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Organic iodine(III) compounds represent the most widely used hypervalent halogen compounds in organic synthesis, where they typically perform the role of an electrophile or oxidant to functionalize electron-rich or -nucleophilic organic compounds. In contrast to this convention, we discovered their unique reactivity as organometallic-like nucleophiles toward arynes. Equipped with diverse transferable ligands and supported by a tethered spectator ligand, the organoiodine(III) compounds undergo addition across the electrophilic C-C triple bond of arynes while retaining the trivalency of the iodine center. This carboiodanation reaction can forge a variety of aryl-alkynyl, aryl-alkenyl, and aryl-(hetero)aryl bonds along with the concurrent formation of an aryl-iodine(III) bond under mild conditions. The newly formed aryl-iodine(III) bond serves as a versatile linchpin for downstream transformations, particularly as an electrophilic reaction site. The amphoteric nature of the iodine(III) group as a metalloid and a leaving group in this sequence enables the flexible and expedient synthesis of extended π-conjugated molecules and privileged biarylphosphine ligands, where all of the iodine(III)-containing compounds can be handled as air- and thermally stable materials.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is known to be present in sewage, and wastewater-based epidemiology has attracted much attention. However, the physical partitioning of SARS-CoV-2 in wastewater and the removal efficiency of treatment systems require further investigation. This study aimed to investigate the detectability and physical partitioning of SARS-CoV-2 in wastewater and assess its removal in a large-scale septic tank employing anaerobic, anoxic, and oxic processes in a sequential batch reactor, which was installed in a coronavirus disease 2019 (COVID-19) quarantine facility. The amount of SARS-CoV-2 RNA in wastewater was determined with polyethylene glycol (PEG) precipitation followed by quantitative polymerase chain reaction (qPCR), and the association of SARS-CoV-2 with wastewater solids was evaluated by the effect of filtration prior to PEG precipitation (pre-filtration). The amount of SARS-CoV-2 RNA detected from pre-filtered samples was substantially lower than that of samples without pre-filtration. These results suggest that most SARS-CoV-2 particles in wastewater are associated with the suspended solids excluded by pre-filtration. The removal efficiency of SARS-CoV-2 in the septic tank was evaluated based on the SARS-CoV-2 RNA concentrations in untreated and treated wastewater, which was determined by the detection method optimized in this study. Escherichia coli and pepper mild mottle virus (PMMoV) were also quantified to validate the wastewater treatment system's performance. The mean log 10 reduction values of SARS-CoV-2, E. coli, and PMMoV were 2.47 (range, 2.25-2.68), 2.81 (range, 2.45-3.18), and 0.66 (range, 0.61-0.70), respectively, demonstrating that SARS-CoV-2 removal by the wastewater treatment system was comparable to or better than the removal of fecal indicators. These results suggest that SARS-CoV-2 can be readily removed by the septic tank. This is the first study to determine the removal efficiency of SARS-CoV-2 in a facility-level sequencing batch activated sludge system., Competing Interests: Declaration of competing interest Ryo Iwamoto, Ken-ichi Setsukinai, and Hiroyuki Kobayashi are employees of Shionogi & Co., Ltd. Masaaki Kitajima received research funding and patent royalties from Shionogi & Co., Ltd. Satoshi Okabe received research funding from Shionogi & Co., Ltd. Kiyoshi Yamaguchi, Chisato Arakawa, Hiroki Ando, Eiji Haramoto, Kotoe Katayama, Takuya Yamagishi, Sumire Sorano, Michio Murakami, Shigeru Kyuwa, and Seiya Imoto have no competing interests to declare., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Polyethylene glycol (PEG) precipitation is one of the conventional methods for virus concentration. This technique has been used to detect severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA in wastewater. The procedures and seeded surrogate viruses were different among implementers; thus, the reported whole process recovery efficiencies considerably varied among studies. The present study compared five PEG precipitation procedures, with different operational parameters, for the RT-qPCR-based whole process recovery efficiency of murine hepatitis virus (MHV), bacteriophage phi6, and pepper mild mottle virus (PMMoV), and molecular process recovery efficiency of murine norovirus using 34 raw wastewater samples collected in Japan. The five procedures yielded significantly different whole process recovery efficiency of MHV (0.070%-2.6%) and phi6 (0.071%-0.51%). The observed concentration of indigenous PMMoV ranged from 8.9 to 9.7 log (8.2 × 10 8 to 5.6 × 10 9 ) copies/L. Interestingly, PEG precipitation with 2-h incubation outperformed that with overnight incubation partially due to the difference in molecular process recovery efficiency. The recovery load of MHV exhibited a positive correlation (r = 0.70) with that of PMMoV, suggesting that PMMoV is the potential indicator of the recovery efficiency of SARS-CoV-2. In addition, we reviewed 13 published studies and found considerable variability between different studies in the whole process recovery efficiency of enveloped viruses by PEG precipitation. This was due to the differences in operational parameters and surrogate viruses as well as the differences in wastewater quality and bias in the measurement of the seeded load of surrogate viruses, resulting from the use of different analytes and RNA extraction methods. Overall, the operational parameters (e.g., incubation time and pretreatment) should be optimized for PEG precipitation. Co-quantification of PMMoV may allow for the normalization of SARS-CoV-2 RNA concentration by correcting for the differences in whole process recovery efficiency and fecal load among samples., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest associated with this manuscript., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: No previous study has examined the effect of dual-task training using changes in regional cerebral blood flow (rCBF) using single-photon emission computed tomography (SPECT) as an outcome., Objective: This study aimed to examine the effects of simultaneous dual-task training of exercise and cognitive tasks on rCBF using SPECT in older adults with amnestic mild cognitive impairment (aMCI)., Methods: In this non-randomized control trial, 40 older adults with aMCI participated from May 2016 to April 2018. Outpatients in the intervention group (n = 22) underwent 24 sessions (12 months) of dualtask training twice a month for 60 mins per session. Participants in the control group (n = 18) continued to have regular outpatient visits. The primary outcome was rCBF at baseline and after 12 months, which was compared in each group using the two-sample t-test. The secondary outcomes were the rate of reversion and conversion from aMCI after 12 months., Results: Of the 22 participants in the intervention group, six dropped out; therefore, 16 were included in the analysis. The intervention group showed more significant increases in rCBF in multiple regions, including the bilateral frontal lobes, compared with the control group. However, the rates of reversion or conversion from mild cognitive impairment (MCI) were not significantly different., Conclusion: Dual-task training for older adults with aMCI increased rCBF in the frontal gyrus but did not promote reversion from MCI to normal cognition. Future intervention studies, such as follow-up examinations after the intervention, are warranted to consider long-term prognosis., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Aims: This study aimed to evaluate the anti-adiposity effect of heat-killed Lactobacillus brevis KB290 originating from traditional Japanese fermented pickles in mice fed a high-fat diet (HFD)., Methods and Results: C57BL/6J mice were fed a normal-fat diet, HFD or HFD supplemented with heat-killed KB290 for 8 weeks. Epididymal and renal adipose tissue weights, as well as areas of epididymal adipocytes, were significantly lower in the mice fed a HFD supplemented with KB290 than in those fed an unsupplemented HFD. Mice whose diets were supplemented with KB290 had elevated adiponectin and β3-adrenergic receptor expression in epididymal adipose tissue and an accompanying higher serum free fatty acid level. Furthermore, the HFD-induced elevations in serum glucose, insulin and HOMA-IR were significantly suppressed by dietary supplementation with KB290. Amplicon sequencing of 16S rRNA genes revealed that KB290 ingestion altered the composition of the intestinal microbiota., Conclusions: Heat-killed L. brevis KB290 suppressed diet-induced visceral fat accumulation and ameliorated diet-induced metabolic symptoms and intestinal gut microbiota modifications, suggesting possibility of novel paraprobiotic., Significance and Impact of the Study: Heat-killed L. brevis KB290 is useable as a material to develop functional foods that attenuate visceral fat accumulation., (© 2021 The Authors. Journal of Applied Microbiology published by John Wiley & Sons Ltd on behalf of Society for Applied Microbiology.)

