Recently, we reported that Toll-like receptor 9 (TLR9) is involved in host defense against C. neoformans: specifically, it detects the pathogen's DNA. In the present study, we aimed to elucidate the mechanisms underlying TLR9-mediated activation of innate immune responses by using the URA5gene, which encodes a virulent component of this fungal pathogen. A PCR-amplified 345-bp URA5gene fragment induced interleukin-12 p40 (IL-12p40) production by bone marrow-derived dendritic cells (BM-DCs) in a TLR9-dependent manner. Similar activity was detected in the 5′ 129-bp DNA fragment of URA5and in a synthesized oligodeoxynucleotide (ODN) with the same sequence. Shorter ODN fragments, which contained GTCGGT or GACGAT but had only 24 or 21 bases, induced IL-12p40 production and CD40 expression by BM-DCs, but this activity vanished when the CG sequence was replaced by GC or when a phosphorothioate modification was introduced. IL-12p40 production caused by active ODN was strikingly enhanced by treatment with DOTAP, a cationic lipid that increases the uptake of DNA by BM-DCs, though DOTAP failed to induce IL-12p40 production by inactive ODN and did not affect the activity of an ODN-containing canonical CpG motif. There was no apparent difference in intracellular trafficking between active and inactive ODNs. Finally, an extremely high dose of inactive ODN suppressed IL-12p40 production by BM-DCs that had been stimulated with active ODN. These results suggest that the C. neoformansURA5gene activates BM-DCs through a TLR9-mediated signaling pathway, using a mechanism possibly independent of the canonical CpG motif.

Human T-cell leukemia virus type 1 (HTLV-1) is an oncogenic retrovirus that is etiologically associated with adult T-cell leukemia. The HTLV-1 bZIP factor (HBZ), which is encoded by the minus strand of the provirus, is involved in both regulation of viral gene transcription and T-cell proliferation. We showed in this report that HBZ interacted with Smad2/3, and enhanced transforming growth factor-β (TGF-β)/Smad transcriptional responses in a p300-dependent manner. The N-terminal LXXLL motif of HBZ was responsible for HBZ-mediated TGF-β signaling activation. In a serial immunoprecipitation assay, HBZ, Smad3, and p300 formed a ternary complex, and the association between Smad3 and p300 was markedly enhanced in the presence of HBZ. In addition, HBZ could overcome the repression of the TGF-β response by Tax. Finally, HBZ expression resulted in enhanced transcription of Pdgfb, Sox4, Ctgf, Foxp3, Runx1, and Tsc22d1genes and suppression of the Id2gene; such effects were similar to those by TGF-β. In particular, HBZ induced Foxp3 expression in naive T cells through Smad3-dependent TGF-β signaling. Our results suggest that HBZ, by enhancing TGF-β signaling and Foxp3 expression, enables HTLV-1 to convert infected T cells into regulatory T cells, which is thought to be a critical strategy for virus persistence.

Birth trauma and pelvic injury have been implicated in the etiology of stress urinary incontinence (SUI). This study aimed to assess changes in the biomechanical properties and adrenergic-evoked contractile responses of the rat urethra after simulated birth trauma induced by vaginal distension (VD). Urethras were isolated 4 days after VD and evaluated in our established ex vivo urethral testing system that utilized a laser micrometer to measure the urethral outer diameter at proximal, middle, and distal positions. Segments were precontracted with phenylephrine (PE) and then exposed to intralumenal static pressures ranging from 0 to 20 mmHg to measure urethral compliance. After active assessment, the urethra was rendered passive with EDTA and assessed. Pressure and diameter measurements were recorded via computer. Urethral thickness was measured histologically to calculate circumferential stress-strain response and functional contraction ratio (FCR), a measure of smooth muscle activity. VD proximal urethras exhibited a significantly increased response to PE compared with that in controls. Conversely, proximal VD urethras had significantly decreased circumferential stress and FCR values in the presence of PE, suggesting that VD reduced the ability of the proximal segment to maintain smooth muscle tone at higher pressures and strains. Circumferential stress values for VD middle urethral segments were significantly higher than control values. Histological analyses using antibodies against general (protein gene product 9.5) and sympathetic (tyrosine hydroxylase) nerve markers showed a significant reduction in nerve density in VD proximal and middle urethral segments. These results strongly suggest that VD damages adrenergic nerves and alters adrenergic responses of proximal and middle urethral smooth muscle. Defects in urethral storage mechanisms, involving changes in adrenergic regulation, may contribute to stress urinary incontinence induced by simulated birth trauma.

We prepared a new Ru2(III, IV) complex containing a pyrophosphate as the dinucleating component, by the reaction between the mononuclear complex [Ru(Me3tacn)Cl3] and Na4P2O7·10H2O in aqueous solution. Cyclic voltammetric measurement for the complex [{Ru(Me3tacn)}2(µ-O)(µ-P2O7)]PF6(1) in aqueous solution revealed the formation of two species with higher oxidation states, such as [O=Ru(IV)Ru(IV)=O] and [O=Ru(IV)Ru(V)=O]+. Furthermore, this complex showed activity for water oxidation reaction with Ce(NH4)2(NO3)6as the chemical oxidant in acidic aqueous solution.A new dinuclear Ru2(III, IV) complex, [{Ru2(Me3tacn)}2(µ-O)(P2O7)]+with both pyrophosphate (P2O74−) and oxido bridge, is prepared. It could form higher oxidation states such as Ru2(IV, IV) and Ru2(IV, V) in aqueous solution. Evolution of O2was detected from the water oxidization reaction between the present complex and CeIV(NH4)2(NO3)6in acidic aqueous solution.

