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Allyl isothiocyanate (AITC) activates transient receptor potential ankyrin 1 (TRPA1) channel, which is involved in the control of intestinal mucosal blood flow. However, the mechanism underlying the increased gastric mucosal blood flow (GMBF) in response to AITC remains unknown. We examined the effect of AITC on GMBF in the ex vivo stomachs of normal and sensory deafferented rats using a laser Doppler flowmeter. Mucosal application of AITC increased GMBF in a concentration-dependent manner. Repeated AITC exposure resulted in a marked desensitization. The increased GMBF response induced by AITC was entirely blocked by co-application of TRPA1 channel blockers HC-030031 or AP-18. Increased GMBF in response to AITC was significantly attenuated by chemical deafferentation following systemic capsaicin injections (total dose: 100 mg/kg). In contrast, increased GMBF responses to capsaicin, a transient receptor potential vanilloid 1 (TRPV1) activator, were completely abolished by chemical deafferentation. The increased GMBF response to AITC was markedly inhibited by BIBN 4096, a calcitonin gene-related peptide receptor (CGRP) antagonist, or AGP-8412, an adrenomedullin receptor antagonist. These results suggest that AITC-stimulated TRPA1 activation results in the increased GMBF through the release of CGRP and adrenomedullin.

To clarify the effects of long-term administration of SGLT2 inhibitor, a hypoglycemic agent, on basal sympathetic nerve activity (SNA) and on SNA under development of insulin resistance, we measured peripheral SNA in response to a glucose load in standard chow- (SCF) and high-fat-fed (HFF) rats treated with or without dapagliflozin for 7 weeks. We conducted an intravenous glucose administration (IVGA), and evaluated SNA microneurographically recorded in the unilateral sciatic nerve. Dapagliflozin did not affect the steady state action potential (AP) rate just before the IVGA (baseline) in both the SCF and HFF rats. After the IVGA, in the SCF rats, the AP rate in dapagliflozin-treated group transiently decreased within 20 min after the IVGA, and was significantly lower (P

Abstract Background Treatment of congenital hemophilia A (HA) in Japan has greatly improved with the widespread adoption of prophylactic factor (F)VIII concentrates. However, it is unknown if this has translated into a real‐world reduction in disease and treatment burden. Objectives To describe HA disease burden in Japan based on information from two medical information databases, JMDC and Real World Data Co., Ltd. (RWD). Methods Eligible individuals were diagnosed with congenital HA and prescribed FVIII concentrates, bypassing agents, or emicizumab. Treatment patterns and disease burden data were derived from health insurance claims and electronic medical records. Results Data on 459 people with HA were retrospectively collected from 2005 to 2020 in the JMDC database (median [min, max] of 37 [2, 186] months of available records), and 229 people with HA from 1985 to 2020 in the RWD database (median [min, max] of 154 [0, 409] months of available records). Mean (standard deviation) ages at the time of the first record were 25.0 (16.8) years (JMDC) and 19.2 (20.3) years (RWD). In the JMDC database, mean monthly FVIII dose increased from 2201 IU in 2005 to 8239 IU in 2013 to 11,377 IU in 2019; HA‐related drug costs increased accordingly. Mean (95% confidence interval) annual outpatient and out‐of‐hours visits decreased slightly between 2013 and 2019 (outpatient visits: from 22.9 [16.8–29.0] to 14.3 [12.6–16.1] per person; out‐of‐hours visits: from 1.3 [0.2–2.5] to 0.6 [0–1.4]). There was no change in mean number of hospitalizations. Conclusions Challenges remain in HA, including treatment burden, outpatient visits, and hospitalizations.

Desalination is an important source of potable water for a large portion of the world that is expected to expand in response to population increase and climate change. Despite its benefits, desalination produces a hypersaline waste, termed ‘brine’, which has negative impacts on the marine ecosystem and is costly to dispose of safely. An integral step in making desalination more environmentally friendly is the elimination of liquid wastes, so-called ‘Zero Liquid Discharge’. To make Zero Liquid Discharge financially viable, it is critical to separate and purify the constituent salts into products. We report on the design and operation of a system for continuous production of high purity Mg-chloride from desalination brine. This system is part of a Zero Liquid Discharge process that makes desalination net negative in terms of CO2 emissions by converting magnesium chloride into magnesium carbonate. Precipitation of sodium and potassium chloride from brine was achieved by absorption of a super azeotropic HCl gas. The super azeotropic HCl gas was regenerated by mixing the acidified brine in a low-temperature, saturated magnesium chloride solution. The system recovered 89% of the Mg2+ content of desalination brine as 99.6 mol% purity magnesium chloride. This level of recovery and purity without the use of consumable chemicals is not found elsewhere in industry or the literature. Internal regeneration of HCl reached 66% at a HCl concentration of 54 wt%. Empirical results suggest a longer operation would yield 92% regeneration of 65 wt% HCl. Using lessons learned from this test program, a range of long-term continuous operation conditions were found that could regenerate >95% of HCl at a concentration of >90 wt%. Such performance may make this novel HCl regeneration process interesting to industries that require hydrochloric acid recycling, such as hydrometallurgy. With the recovery and purity of magnesium chloride achieved in the current system, desalination brine can be converted into product streams, including those applicable for atmospheric CO2 removal.