Influenza, a seasonal acute respiratory disease caused primarily by the influenza virus A or B, manifests with severe symptoms leading to considerable morbidity and mortality and is a major concern worldwide. Therefore, effective preventive measures against it are required. The aim of this trial was to evaluate the preventive effects of heat-killed Levilactobacillus brevis KB290 (KB290) in combination with β-carotene (βC) on influenza virus infections in healthy Japanese subjects aged between 20 and 59 y throughout the winter season. We performed a randomized, double-blind, placebo-controlled, parallel-group trial from 16 December 2019 to 8 March 2020, comparing KB290 + βC beverage with placebo beverage. The primary endpoint was the incidence of influenza based on a doctor's certificate. The incidence of influenza was not significantly different between the two groups. However, the subgroup analysis showed a significant difference between the two groups (influenza incidence: the KB290 + βC group 1.9%, and the placebo group 3.9%) in the subgroup of subjects aged ˂40 y, but not in the subgroup of subjects aged ≥40 y. The results of this trial suggest that the combination of KB290 and βC might be a possible candidate supplement for protection against the seasonal influenza virus infection in humans aged <40 y, although further clinical studies are needed to confirm the concrete preventive effect of this combination on influenza.

Introduction: The regional cerebral blood flow (rCBF) distribution can affect brain functioning, leading to amnestic mild cognitive impairment (aMCI) and mild Alzheimer disease (AD). This study aimed to clarify the detailed characteristics of rCBF distribution in patients with mild AD and aMCI., Methods: This cross-sectional study from April 2015 to March 2018 included 103 older adults (mean age 78.9 years; 60% females), out of a total of 302 adults, and categorized them into 3 groups according to cognitive symptoms. The normal control (NC), aMCI, and mild AD groups included 20, 50, and 33 participants, respectively. The primary outcome was rCBF, which was compared among the 3 groups using a 2-sample t test without correction for multiple comparisons., Results: In the aMCI group, the rCBF decreased in the bilateral parietal and left frontal association cortex and the bilateral premotor cortex ( p < 0.01) but increased in the bilateral cerebellum ( p < 0.01). In the mild AD group, the rCBF decreased in the bilateral parietal and occipital association cortex, the bilateral premotor cortex, the left temporal and frontal association cortex, and the left limbic lobe ( p < 0.01). Conversely, the rCBF increased in some parts of the cerebellum, the bilateral frontal and temporal association cortex, the left occipital association cortex, and the right premotor cortex ( p < 0.01)., Conclusion: Based on the analysis of the values obtained, it was inferred that the rCBF undergoes reduction and elevation in aMCI and AD patients., Competing Interests: The authors have no conflict of interests to declare., (Copyright © 2021 by S. Karger AG, Basel.)

Background: The minimum narcolepsy criteria "mean sleep latency (MSL) ≤8 min and ≥2 sleep onset rapid eye movement (REM) periods (SOREMPs) on polysomnography (PSG) and the multiple sleep latency test (MSLT)," according to The International Classification of Sleep Disorders, Third Edition (ICSD-3), are not specific to narcolepsy. Recently, the characteristic sleep stage sequences preceding SOREMPs in narcolepsy have received attention, but their diagnostic utility remains unclear., Methods: We retrospectively reviewed PSG/MSLT records and chart data for 102 Japanese patients with hypersomnia and at least one SOREMP. We examined the sporadic rates of two sleep stage sequences preceding the SOREMPs-wakefulness or stage 1 to REM (W/S1→R) and stage 2 to REM (S2→R)-comparing these between patient groups with narcolepsy type 1 (N = 28), narcolepsy type 2 (N = 19), and other hypersomnia (N = 55). We also examined the utility of three simple indices using the occurrence of W/S1→R SOREMPs for distinguishing between narcolepsy and other hypersomnia in patients who satisfied the minimum narcolepsy criteria., Results: W/S1→R SOREMPs were significantly more frequent in narcolepsy than in other hypersomnia, and this tendency was also observed even in the patients who satisfied the minimum narcolepsy criteria. The three indices had moderate sensitivities and specificities for distinguishing between narcolepsy and other hypersomnia in patients satisfying the minimum narcolepsy criteria., Conclusions: The W/S1→R pattern was observed significantly more frequently in narcolepsy than in other hypersomnia, suggesting it may help with differentiating narcolepsy from other hypersomnia in patients demonstrating the narcolepsy criteria, although its ability to do so may be modest., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Microcirculatory obstruction is a hallmark of severe malaria, but mechanisms of parasite sequestration are only partially understood. Here, we developed a robust three-dimensional microvessel model that mimics the arteriole-capillary-venule (ACV) transition consisting of a narrow 5- to 10-μm-diameter capillary region flanked by arteriole- or venule-sized vessels. Using this platform, we investigated red blood cell (RBC) transit at the single cell and at physiological hematocrits. We showed normal RBCs deformed via in vivo-like stretching and tumbling with negligible interactions with the vessel wall. By comparison, Plasmodium falciparum -infected RBCs exhibited virtually no deformation and rapidly accumulated in the capillary-sized region. Comparison of wild-type parasites to those lacking either cytoadhesion ligands or membrane-stiffening knobs showed highly distinctive spatial and temporal kinetics of accumulation, linked to velocity transition in ACVs. Our findings shed light on mechanisms of microcirculatory obstruction in malaria and establish a new platform to study hematologic and microvascular diseases., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Vascularization remains an obstacle when engineering complex tissues for regeneration and disease modeling. Although progress has been made in recreating 3D vascular structures, challenges exist in generating a mature, functional endothelium. It is demonstrated that perfusing engineered microvessels with platelet-rich plasma, a critical homeostatic component in vivo that is often overlooked in vitro, substantially transforms the endothelium, both maturing endothelial cells and improving functionality in 24 h. Platelets readily adhered to the exposed collagen-I substrate through small gaps within engineered vessels without forming thrombi. The adherent platelets improve barrier function, enhance endothelial glycolysis, reduce thrombogenicity, and enrich smooth muscle cell growth surrounding the endothelium. These findings demonstrate that platelets are essential to the function of endothelium during vascular maturation and remodeling. This study sheds light on a potential strategy to engineer stable, implantable vascular networks., Competing Interests: The authors declare no conflict of interest., (© 2019 University of Washington. Published by WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim.)

