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DS-1040 is a novel inhibitor of the activated form of thrombin-activatable fibrinolysis inhibitor that may have therapeutic potential in thromboembolic diseases, such as acute ischemic stroke (AIS) or pulmonary embolism. We undertook a Phase I clinical trial to investigate the safety, pharmacokinetics, and pharmacodynamics of DS-1040 in Japanese patients who were eligible for thrombectomy following AIS.The trial enrolled patients with AIS due to large vessel occlusion, who were planned for thrombectomy within 8 h of symptom onset. Subjects were randomized to receive a single intravenous infusion of placebo or DS-1040 (0.6, 1.2, 2.4 or 4.8 mg) in a sequential-cohort design. The primary endpoints were the incidence of intracranial hemorrhage (ICH) and major extracranial bleeding within 36 and 96 h, respectively, of treatment initiation. Treatment-emergent adverse events (TEAEs) and pharmacokinetic/pharmacodynamic parameters were also assessed.Nine patients received placebo and 32 patients received DS-1040. There were no cases of symptomatic ICH or major extracranial bleeding with either placebo or DS-1040 after 36 and 96 h. One patient, who received DS-1040 0.6 mg, experienced a subarachnoid hemorrhage that was considered to be drug-related. Three patients died (2 placebo, 1 DS-1040), but no deaths were adjudicated as study drug-related. In vivo exposure to DS-1040 increased in proportion to dosage, but no clear dose-response relationship was seen for D-dimer levels and thrombin-activatable fibrinolysis inhibitor activity.Single doses of DS-1040 0.6-4.8 mg were well tolerated in Japanese patients with AIS undergoing thrombectomy.NCT03198715; JapicCTI-163164.

Surgical treatment should be considered for patients with severe vertebrobasilar artery (VBA) stenosis or progressive symptoms, but there is currently no clear treatment algorithm. We report a case of symptomatic intracranial vertebral artery stenosis with repeated cerebral infarction treated by percutaneous transluminal angioplasty (PTA) and stenting and monitoring of oxygen saturation by a brain oximeter. The patient was a 76-year-old man referred to our hospital due to infarction in the right cerebellum. Angiography showed 60% stenosis in the right vertebral artery and 90% stenosis in the left vertebral artery with progressive stenosis in the left. The patient was treated with intravenous and oral triple antiplatelet therapy but had dizziness again with new cerebral infarctions in the left cerebellum and right pontine. We shaved the patient's hair up to the superior nuchal line and placed left and right oximeter probes on each cerebellar hemisphere (2 cm lateral and 2 cm caudal from the external occipital protuberance). Under evaluation of blood flow in the posterior circulation with INVOS Cerebral/Somatic Oximeter, PTA and stent placement were performed for left vertebral artery stenosis. Postoperatively, the dizziness disappeared, and the patient was discharged on his own with good outcome. He has not had a recurrent stroke in over 6 years. Although medical treatment is generally considered the first choice for VBA stenosis, recurrent cerebral infarction occurs at a high rate in symptomatic lesions, and the prognosis is poor. In addition, the perioperative complication rate is not low, and there is no established method for evaluating perfusion of posterior circulation. The brain oximeter is already known to be useful in carotid artery (CA) revascularisation. In this report, we were able to perform a minimally invasive evaluation of blood flow in the posterior circulation using the brain oximeter which might be useful for surgical revascularisation not only in CA but also in VBA.

In November 2013, a 13-valent pneumococcal conjugate vaccine (PCV13) for all infants aged younger than 5 years was incorporated into the Japan national immunization program. An annual survey of nasopharyngeal carriage rates was performed on healthy infants aged 2-24 months from Okinawa, Japan to evaluate the effect of PCV13 on pneumococcal colonization. Of 756 evaluable infants, 203 pneumococcal strains were detected in 193 infants. The overall nasopharyngeal carriage rate was 25.5%, which was not different from our previously reported isolation rate before the introduction of PCV13. The main serotypes of the Streptococcus pneumoniae strains are 15A (18.2%), non-typeable (14.8%), and 15B (11.8%). The carriage rates of pneumococcal strains with 7-valent pneumococcal conjugate vaccine serotypes and PCV13 serotypes were 3.0% and 9.9%, respectively. These values were significantly lower than we reported before the introduction of PCV13. However, the carriage rates of non-PCV13 serotypes have increased. Multivariate logistic regression analysis suggested that siblings and day care attendance are risk factors for pneumococcal carriage.

Objectives Preterm children with severe dyskinetic cerebral palsy due to bilirubin encephalopathy often suffer from marked generalised hypertonus as they age. We performed a questionnaire survey to investigate patient-reported outcomes of treatments for improving their activities of daily life. Methods A mail questionnaire was administered to the caregivers of 67 children with preterm bilirubin encephalopathy aged >4 years. We asked about the type of treatments they received and their efficacy using a five-point subjective scale for the following five domains: motor function, postural stability, sleep, pain, and care burden. The names of oral drugs and their efficacies were also explored. Results The response rate of the questionnaires was 62.7% (42/67), and we analysed the results from 41 validated cases. All children underwent rehabilitation. A total of 30 children received oral drugs, 22 botulinum toxin, 12 orthopaedic surgery, and 3 intrathecal baclofen. Each of these treatments was subjectively reported to be effective in more than half of the recipients for each of the five domains, whereas 23 (56%) required more than two types of treatments other than rehabilitation. Chlordiazepoxide was the most commonly used oral drug, by 28 children (68%), and was discontinued in 7 patients (25%) only. In the sleep domain, the rate of a positive effect was significantly higher for oral drugs (92.7%) than the other treatments (p Conclusion All treatments were partially effective, but their appropriate combination based on a multidisciplinary approach is essential for muscle tone management in children with preterm bilirubin encephalopathy.