Background: Complementary and alternative medicine, including Japanese traditional medicine (JTM), has been used for various allergic diseases, but the evidence is limited. Shoseiryuto (Xiao-Qing-Long-Tang), one of the representative JTM drugs, is frequently used to treat allergic rhinitis (AR). However, its efficacy for seasonal AR has not been fully established. Using an Environmental challenge chamber (ECC), we evaluated the therapeutic effects of shoseiryuto on AR induced by Japanese cedar pollen (JCP). Methods: A placebo-controlled double-blind crossover study with shoseiryuto was conducted using the ECC. The shoseiryuto or placebo was orally administered from 2 weeks before the exposure test. The pollen exposure test was conducted for 3 h, and the pollen concentration was set at 8000 pollen/m3. The primary endpoint of the study was the total nasal symptom score (TNSS) during pollen exposure. A physician certified by the Japanese Society of Oriental Medicine as a specialist checked each participant's “pattern”, a comprehensive expression of signs obtained from individual patients' subjective symptoms and other personal findings. Blood samples collected just before the first pollen exposure were stimulated with cedar antigens and used for immunological studies. Results: The results of the 46 participants were analyzed, and no significant side effects were detected. There was no significant difference in TNSS during pollen exposure for 3 h in the ECC between the shoseiryuto and placebo groups. However, some symptoms were improved in the shoseiryuto group after leaving the ECC. There was no significant correlation between the “fluid retention pattern” and TNSS. In immunological studies, shoseiryuto did not inhibit Th2-type cytokine production and mRNA expression. Conclusions: Oral administration of shoseiryuto from 2 weeks before pollen exposure did not prevent or inhibit immediate symptoms of AR induced by JCP in the ECC. Further study is needed to reevaluate the shoseiryuto specific “pattern” in JTM.

The platter, which is the data-storage component of hard-disk drives, contains platinum group metals on a substrate. It is necessary to separate the metal layer from the substrate to recover the platinum group metals and other valuable elements. The separation of the metal layer from the glass substrate were investigated by using two types of pulsed-power generators (PPGs), namely a nanosecond and a microsecond PPG. By conducting repetitive pulse discharges to the platter surface, the metal layer was peeled off and the maximum exfoliation rate reached about 60% for both the nanosecond PPG and the microsecond PPG. The higher the single pulse energy, the higher the exfoliation efficiency. The maximum peeling energy efficiency were 16%/kJ and 30%/kJ for the nanosecond PPG and microsecond PPG, respectively. It was demonstrated that the pulse width affected the formation of the discharge plasma. In the nanosecond PPG, a discharge plasma was formed between the edge of the metal layer and the electrode, whereas in the microsecond PPG, a discharge plasma channel was formed across the metal layer. SEM images of the substrate surface after discharge treatment showed that part of the removed metal layer was molten and reattached to the glass substrate. The reattached particles were spherical with a diameter of ∼10 μm, and were enriched by 20% in terms of ruthenium mass. The exfoliation process of the metal layer by electric pulses and the generation of metal particles were explained.

Non-alcoholic fatty liver disease (NAFLD), which includes the subtype non-alcoholic steatohepatitis (NASH), is a major complication of type 2 diabetic mellitus (T2DM), even among non-obese patients. However, the exact cause of NAFLD/NASH in non-obese patients with T2DM is unclear. We studied a non-obese mouse model of T2DM created through the malnourishment of embryos by culture in vitro for 48 h in α-minimum essential medium (MEM) at the two-cell stage. We compared the development of steatohepatitis in these MEM mice with control mice that were similarly cultured in standard potassium simplex-optimized medium (KSOM). We also studied the effects of 10 weeks of consumption of barley, which contains large amounts of the soluble fiber β-glucan, on the steatohepatitis of the adult MEM mice. The size of lipid droplets, the area of fibrosis, and the mRNA expression of the transforming growth factor beta (Tgfb) gene in the liver were higher in adult MEM mice fed a rice-based diet than in KSOM mice fed the same diet. However, barley consumption reduced the area of fibrosis and TGFB expression in MEM mice. In conclusion, adult mice that are cultured in MEM at the two-cell embryo stage develop steatohepatitis and T2DM, accompanied by higher hepatic TGFB expression, than KSOM controls. Furthermore, the consumption of barley during adulthood ameliorates the steatohepatitis and reduces the TGFB expression.