Abstract: Non-24-hour sleep-wake rhythm disorder (N24SWD) occurs when the intrinsic circadian pacemaker does not entrain (synchronize) to the 24-hour light/dark cycle. There is currently no established treatment for sighted patients with N24SWD. To the best of our knowledge, there have been very few reports on the efficacy of ramelteon administered to sighted patients with N24SWD. We report the case of a sighted patient with N24SWD whose free-running sleep-wake pattern recorded by actigraphy was stopped after the administration of a low dose of ramelteon combined with behavioral education., (© 2018 American Academy of Sleep Medicine.)

Photopolymerizable hydrogels derived from naturally occurring polymers have attracted significant interest in tissue-engineering applications due to their excellent biocompatibility, hydrophilic nature favourable for cell ingrowth and ability to be cured in situ through a minimally invasive procedure. In this study, we developed a composite hydrogel consisting of photocrosslinkable methacrylated glycol chitosan (MeGC) and semi-interpenetrating collagen (Col) with a riboflavin photoinitiator under blue light. The incorporation of Col in MeGC hydrogels enhanced the compressive modulus and slowed the degradation rate of the hydrogels. MeGC-Col composite hydrogels significantly enhanced cellular attachment, spreading, proliferation and osteogenic differentiation of mouse bone marrow stromal cells (BMSCs) seeded on the hydrogels compared with pure MeGC hydrogels, as observed by upregulated alkaline phosphatase (ALP) activity as well as increased mineralization. Similarly, when cells were encapsulated within hydrogels, BMSCs exhibited greater proliferation, ALP activity and mineral deposits in the presence of Col. These findings demonstrate that MeGC-Col composite hydrogels may be useful in promoting bone regeneration. Copyright © 2014 John Wiley & Sons, Ltd., (Copyright © 2014 John Wiley & Sons, Ltd.)

Background: Acute encephalitis is a serious neurological condition having a high mortality rate and affecting both children and adults. This study aimed to develop a multiplex PCR method for the simultaneous screening of clinical samples for the presence of the 10 viruses presently considered as the major viral causes of acute encephalitis/ encephalopathy in Asia., Methods: Using previously published primers that have been widely used to screen for herpes virus-6, influenza A virus, human parechovirus, herpes simplex viruses 1 and 2, Japanese encephalitis virus, group A rotavirus, enterovirus, adenovirus, and dengue virus in clinical samples, a single-tube multiplex PCR assay was developed and was tested for its sensitivity and specificity. The method was then applied to screen 57 clinical samples, consisting of 13 fecal samples, 5 throat swabs, 3 post-nasal swabs, 18 serum samples, and 18 cerebrospinal fluid (CSF) samples, collected from 18 hospitalized Japanese children with suspected viral encephalitis/encephalopathy for the target viruses, and the results were compared with those of a monoplex PCR method., Results: Positive viral controls of the 10 viruses were correctly typed using this multiplex PCR method. The multiplex PCR method showed high specificity with no unspecific amplification to non-target viruses. The results of applying this PCR method for screening clinical samples showed that 6 fecal samples, 2 serum samples, and 1 CSF sample collected from 7 patients were positive for a virus, specifically group A rotavirus (4 patients, 22.2%), enterovirus (2 patients, 11.1%), or adenovirus (1 patient, 5.6%). In comparison with monoplex PCR, for group A rotavirus, enterovirus, and adenovirus, the sensitivity of this multiplex PCR method decreased for serum, cerebrospinal fluid, and throat swab samples., Conclusions: This newly developed multiplex PCR method is a simple, rapid diagnostic tool and can be used to screen clinical samples for viruses causing acute encephalitis/encephalopathy in children in Asian countries.

Background: Premature cranial suture fusion may prevent neonatal skull malleability during birth, increasing the risk of unplanned cesarean delivery and neonatal birth trauma caused by cephalopelvic disproportion. We sought to determine the incidence of perinatal maternofetal complications in cases of craniosynostosis., Methods: Records of children presenting with nonsyndromic craniosynostosis to a tertiary pediatric hospital from 1996 to 2012 were reviewed retrospectively with focus on birth history and birth-related complications., Results: Six hundred eighteen births were reviewed. Rates of cesarean delivery among mothers of children with craniosynostosis [n = 201 (32.5 percent)] exceeded the overall regional rate of 24.5 percent (OR, 1.50; p < 0.0001). Unplanned cesarean delivery occurred in 19.7 percent of births, and were most associated with nulliparous mothers, breech fetal presentations, and lambdoid or multisuture synostosis patterns. Eleven neonates (1.8 percent) exhibited cranial birth trauma, including cephalohematoma and subgaleal hematoma. Neonates with sagittal or multisuture synostosis patterns were more likely to suffer birth trauma and had a higher mean head circumference than those who did not (81st versus 66th percentile, p < 0.05)., Conclusions: In the setting of craniosynostosis, birth trauma is increased-for mothers in the form of increased cesarean delivery risk, and for fetuses in the form of subgaleal and subperiosteal perinatal bleeding. Difficult maternal labor may be mediated especially by multisuture or lambdoid synostosis, whereas fetal birth trauma may be mediated to a greater extent by large head size. Prenatal diagnosis of craniosynostosis could influence decision-making in the management of labor., Clinical Question/level of Evidence: Risk, IV.