To clarify the role of spinal serotonergic mechanisms in preventing stress urinary incontinence (SUI) during sneezing, we investigated the effect of intrathecal (it) application of 8-OH-DPAT (a 5-HT1Aagonist), mCPP (a 5-HT2B/2Cagonist), and fluoxetine (a serotonin reuptake inhibitor) using a rat model that can examine the neurally evoked continence reflex during sneezing. Amplitudes of urethral pressure responses during sneezing (A-URS), urethral baseline pressure (UBP) at the midurethra, and sneeze-induced leak point pressure (S-LPP) were measured in normal female adult rats and rats with SUI induced by vaginal distention (VD). In normal rats, 8-OH-DPAT decreased A-URS by 48.9%, whereas mCPP increased A-URS by 33.6%. However, A-URS was not changed after fluoxetine. 8-OH-DPAT, mCPP, or fluoxetine did not alter UBP. The effect of 8-OH-DPAT and mCPP was antagonized by WAY-100635 (it), a selective 5-HT1Aantagonist, and RS-102221 (it), a selective 5-HT2Cantagonist, respectively. Fluoxetine in the presence of WAY-100635 did not change either A-URS or UBP, but fluoxetine in the presence of RS-102221 decreased A-URS. In VD rats, S-LPP was decreased by 14.6 cmH2O after 8-OH-DPAT, whereas it was increased by 12.8 cmH2O after mCPP. However, S-LPP was not changed after fluoxetine. These results indicate that activation of 5-HT2Creceptors enhances the active urethral closure reflex during sneezing at the spinal level, whereas 5-HT1Ainhibits it and that no apparent changes in the sneeze-induced continence reflex after fluoxetine treatment are due to coactivation of excitatory 5-HT2Creceptors and inhibitory 5-HT receptors other than the 5-HT1Asubtype. Thus, activation of excitatory 5-HT receptor subtypes such as 5-HT2Ccould be effective for the treatment of SUI.

The micturition reflex is one of the autonomic reflexes mediated by the spinobulbospinal reflex pathway that passes through the pontine micturition center. In the central nervous system, glutamate is a major excitatory amino acid, while glycine and gamma‐aminobutyric acid (GABA) are major inhibitory neurotransmitters and act to inhibit the micturition reflex at supraspinal and/or spinal sites. Glycine and GABA have additive or synergistic inhibitory effects on bladder activity. Hypofunction of glycinergic/GABAergic mechanisms in the lumbosacral spinal cord induces voiding dysfunctions, such as detrusor overactivity (DO) or detrusor‐sphincter dyssynergia (DSD) after spinal cord injury (SCI) or bladder outlet obstruction in rats. Intrathecal, intravenous, or dietary glycine inhibits both bladder and urethral activity in normal and spinal cord injury (SCI) rats. Therefore, glycine might be a useful agent for the treatment of DO. Intrathecal muscimol and baclofen (GABAAand GABABagonists, respectively) also inhibit non‐voiding bladder contractions by suppressing C‐fiber bladder afferents in SCI rats. They also improve DSD by suppressing Onuf's nucleus and C‐fiber bladder afferents. Baclofen is approved for the treatment of DO in SCI patients, but this agent has not been widely used because the therapeutic window of the drug is modest and the dose is limited by side‐effects. Glutamic acid decraboxylase (GAD), the GABA synthesis enzyme, gene delivery by using non‐replicating herpes simplex virus (HSV) vectors inhibits DO by suppressing C‐fiber bladder afferents without affecting voiding contraction in SCI rats. Therefore, GAD gene therapy can restore urine storage function without affecting voiding function; it would be more beneficial than drug therapy for the treatment of urinary problems in SCI patients.

Urethral closure mechanisms during abrupt elevation of intravesical pressure (Pves) were investigated. Middle urethral contractile responses were observed during sneezing and passive Pvesrise for 120 sec. Both responses were decreased when somatic nerves innervating the external urethral sphincter and the pelvic floor muscles were transected. In contrast, while transection of both pelvic and hypogastric nerves had no effect during sneezing, urethral responses during passive Pvesrise were totally abolished or partially reduced after transection of pelvic or hypogastric nerves, respectively. Electrical stimulation of the abdominal muscles for 1 sec elevated Pves, and Pvesinducing fluid leakage from the urethral orifice was lowered after somatic or pelvic nerves were cut, while hypogastric nerve transection showed smaller effects. These results indicate that at least two kinds of urinary continence reflexes close the middle urethra; one is preprogrammed to close irrespective of bladder afferent activity, the other is triggered by bladder afferent activity. During momentary stress events lasting within 1 sec, the striated muscle mainly contributes to urethral closure, while during events lasting a relatively long period, like passive Pvesrise for 120 sec, both striated and smooth muscles are related to the prevention of urinary incontinence.