Objective: To examine the association between human papillomavirus (HPV) infection and penile cancer among Japanese patients. Methods: Thirty-four patients with penile cancer were enrolled in this study. DNA was extracted from paraffin-embedded tumor tissue samples, and HPV-DNA tests and genotyping were performed. For all of the samples, in situ hybridization (ISH) was performed to locate HPV-DNA in tumor tissue. Furthermore, expression levels of p16-INK4a, mini-chromosome maintenance protein 7 (mcm-7), HPV-L1, and Ki-67 were analyzed using immunohistochemical methods. Results: HPV and high-risk (HR)-HPV were detected in 14 (41.1%; 95% confidence interval (CI) 24.6–57.7%) and 12 (35.2%; 95% CI 19.2–51.4%) cases, respectively. HPV16 was the most frequently detected HPV type. Among the HR-HPV-positive cases, a punctate HR-HPV-DNA signal pattern was detected by ISH in tumor cell nuclei. P16-INK4a was expressed in 66.7% (95% CI 42.8–90.1%) of HR-HPV-positive cases and was significantly more frequent and stronger in HR-HPV-positive cases than in HPV-negative cases. There was no significant difference in the occurrence or distribution of mcm-7 or Ki-67 expression between HPV-positive and HPV-negative cases. HPV-L1 expression was not observed in any of the cases examined. Conclusions: HPV infection may have had an etiological role in 41% of the examined cases of penile cancer in Japan. Keywords: Penile cancer, Human papillomavirus, p16-INK4a, Mini-chromosome maintenance protein 7, Ki-67

Summary: Duchenne muscular dystrophy (DMD) is a muscle degenerating disease caused by dystrophin deficiency, for which therapeutic options are limited. To facilitate drug development, it is desirable to develop in vitro disease models that enable the evaluation of DMD declines in contractile performance. Here, we show MYOD1-induced differentiation of hiPSCs into functional skeletal myotubes in vitro with collagen gel and electrical field stimulation (EFS). Long-term EFS training (0.5 Hz, 20 V, 2 ms, continuous for 2 weeks) mimicking muscle overuse recapitulates declines in contractile performance in dystrophic myotubes. A screening of clinically relevant drugs using this model detects three compounds that ameliorate this decline. Furthermore, we validate the feasibility of adapting the model to a 96-well culture system using optogenetic technology for large-scale screening. Our results support a disease model using patient-derived iPSCs that allows for the recapitulation of the contractile pathogenesis of DMD and a screening strategy for drug development.

Summary: Antiviral treatments targeting the coronavirus disease 2019 are urgently required. We screened a panel of already approved drugs in a cell culture model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and identified two new agents having higher antiviral potentials than the drug candidates such as remdesivir and chroloquine in VeroE6/TMPRSS2 cells: the anti-inflammatory drug cepharanthine and human immunodeficiency virus protease inhibitor nelfinavir. Cepharanthine inhibited SARS-CoV-2 entry through the blocking of viral binding to target cells, while nelfinavir suppressed viral replication partly by protease inhibition. Consistent with their different modes of action, synergistic effect of this combined treatment to limit SARS-CoV-2 proliferation was highlighted. Mathematical modeling in vitro antiviral activity coupled with the calculated total drug concentrations in the lung predicts that nelfinavir will shorten the period until viral clearance by 4.9 days and the combining cepharanthine/nelfinavir enhanced their predicted efficacy. These results warrant further evaluation of the potential anti-SARS-CoV-2 activity of cepharanthine and nelfinavir.

We present a case of reverse Z-effect phenomenon in a basicervical femoral fracture using a cephalomedullary nail together with two superior antirotation screws and evaluate the procedure. An 86-year-old woman fell in her home and could not stand due to right hip joint pain. X-ray and CT imaging showed a right basicervical femoral fracture (AO/OTA classification; 31B3), and open reduction and internal fixation (OR/IF) was performed with a cephalomedullary nail and two superior antirotation screws (TES Nail, HOMS, Tokyo, Japan). Two months later, X-ray showed penetration of the femoral head by the inferior lag screw with lateral migration of the two superior antirotation screws; the so-called “reverse Z-effect”; without any trauma. We performed the exchange of a shorter inferior lag screw for the longer one, and replaced the sliding type end cap with one of rocking type. The reverse Z-effect has been reported in cases with two lag screws, i.e. one inferior and one superior, in the past; however, to our knowledge, there has been no case reported in the literature using two superior antirotation screws together with one inferior lag screw.