Patients with 2q37 deletions manifest brachydactyly mental retardation syndrome (BDMR). Recent advances in human molecular research have revealed that alterations in the histone deacetylase 4 gene (HDAC4) are responsible for the clinical manifestations of BDMR. Here, we report two male patients with 2q37.3 deletions. One of the patients showed a typical BDMR phenotype, and HDAC4 was included in the deletion region. HDAC4 was preserved in the other patient, and he showed a normal intelligence level with the delayed learning of complex motor skills. Detailed neuropsychological examinations revealed similar neuropsychological profiles in these two patients (visuo-spatial dyspraxia) that suggested developmental dyspraxia. These observations suggested that some other candidate genes for neuronal development exist in the telomeric region of HDAC4., (© 2014 Wiley Periodicals, Inc.)

Background: Wolf-Hirschhorn syndrome is a congenital malformation syndrome resulting from deletion of the short arm of chromosome 4. Individuals with Wolf-Hirschhorn syndrome may have a "Greek warrior helmet" appearance, growth retardation, developmental delay, muscular hypotonia, epilepsy, and difficulty with language including verbal communication. An affinity for music has not previously been reported in these patients., Patients: We describe two patients with Wolf-Hirschhorn syndrome who both have a strong affinity for music. One patient is a 20-year-old woman who likes to listen to music all day and can hum many tunes. The other patient is a 9-year-old girl who is calmed by music and received music therapy, with subsequent improvement in her communication skills (eye contact, joint attention, and vocalizations to request music)., Conclusions: Individuals with Wolf-Hirschhorn syndrome may have a strong affinity for music and may benefit from music therapy. Additional studies are needed to investigate the interest in music in individuals with Wolf-Hirschhorn syndrome., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Even in cases where there is no obvious family history of disease, genome sequencing may contribute to clinical diagnosis and management. Clinical application of the genome has not yet become routine, however, in part because physicians are still learning how best to utilize such information. As an educational research exercise performed in conjunction with our medical school human anatomy course, we explored the potential utility of determining the whole genome sequence of a patient who had died following a clinical diagnosis of idiopathic pulmonary fibrosis (IPF). Medical students performed dissection and whole genome sequencing of the cadaver. Gross and microscopic findings were more consistent with the fibrosing variant of nonspecific interstitial pneumonia (NSIP), as opposed to IPF per se. Variants in genes causing Mendelian disorders predisposing to IPF were not detected. However, whole genome sequencing identified several common variants associated with IPF, including a single nucleotide polymorphism (SNP), rs35705950, located in the promoter region of the gene encoding mucin glycoprotein MUC5B. The MUC5B promoter polymorphism was recently found to markedly elevate risk for IPF, though a particular association with NSIP has not been previously reported, nor has its contribution to disease risk previously been evaluated in the genome-wide context of all genetic variants. We did not identify additional predicted functional variants in a region of linkage disequilibrium (LD) adjacent to MUC5B, nor did we discover other likely risk-contributing variants elsewhere in the genome. Whole genome sequencing thus corroborates the association of rs35705950 with MUC5B dysregulation and interstitial lung disease. This novel exercise additionally served a unique mission in bridging clinical and basic science education.

This study determines the present condition of self-management of infection control behavior of adult recipients who underwent living-donor liver transplantation (LDLT). The design was a qualitative study using a semistructured interview. The subjects were recipients who underwent LDLT at Kyoto University Hospital within 5 years to March 2011 and gave their consents to participate in this study. The subjects were 10 recipients (4 male and 6 female), and their average age was 56.7 years. Of 502 sentences about self-management behavior extracted from the verbatim records of all subjects, 61 sentences were about infection control behavior. Cluster analysis was used to classify these sentences into 5 groups: basic preventive behavior, application preventive behavior, active preventive behavior, change of preventive behavior depending on physical condition, and establishment of preventive behavior., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Mycoplasma pneumoniae is a common cause of respiratory tract illness in children. Among the most common extrapulmonary manifestations are disorders of the central nervous system, including meningitis, meningoencephalitis, cerebellitis, polyneuropathy, acute disseminated encephalomyelitis, and Guillain-Barré syndrome. Guillain-Barré syndrome, also known as acute inflammatory demyelinating polyradiculoneuropathy, is an acute-onset, immune-mediated disorder of the peripheral nervous system. The central nervous system is usually intact in patients with Guillain-Barré syndrome. However, there have been some reports of an association of Guillain-Barré syndrome with central nervous system involvement in children. We report a 3-year-old boy with M. pneumoniae infection associated with Guillain-Barré syndrome and encephalitis. Both serum anti-GM1 ganglioside (IgG and IgM) and anti-galactocerebroside IgG antibodies were detected in our patient: the former in the earlier stage of the disease, and the latter in the later stage. We speculate that anti-GM1 ganglioside was associated more with encephalitis, and anti-galactocerebroside antibody was associated more with GBS in our case. Our patient is the youngest report of Guillain-Barré syndrome with central nervous system involvement, and the first report of a pediatric patient with associated M. pneumoniae infection. Such cases are rarely reported, but highlight the need for awareness of the association of the infection with Guillain-Barré syndrome with central nervous system involvement., (Copyright © 2013 Japanese Society of Chemotherapy and The Japanese Association for Infectious Disease. Published by Elsevier Ltd. All rights reserved.)

Objective: We investigated the clinical efficacy and pharmacokinetics of lamotrigine (LTG) as an add-on therapy in childhood-onset intractable epilepsy., Methods: We reviewed the charts of 28 outpatients who had received LTG as an add-on therapy. The data collected included epilepsy type, seizure frequency, concomitant anti-epileptic drugs, dosage of LTG and LTG serum levels. Furthermore, we reviewed the relationship between the LTG serum levels (microg/ml) and dosage of LTG (mg/kg/day), as well as the relationship between the LTG serum levels (microg/ml) and clinical efficacy in the following 2 groups:the valproate sodium (VPA) combination group and the non-VPA combination group., Results: A reduction of 50% or more in seizure frequency was observed in 10 patients. In addition, there was a high correlation between the LTG serum levels and the dosage of LTG in each group. In the VPA combination group, the average of LTG serum levels in patients with adequate therapeutic response (50% reduction in seizure frequency) was higher than that in patients without adequate therapeutic response. In the non-VPA combination group, the average LTG serum level in adequate response patients was lower than that in patients without adequate therapeutic response. However, the epilepsy types of adequate response patients differed in the two groups., Conclusions: The LTG serum level is predictable based on the dosage of LTG. It was judged that the effective blood concentration of LTG differed when used with VPA, although factors other than the combined use of VPA should have been taken into consideration also.

Objectives: In April 2009, a novel influenza A (H1N1) pdm virus was identified in Mexico and spread quickly around the world. However, the clinical features of acute encephalopathy associated with 2009 pandemic influenza have not yet been elucidated., Methods: We treated 8 patients (3 boys and 5 girls) aged 4 to 11 years (average age, 8 y 3 months) with influenza virus-associated encephalopathy, who presented at our 2 hospitals between July 2009 and March 2010. We investigated the clinical characteristics, treatments, and outcomes in the patients., Results: In all patients, brain computed tomography showed mild to severe diffuse cerebral edema, and electroencephalography revealed diffuse high-voltage slow waves. They were all treated with oseltamivir and methylprednisolone pulse therapy. Six patients recovered without any sequelae; however, the remaining 2 had residual neurological sequelae. These 2 patients presented with severe disturbance of consciousness, and their central nervous system symptoms appeared within 12 hours after the onset of fever. One patient had periventricular leukomalacia and symptomatic epilepsy by perinatal brain hypoxia, and the other patient had 1 complex febrile and 2 febrile seizures., Conclusions: This study showed that patients with influenza-associated encephalopathy caused by influenza A (H1N1) pdm infection were all older than those with seasonal influenza. Underlying neurological disease or history may be associated with poor prognosis.

Objectives: This study investigated the effect of a brief, simple, home-based yoga program on body pain and health status in child-care workers., Design: This was a randomized, controlled trial comparing a home-based yoga group and a control group., Participants: The trial comprised 98 healthy female nursery school and kindergarten teachers., Interventions: A DVD of a simple home-based yoga program was provided for a period of 2 weeks., Outcome Measures: The primary outcome measure was the reported change in body pain at 2 weeks (after intervention) and 4 weeks (follow-up). The secondary outcome measure was the 30-item General Health Questionnaire (GHQ30) score and physical function., Results: The 67 yoga group participants reported improved menstrual pain at 4 weeks; menstrual pain was reduced from 57.0 ± 27.8 to 37.8 ± 26.7 in the yoga group, versus 52.4 ± 36.5 to 46.9 ± 32.1 in the control group (change from baseline in the yoga group versus change from baseline in the control group, -15.3 points; p=0.044). The total GHQ30 score and the GHQ subscale scores ("sleep disturbance" and "anxiety and dysphoria") improved significantly at 4 weeks in the yoga group, but not in the control group. In the good-adherence group, low back pain improved during the intervention (p=0.006) and follow-up (p=0.001) periods. Menstrual pain was also improved (p=0.044). No adverse events were observed., Conclusions: A home-based simple yoga program may improve the health status of child-care workers.

We report on a 4-year-old boy who died from influenza encephalopathy. The clinical course and microscopic findings of the autopsied liver were compatible with Reye's syndrome. We examined the mitochondrial respiratory chain function by blue native polyacrylamide gel electrophoresis (BN-PAGE), western blotting, and respiratory chain enzyme activity assays. The activity of liver respiratory chain complex (CO) I was markedly decreased (7.2% of the respective control activity); whereas, the other respiratory chain complex activities were substantially normal (CO II, 57.9%; CO III, 122.3%; CO IV, 161.0%). The activities of CO I-IV in fibroblasts were normal (CO I, 82.0%; CO II, 83.1%; CO III, 72.9%; CO IV, 97.3%). The patient was diagnosed with liver-specific complex I deficiency. This inborn disorder may have contributed to the fatal outcome. We propose that relying only on fibroblast respiratory chain complex activities may lead to the misdiagnosis of liver-specific complex I deficiency., (Copyright © 2011 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

We recently demonstrated that the futalosine pathway was operating in some bacteria for the biosynthesis of menaquinone and that futalosine was converted into dehypoxanthinyl futalosine (DHFL) by an MqnB of Thermus thermophilus. In this study, we found that aminodeoxyfutalosine, which has adenine instead of hypoxanthine in futalosine, was directly converted into DHFL by an MqnB of Helicobacter pylori. Therefore, this step is potentially an attractive target for the development of specific anti-H. pylori drugs.

In this study, we report 11 patients with intractable childhood epilepsy that improved following acute viral infection. The patients were 8 boys and 3 girls. Six of the 11 children were diagnosed as West syndrome (5 of the symptomatic type and 1 of the cryptogenic type). The remaining 5 children were myoclonic seizures. The patients became seizure free within 6 days following acute viral infections without an exchange or addition of antiepileptic drugs (AEDs). The types of acute viral infections were Exanthema subitum (Roseola infantum) in 5 patients, Rotavirus gastroenteritis in 2 patients, Measles infection in 2 patients, Herpetic stomatitis in 1 patient and Common cold in the remaining patient. Salaam seizures and/or tonic spasms disappeared within 6 days after the onset of viral infections, and hypsarrhythmia evolved to localized spikes on electroencephalography (EEG) in the patients with West syndrome. Epileptic seizures disappeared rapidly and EEG gradually normalized or improved in patients with myoclonic seizures. Four patients became seizure free for 5 years to 20 years. In 6 patients, seizures relapsed within 14 days to 1 month after the disappearance of seizures. One child remained seizure free for 12 months after viral infection. Common factors in 4 children who were continuously seizure free include (1) normal or almost normal findings of brain CT/MRI, (2) normal development prior to the onset of epileptic seizures, and (3) a short time interval between the onset of seizures and the acute viral infection. We propose several hypotheses including an immunological effect for the improvement of intractable childhood epilepsy following acute viral infection. Further study may provide important information concerning the mechanism of seizure control and the applicable to treatment for intractable childhood epilepsy., (Copyright © 2010 Elsevier B.V. All rights reserved.)

We report on two children with mild encephalopathy with a reversible splenial lesion associated with group A rotavirus (GARV) infection. We examined stool, serum, and cerebrospinal fluid samples to determine the presence of the GARV VP7 gene and GARV antigen by reverse-transcription PCR and enzyme-linked immunosorbent assay, respectively. GARV antigen was detected in stool samples from both patients. The GARV G genotype was G9 in one child and G3 in the other. GARV antigens were also found in both serum samples. However, the GARV VP7 gene was detected in only one serum sample, which was collected on the first day of symptomatic illness. Neither GARV antigen nor the VP7 gene was detected in cerebrospinal fluid samples. Both patients had excellent outcomes. Our results suggest that the reversible splenial changes in our patients might have been caused by indirect effects to the central nervous system subsequent to viral infection.

The purpose of this study was to examine the correlation of medical incidents and errors among nurses with factors describing their lifestyle, health, and work environment. We analyzed questionnaires completed by 6,445 female hospital nurses engaged in shift work in Japanese hospitals with general wards of more than 200 beds. Logistic regression analysis indicated that the risk for medical incidents/errors was predicted by being under treatment, absence due to sickness in the past 6 months, workplace, break times during night shift, bodily pain, and role (emotional). These results indicate that to prevent the occurrence of medical incidents/errors, it is necessary to regard current/recent illness, bodily pain, and role (emotional) as a nurse's personal problems and break times during the night shift and workplace as administrative problems.