Murine contact hypersensitivity (CHS) is an animal model of allergic contact dermatitis (ACD). We investigated the inhibitory effects of dietary pomegranate polyphenol concentrate (PPC) on CHS. Mice were fed diets containing low or high doses of PPC for 3 weeks prior to CHS induction. Both the low- and high-dose PPC diets attenuated ear swelling and edema, and resulted in reduced infiltration of Gr-1-positive myeloid cells into ear tissues. The ear tissues of PPC-treated mice exhibited reduced mRNA expression of Cxcl2 and Cxcl3 and decreased production of chemokine (C-X-C motif) ligand 2 (CXCL2) and chemokine (C-C motif) ligand 12 (CCL12). Furthermore, the effects of urolithin A (UA) on splenic cell activation were studied. UA reduced the number of INF-γ-producing cells. These results indicate that low doses of dietary PPC alleviate CHS symptoms, suggesting that dietary PPC may provide beneficial effects on ACD at physiologically relevant doses to humans.

Five researchers reported on their studies to quantify and objectify traditional medicine at the symposium “Verification of Traditional Chinese Medicine” during the 2016 annual meeting of the Japan Traditional Chinese Medicine Association. Takao Namiki reported on a methodology to quantify tongue diagnosis. Tetsuhiro Yoshino presented work on predictive prescribing two Kampo formulas for dysmenorrhea, Tangkuei and Peony Powder (Danggui Shaoyao San) and Cinnamon Twig and Poria Pill (Guizhi Fuling Wan). Koh Iwasaki presented work on validation of a questionnaire for assessing qi stagnation and Mitsuyuki Takamura reported on application of the questionnaire to evaluate the efficacy of Pinellia and Magnolia Bark Decoction (Banxia Houpo Tang). Kaoru Sakatani presented research on near-infrared spectroscopy as a diagnostic tool for wei bing, a concept of pre-symptomatic state in traditional Chinese medicine.

Background: Prevalence of fluoroquinolone (FQ)-resistant Escherichia coli has been recently increasing worldwide. We analyzed the incidence and characteristics of acute bacterial prostatitis after transrectal ultrasound-guided needle prostate biopsy (TRUSP-Bx) with prophylactic tazobactam/piperacillin (TAZ/PIPC) treatment as an alternative regimen. Methods: A total of 391 patients who underwent TRUSP-Bx were included in the study. All patients received intravenous TAZ/PIPC (4.5 g) 30 minutes before and 6 hours after TRUSP-Bx. Results: Acute bacterial prostatitis developed in six patients (1.5%); the frequency of its occurrence was significantly higher in patients in whom rectal disinfection was not performed (P

We have carried out cDNA array analysis in order to characterize the gene expression profiles of reactive astrocytes from dopamine-depleted striatum. Astrocytes were cultured from the striatum of normal adult rats (adult astrocytes) or adult rats in which the substantia nigra had been lesioned 1 week earlier with 6-hydroxydopamine (reactive astrocytes), an animal model for Parkinson's disease. Three antibodies, 19D1, O1E4, and 13A11, known to label only reactive astrocytes in vivo, stained cultured reactive astrocytes but not adult astrocytes. Analysis with cDNA arrays showed that 38 genes were up-regulated and 75 genes down-regulated in reactive astrocytes compared to normal adult astrocytes. The expression of growth factor and transcription factor genes predominated among the up-regulated genes while those for signal transduction molecules, metabolic enzymes, and receptors for growth factors, hormones, and neurotransmitters predominated among the down-regulated genes. These results will allow the field to address the molecular profiles and functions of astrocytes activated in response to dopamine depletion and may be useful for developing new therapies for Parkinson's disease.