Objectives: The aim of this study was to investigate the parameters of halitosis and sialometry in patients who had undergone head and neck radiotherapy, correlating oral concentration of volatile sulfur compounds (VSC) with the presence of tongue coating, salivary flow rate and BANA test., Material and Methods: 35 patients allocated in two groups were examined: group I (control)--patients with systemic and oral health; group II--patients submitted to head and neck radiotherapy. All volunteers were submitted to halitosis measurements through a sulphide monitor, evaluation of tongue coating weight, non-stimulated sialometry and BANA test., Results: The results were analyzed through analysis of variance, Pearson®s correlation and Student's t-test, showing that there was statistically significant difference in halimetry between the groups, where the irradiated patients showed halitosis. There was a relation between the presence of tongue coating and the levels of VSCs in both groups and it was also noted that the irradiated patients showed a decreased salivary flow rate compared to healthy patients., Conclusion: On the conditions of the present research, it was concluded that halitosis can be considered an adverse effect of radiotherapy, connected to hiposalivation and poor oral health.

A five year old girl was admitted to the hospital for evaluation of intermittent ataxia. She had undergone serial resections of the small intestine after birth, resulting in short bowel syndrome. Lactomin was prescribed for watery diarrhea at twice the regular dose 2 weeks before the onset of neurologic symptoms. D-lactic acidosis was diagnosed on the basis of a plasma D-lactate level of 5.537 mmol/l. Lactomin was discontinued, and she was treated with sodium bicarbonate and oral antibiotics. The probiotics the patient had taken were likely the cause of D-lactic acidosis and should therefore be avoided in patients with short bowel syndrome., (Copyright 2009 Elsevier B.V. All rights reserved.)

To evaluate auditory spatial cognitive function, age correlations for event-related potentials (ERPs) in response to auditory stimuli with a Doppler effect were studied in normal children. A sound with a Doppler effect is perceived as a moving audio image. A total of 99 normal subjects (age range, 4-21 years) were tested. In the task-relevant oddball paradigm, P300 and key-press reaction time were elicited using auditory stimuli (1000 Hz fixed and enlarged tones with a Doppler effect). From the age of 4 years, the P300 latency for the enlarged tone with a Doppler effect shortened more rapidly with age than did the P300 latency for tone-pips, and the latencies for the different conditions became similar towards the late teens. The P300 of auditory stimuli with a Doppler effect may be used to evaluate auditory spatial cognitive function in children.

Group A rotavirus (GARV) genes (the VP7 and NSP3 genes) in acute-phase cerebrospinal fluid (CSF), sera and stool samples from 6 children with convulsions accompanied by GARV gastroenteritis were investigated by reverse transcription-polymerase chain reaction (RT-PCR). When the VP7 gene was amplified from the samples, the G genotype (G type) of GARV was determined by RT-PCR. GARV genes were detected in the CSF samples of all 6 children, in 2 of the 3 blood samples, and in all of 4 stool samples. The G typing of GARV from 12 of a total of 13 samples indicated that G3 was the predominant G type in all samples. GARV antigens were detected by enzyme-linked immunosorbent assay in all of the 3 tested sera samples, while no GARV antigens were detected in any of the 5 tested CSF samples. We confirmed the presence of GARV genomes in the CSF samples from all of the children with rotavirus-associated seizures, including encephalopathy. However, the relationship between convulsions and the existence of GARV RNA in CSF remains unclear and further study is required.

We report a patient with antineutrophil cytoplasmic antibody-associated vasculitis with oculomotor nerve palsy. The patient presented with a high fever, diplopia, blepharoptosis and impairment of ocular movement of the left eye except for lateral gaze. Multiple erythematous and livedoid lesions were observed on the forehead, both cheeks and both legs. Laboratory examination showed positive results for myeloperoxidase antineutrophil cytoplasmic antibodies. Skin biopsy revealed leucocytoclastic vasculitis of the small arteries in the lower dermis. The patient was successfully treated with systemic corticosteroids.

Sterol oxidation products derived from cholesterol and phytosterol are formed during the processing and storage of foods. The objective of the present study was to assess the potential unfavorable effects of oxysterols in mice. C57BL/6J mice were fed an AIN-93G-based diet containing 0.2 g/kg of oxycholesterol or oxyphytosterol for 4 weeks. The most abundant oxysterol in the diet was 7-ketosterol, but alpha-epoxycholesterol, beta-epoxycholesterol, or 7alpha-hydroxyphytosterol, and 7beta-hydroxyphytosterol were more prominent than 7-ketosterol in the serum and liver respectively. Consumption of both oxysterols resulted in an increased in 4beta-hydroxycholesterol and total oxycholesterol in the liver, but the oxycholesterol-fed mice had a lower level of cerebral 24S-hydroxycholesterol and a higher level of the serum triacylglycerols than the control and oxyphytosterol groups. These results indicate that both oxysterols in the diet are accumulated in the body, but that the biological effect of oxycholesterol is different from that of oxyphytosterol.

We report a patient with acute heart failure due to human parvovirus B19 infection. The patient was a 36-year-old man with polyarthralgia, fatigue and swelling of his upper eyelids and all four limbs. These symptoms disappeared, but 5 days after the first consultation, the patient presented with severe exertional dyspnoea, chest pain and swelling of his whole body. Erythema was observed on the skin of hands, fingers and abdomen. Pleural and pericardial effusion, ascites and hepatosplenomegaly were detected. Laboratory examination showed positive results for anti-human parvovirus B19 IgM and B19 DNA in the serum. A diagnosis of acute heart failure by pericarditis caused by B19 was made. This case report suggests that B19 should be considered as a cause of acute heart failure through acute pericarditis.

Background: It is unclear how often chronic fatigue syndrome (CFS) appears after human parvovirus B19 (B19) infection and whether prolonged B19 viremia or some other factors cause CFS., Objectives: To determine how often CFS appears after B19 infection and whether prolonged B19 DNA presence, antibody production and persistently reduced complement levels occur in CFS patients after B19 infection., Methods: Clinical findings were examined in 210 patients after B19 infection, and CH50, C3 and C4 levels were determined. B19 DNA and antibodies to B19 were also tested in 38 patients' sera including 3 with CFS., Results: Serum B19 DNA disappeared after 4-5 months in all 18 patients tested. There are no differences in B19 DNA-positive period between patients with and without persistent symptoms. IgM antibody titers to B19 became reduced after 2 months in all 38 patients. Complement levels persistently decreased in a greater proportion of patients with persistent symptoms., Conclusions: The present study suggests that we should consider the possibility of CFS after B19 infection and that CFS may be derived from several aspects other than prolonged B19 DNA presence in sera., (Copyright 2008 S. Karger AG, Basel.)

The work described in this paper examined the possible relationship between fish consumption and human fecundity among Japanese women using hair mercury level and time to pregnancy (TTP) as indicators of fish consumption and fecundity. We hypothesized that hair mercury concentrations reflect the level of fish consumption and, consequently, can also be taken to indicate the level of intake of organochlorine compounds (OCs) such as dioxins and polychlorinated biphenyls (PCBs) for which fish are the primary source, and which can disrupt normal human reproductive processes. TTP was obtained by a self-administered questionnaire from women who had been delivered of a baby at either of two hospitals in Sendai, Japan, during the period of January 2002-March 2004. Total mercury concentration in their hair (0-3cm from the scalp) was determined by cold vapor atomic absorption spectrometry. Of the 298 women approached, 193 (65%) reported their TTP. The subjects were classified into two groups according to their TTP: group 1, 0-12 months TTP; and Group 2, >12 months TTP. A step-down procedure backward binominal logistic regression analysis was performed by using age, BMI, parity, frequency of intercourse, life-style parameters (smoking, drinking and dietary habits) and hair mercury level of the female subjects and their partners as independent variables. Two separate analyses were performed by including/excluding information on the partners of the subjects. The analyses did not extract hair mercury concentration as significant indicating that fish consumption did not prolong TTP, which was not consistent with the results of our previous study, i.e., in that study frequent fish eaters showed prolonged TTP. Possible reasons of the negative result are discussed and it is suggested that the hair mercury levels in the present study were not an appropriate indicator of fish consumption of the subjects or of their exposure to OCs. Further study on the relationship between fish consumption (and, ultimately, of OCs intake) and fecundity with more appropriate indicators of fish consumption and/or fish-mediated pollutants intake are warranted to characterize the health risk posed by fish consumption.

We investigate the process of slow intergranular crack propagation by the finite element method model and show that branching is induced by partial arresting of a crack front owing to the geometrical randomness of grain boundaries. A possible scenario for the branching instability of crack propagation in a disordered continuous medium is also discussed.

Objective: The daily bisphenol A (BPA) intake level of Japanese pregnant women was surveyed based on the measurement of the urinary excretion level of a BPA metabolite., Methods: Spot urine samples were collected from 56 pregnant women who visited the gynecology division of a hospital for a routine health check between June and October 2003. The urinary concentrations of the BPA metabolite and creatinine were measured by GC/MS/MS and spectrophotometry, respectively. Daily BPA intake was assumed to be equal to daily excretion., Results: The daily intake of BPA among Japanese pregnant women was estimated to be in the range of < 0.3 to 7.9 microg/day (median < 2.0 microg/day), being consistent with the levels in previous studies for non-pregnant Japanese women. This level was far below the current Acceptable Daily Intake (0.01 mg/kg/day) which was set by the European Commission. The maximum estimated intake per body weight (0.16 microg/kg/day) reached 1/10 of the Lowest Adverse Effect Level of BPA for pregnant mice for a reproductive effect on the offspring (2 microg/kg/day)., Conclusion: It is desirable to lessen BPA intake from a precautionary viewpoint, particularly in pregnant women.

Objectives: Concerns over dietary exposure to bisphenol A (BPA), an endocrine disruptor, have been raised because BPA is contained in resins and plastics commonly used for the preservation of food and beverages. The purpose of the present study was to assess daily intake levels of BPA in a group of male subjects by measuring total urinary BPA (free BPA plus BPA released by treatment with β-glucuronidase), as well as determining intra-individual variation in BPA excretion., Methods: Twenty-four-hour urine was collected from 5 subjects for 5 consecutive days for the evaluation of between-day variation in urinary BPA excretion and from 36 male subjects for the estimation of the level of daily BPA intake. BPA in the urine samples was measured by GC/MS/MS following enzymatic hydrolysis of BPA glucuronate, solid phase extraction, and derivatization., Results: A large between-day variation was found over 5 days for the daily excretion of urinary BPA in the 5 subjects. The daily excretion of urinary BPA was distributed log-normally in the 36 male subjects, with the median value being 1.2 μg/day (range: <0.21-14 μg/day), which was far below the Tolerable Daily Intake (0.01 mg/kg bw) recommended by a scientific committee in the European Commission in 2002. However, the maximum estimated intake per body weight (0.2 μg/kg/day) was only one order of magnitude lower than the reported lowest level for reproductive/behavioral effects in pregnant mice (2 μg/kg/day)., Conclusions: Measuring urinary BPA in urine is a suitable approach for estimating short-term BPA intake levels in individuals and/or estimating the average exposure level of populations. Urine analyses will be increasingly important in the human health risk assessment of BPA.

Background: Debate has been continuing whether endocrine disrupting chemicals (EDC) in the environment affect human reproduction. We are planning to use time to pregnancy (TTP) as a measure of human fecundity to relate EDC exposure in a future research. TTP is expressed as the number of non-contracepting menstrual cycles or months required for a couple to conceive. An extended TTP might be considered to reflect an injury to reproductive processes. Since this parameter has never been measured in Japan. the present preliminary study aimed at establishing a Japanese version of the TTP questionnaire and determining if TTP could be reliably measured in Japan., Methods: We prepared a self-administered questionnaire that consisted of questions on TTP, sexual life and dietary habits. Women who visited a gynecology clinic in Tokyo for confirmation of pregnancy during the period October 2000 to March 2001 were the subjects asked to fill in the questionnaire. The results were statistically analyzed by chi-square test, t-test and binorminal logistic model after classifying the subjects into two groups: (a) Group I (TTP < or = 6 months; n = 53) (b) Group II (TTP > 6 months; n = 16), Results: Of the 92 women approached, 69 (75.0%) could report TTP. The distribution of TTP, the mode being around 1-2 months with a positive skew toward longer value, was similar to those reported so far in Western countries. There were statistically significantly more smokers in Group II (smoker 62.5%) than in I (15.6%). Logistic regression analysis indicated prior gravidity and fish and milk consumption, in addition to cigarette smoking, to be related to TTP., Conclusions: The present preliminary study indicated that TTP surveys are feasible with Japanese based on the high response rate and plausible distribution of reported value. It also indicated that TTP was related to cigarette smoking, gravidity and dietary habits, again consistent with previous studies.