The effects of orally administered dipeptidyl peptidase IV (DPP-IV) inhibitor on the glucose-lowering effect of glibenclamide are still unknown. We evaluated the effects of combination treatment with a long-lasting DPP-IV inhibitor, K579 ((S)-1-[4-methyl-1-(2-pyrimidinyl)-4-piperidylamino]acetyl-2-pyrrolidinecarbonitrile), and glibenclamide on the glycemic responses to glucose loading in rats. Treatment with K579 inhibited the plasma DPP-IV activity even 8 h after the administration. K579 significantly suppressed the blood glucose elevation in glibenclamide-pretreated rats without excessive hypoglycemia. These profiles of K579 indicate that it could be useful agent to correct the postprandial glucose excursion in type 2 diabetes patients by combination treatment with glibenclamide. Keywords:: dipeptidyl peptidase IV, glibenclamide, glucose tolerance

This review describes the latest surgical treatments for peritoneal carcinomatosis (PC) arising from gastric cancer. Systemic chemotherapy is less effective against PC because of the existence of the blood-peritoneal barrier. Accordingly, perioperative intraperitoneal chemotherapy plus cytoreductive surgery (CRS) is a new trend of multidisciplinary therapy for PC. Intraperitoneally administered drugs penetrate directly into the peritoneal dissemination, resulting in the high loco-regional intensity of drugs. A new bidirectional chemotherapy called neoadjuvant intraperitoneal/systemic chemotherapy (NIPS) has been developed. After NIPS, the disappearance of PFCCs has been reported, and the incidence of complete cytoreduction has increased accordingly. Complete cytoreduction, a low peritoneal carcinomatosis index, and negative PFCCs are significant favorable prognostic factors. Hyperthermic intraperitoneal chemotherapy (HIPEC) after CRS is associated with improved survival with an acceptable postoperative mortality and morbidity. Early postoperative intraperitoneal chemotherapy (EPIC) has also contributed to improving survival after CRS., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

A 24-year-old woman with atopic dermatitis was admitted to our hospital with fever. Echocardiography showed a huge vegetation attached to the posterior mitral commissure without mitral valve dysfunction. Blood culture identified methicillin-sensitive Staphylococcus aureus. The serum level of antiphospholipid antibody was elevated. A splenic infarction occurred on the second hospital day. Surgery to resect the residual mobile vegetation was performed uneventfully on the 6th hospital day. The postoperative course was uneventful, and the patient was discharged after 4 weeks of antibiotic therapy. Preservation of the mitral valve is rare in the face of virulent Staphylococcus infection and the presence of a huge mobile vegetation. These findings were apparently related to the high serum level of infection-related antiphospholipid antibody and atopic dermatitis.

c-Abl plays important roles in cellular response to DNA damage. However, possible roles for Arg (Abl-related gene) in DNA damage response are unknown. Here, we show that ionizing radiation (IR)-induced Rad51 focus formation is reduced in Arg-deficient cells generated from a chicken B cell line by targeted disruption. This is consistent with the findings that Arg-deficient cells display hypersensitivity to IR, elevated frequencies of IR-induced chromosomal aberrations, and reduced targeted integration frequencies. All of these abnormalities in DNA damage repair are also observed in ATM-deficient cells but not in c-Abl-deficient cells. Finally, we show that Arg interacts with and phosphorylates Rad51 in 293T cells. These results suggest that Arg plays a role in homologous recombinational (HR) DNA repair by phosphorylating Rad51.

The logarithm of the 1-octanol-water partition coefficient value (log Poct) was compared with those from CHCl3-water (log PCL) and di-n-butyl ether-water (log PE) for (di)azines substituted singly by nonhydrogen-bonding and hydrogen-accepting substituents (2-substituted pyrazines, 2-substituted pyrimidines, 5-substituted pyrimidines, and 2-substituted pyridines). The difference between log Poct and log PCL for diazines was primarily governed by the number of hydrogen-bonding sites in the substituent. For 2-substituted pyridines, the difference in the hydrogen-bonding association of the ring N-atom with octanol from that with CHCl3 was also significant. In the relationship between log Poct and log PE, the hydrogen-bonding solvations of the ring N-atom(s), as well as the hydrogen-accepting substituent with octanol, should be taken into account because the butyl ether acts as a nonhydrogen-bonding solvent.

The partition coefficient in a 1-octanol-water system (log P) of a number of disubstituted pyrazines was measured. The increment produced by introduction of two substituents [pi(disubst)PR] was analyzed in terms of the pi value of substituents in monosubstituted pyrazine (pi 2PR) and other physicochemical substituent parameters, considering electronic and steric interactions operating bidirectionally between individual partners of substituents and aza-functions. When the substituents were nonamphiprotic and their steric interaction was not significant, the pi (disubst)PR value was approximately predicted by the summation of the pi 2PR values of corresponding substituents. For amphiprotic substituents, a correction for electronic interactions between the two substituents was needed but it was less important than that required in disubstituted benzenes. The results suggest that the difference in the pi values between disubstituted pyrazine and benzene systems was mostly governed by that between monosubstituted pyrazine and benzene systems with component substituents. In 2,6- and 2,3-disubstituted derivatives, bulky substituents had steric effects in such a way that the log P value was lowered.