Surveys for Pineapple mealybug wilt-associated virus-1 (PMWaV-1) and PMWaV-2 were conducted on pineapple samples from Hawaii and around the world. Tissue blot immunoassays (TBIAs) with two different monoclonal antibodies (MAb) specific to either PMWaV-1 or PMWaV-2 indicated that both closteroviruses are widely distributed throughout the pineapple-growing areas of the world. In the worldwide survey, PMWaV-1 was found in 80% of the mea-lybug wilt of pineapple (MWP)-symptomatic and 78% of the asymptomatic pineapple plants tested. A subset of plants was tested for PMWaV-2; 100% of the symptomatic plants and 12% of the asymptomatic plants were positive for this virus. A reverse transcription-polymerase chain reaction (RT-PCR) assay was developed to differentiate between PMWaV-1 and PMWaV-2. Oligonucleotide primers were designed using distinct regions of the HSP 70 homolog genes of the two viruses. PMWaV-specific RT-PCR assays and TBIAs were used to screen the pineapple accessions maintained at the United States Department of Agriculture-Agricultural Research Service National Clonal Germplasm Repository for PMWaV infection; 73% of the accessions were found infected with at least one PMWaV. Pineapple accessions found PMWaV-free were challenged with viruliferous mealybugs to test for immunity to PMWaV-1. No immune germ plasm was identified. Potential alternative virus hosts were screened for infection with virus-specific RT-PCR assays and TBIAs and were also challenged with viruliferous mealybugs. No alternate hosts of PMWaV-1 or PMWaV-2 were identified. PMWaV-1 infection was eliminated through axillary and apical bud propagation from infected crowns. Strategies to manage MWP are discussed.

Infectious hematopoietic necrosis virus (IHNV) is a rhabdovirus which causes a serious disease in salmonid fish. The T1 ribonuclease fingerprinting method was used to compare the RNA genomes of 26 isolates of IHNV recovered from sockeye salmon (Oncorhynchus nerka), chinook salmon (O. tshawytscha), and steelhead trout (O. mykiss) throughout the enzootic portion of western North America. Most of the isolates analyzed in this study were from a single year (1987) to limit time of isolation as a source of genetic variation. In addition, isolates from different years collected at three sites were analyzed to investigate genetic drift or evolution of IHNV within specific locations. All of the isolates examined by T1 fingerprint analysis contained less than a 50% variation in spot location and were represented by a single fingerprint group. The observed variation was estimated to correspond to less than 5% variation in the nucleic acid sequence. However, sufficient variation was detected to separate the isolates into four subgroups which appeared to correlate to different geographic regions. Host species appeared not to be a significant source of variation. The evolutionary and epizootiologic significance of these findings and their relationship to other evidence of genetic variation in IHNV isolates are discussed.

The antihypertensive effects of NIP-121, a novel potassium channel opener, were examined in comparison with cromakalim and its active enantiomer, lemakalim. In experiments by direct blood pressure measurements, orally administered NIP-121 dose-relatedly decreased arterial blood pressure in conscious spontaneously hypertensive rats (SHRs), and the ED20 values (the doses to produce 20% decrease of the mean blood pressure) of NIP-121 and cromakalim were 0.010 and 0.11 mg/kg, respectively, NIP-121 thus being about ten times more potent than cromakalim. The duration of the hypotensive effect by NIP-121 was longer than that by cromakalim. The hypotensive effect of NIP-121 was stronger in SHRs than in normotensive rats. All three drugs showed tachycardia that was antagonized by a beta-blocker, propranolol. Intravenously administered NIP-121 also showed a more potent hypotensive action with longer duration than cromakalim in conscious SHRs. The ED20 values for hypotension by NIP-121, cromakalim, and lemakalim were 0.017, 0.040, and 0.016 mg/kg, respectively. The intravenous hypotensive potency of NIP-121 but not cromakalim was similar to that of p.o. administration. The repeated treatments with NIP-121 (0.025, 0.05, and 0.1 mg/kg p.o. once a day) for 15 days did not modify the degree of the hypotensive action. In the anesthetized SHRs, pretreatment with glibenclamide but not other antagonists (atropine, propranolol, diphenhydramine + cimetidine, or indomethacin) suppressed the decrease in blood pressure induced by NIP-121.(ABSTRACT TRUNCATED AT 250 WORDS)

A novel compound, NIP-121, cromakalim and nicorandil caused concentration-dependent relaxation of rat aortas precontracted with 30 mM KCl, with pEC50 (M) values of 8.2, 7.1 and 5.5, respectively. At 60 mM KCl, the vasorelaxation induced by NIP-121 or cromakalim was almost abolished whereas that induced by nicorandil remained. In preparations precontracted with prostaglandin F2 alpha(PGF2 alpha) (10(-5) M), glibenclamide (10(-7) M) and phentolamine (3 x 10(-6), 3 x 10(-5) M) antagonized the relaxation induced by NIP-121 and cromakalim but not that induced by nicorandil. Methylene blue (10(-5) M) showed antagonistic effects against the vasorelaxation induced by nicorandil but not that induced by NIP-121. NIP-121 (10(-7), 10(-6) M) and cromakalim (10(-6), 10(-5) M) significantly increased the 86Rb+ efflux rate in rat aorta. The three compounds inhibited the frequency of spontaneous contractions of the rat portal vein (pIC30; NIP-121 = 8.0, cromakalim = 7.1 and nicorandil = 4.9); glibenclamide and phentolamine antagonized the effects of these compounds. In conclusion, NIP-121 is a more potent K+ channel opener than cromakalim in these tissues. Nicorandil apparently behaves as a K+ channel opener in the rat portal vein, but the vasorelaxation may involve some other mechanisms, such as generation of cyclic GMP.

Studies on the antihypertensive and diuretic actions of NZ-105, a new dihydropyridine derivative, were performed in comparison with nicardipine. NZ-105 and nicardipine (5, 10 and 20 mg/kg, p.o.) dose-dependently decreased systolic blood pressure in three types of experimentally hypertensive rats, including spontaneously hypertensive rats, renal hypertensive rats and deoxycorticosterone acetate-salt hypertensive rats and normotensive Wistar-strain rats. The hypotensive effects were larger in hypertensive rats than in normotensive Wistar rats. The hypotensive actions of NZ-105 were very slow in onset and long-lasting in all models, e.g., the hypotension by NZ-105 (10 mg/kg, p.o.) reached a peak (-52 mmHg) at 3 hr and lasted for more than 9 hr in spontaneously hypertensive rats. The hypotensive action in spontaneously hypertensive rats was reproducible after repeated dosing twice a day for 29 days. The hypotensive action after i.v. injection of NZ-105 (0.1 mg/kg) in spontaneously hypertensive rats was also slow in onset (peak time: 10 min) and long-lasting (more than 120 min). The hypotensive potency of NZ-105 was about the same as that of nicardipine, but the increment in heart rate was smaller than in the case of nicardipine. Both NZ-105 and nicardipine showed diuretic and natriuretic actions in spontaneously hypertensive rats. After repeated administration, these actions of NZ-105 were unchanged, whereas those of nicardipine were reduced. These results suggest that NZ-105 is a useful antihypertensive drug with concomitant diuretic effects.