Parkinson’s disease is a progressive neurodegenerative disorder characterized by the preferential loss of tyrosine hydroxylase (TH)-expressing dopaminergic neurons in the substantia nigra. Although the abnormal accumulation and aggregation of α-synuclein have been implicated in the pathogenesis of Parkinson’s disease, the underlying mechanisms remain largely elusive. Here, we found that TH converts Tyr136 in α-synuclein into dihydroxyphenylalanine (DOPA; Y136DOPA) through mass spectrometric analysis. Y136DOPA modification was clearly detected by a specific antibody in the dopaminergic neurons of α-synuclein-overexpressing mice as well as human α-synucleinopathies. Furthermore, dopanized α-synuclein tended to form oligomers rather than large fibril aggregates and significantly enhanced neurotoxicity. Our findings suggest that the dopanization of α-synuclein by TH may contribute to oligomer and/or seed formation causing neurodegeneration with the potential to shed light on the pathogenesis of Parkinson’s disease.

Cerebral hyperperfusion syndrome (CHS) is a rare but fatal perioperative complication after surgical correction of carotid stenosis. Despite numerous treatment options for preventing CHS, it does occur in some patients. We developed the outlet gate technique (OGT), in which the embolic balloon was deflated gradually in accordance with the ratio of oxygen saturation measured by a brain oximeter of the ipsilateral brain region to that in the contralateral region. Between June 2017 and May 2018, 39 patients with carotid stenosis underwent endovascular carotid revascularization procedures; of these, 20 underwent the procedure with the OGT. CBO was measured five times in those 20 patients: before the procedure, with the embolic protection device (EPD) on, with the EPD off, during the procedure, and after the procedure. Preventive treatment options were used more frequently in these patients, and although their surgical status seemed more complicated, perioperative complications were not increased. There were almost significant differences between CBO values except between those during and after the procedure with the OGT. This showed that the OGT allowed for stabilization of the CBO and thus has the potential to prevent CHS.

Data on the clinical effectiveness of the novel anti-influenza drug baloxavir marboxil (baloxavir) in children remain limited. We conducted an observational study to compare the duration of fever and symptoms between baloxavir- and oseltamivir-treated children infected with influenza A and B. In total, 159 outpatients with influenza A(H1N1)pdm09 or B/Victoria-lineage infections, aged19 years, during the 2019-2020 influenza season in Japan were enrolled and assessed the duration of fever and symptoms using the Kaplan-Meier method and a multivariate Cox proportional hazard regression model. Polymerase acidic (PA) variants were examined before and after baloxavir treatment. In the multivariable analysis, the duration of fever and symptoms was unaltered between the A(H1N1)pdm09 (n = 116) and B/Victoria-lineage (n = 43) groups. Conversely, the fever duration was marginally longer in the oseltamivir-treated group (n = 59) than in the baloxavir group (n = 100) (hazard ratio (HR) = 0.67, p = 0.05); however, the duration of symptoms was unaltered between the two groups (HR = 0.74, p = 0.11). No patient presented PA reduced susceptibility marker(s) before baloxavir treatment in the analyzed groups. The PA/E23K variant was detected in one case (1.5%, 1/66) of A(H1N1)pdm09 after baloxavir treatment. One case (2.0%, 1/50) of A(H1N1)pdm09 with an N295S substitution in neuraminidase was detected following oseltamivir treatment. These results suggested that the duration of fever was likely to be shorter with baloxavir than with oseltamivir, but the difference between influenza A (H1N1)pdm09 and B/Victoria-lineage was unclear. It is important to continue evaluating the clinical effectiveness of baloxavir and monitoring its drug susceptibility to the influenza virus.

Research question Is natural cycle IVF treatment beneficial to middle-aged women with poor ovarian response? Design Retrospective investigation of outcomes in women aged 45 years and older, who underwent natural cycle IVF treatment between 2009 and 2018 in a single assisted reproduction clinic with the aim of reporting several successful outcomes. Results In total, 2408 IVF retrievals in women aged 45 years and older were included in this study. Mean serum FSH level on day 3 was 21.4 ± 12.5 (range: 0.3–93.7) IU/ml. One fresh cleavage-stage embryo was transferred in 37.4% (900/2408) of the initiated cycles. The overall clinical pregnancy rate and live birth rate per fresh embryo transfer were 2.8% (25/900) and 0.8% (7/900), respectively. Natural cycle IVF treatment led to seven successful deliveries during the period. All seven women who successfully delivered were poor ovarian responders who met the diagnostic Bologna criteria and, among them, three had elevated serum FSH levels on day 3 (range: 39.0–47.1 mIU/ml). All seven had full-term delivery, and no congenital abnormalities were observed in their infants. No significant difference was found in serum FSH level on day 3 between those with and without positive beta-HCG test results. Conclusions These findings suggest that natural cycle IVF treatment could be an option for older poor responders in countries that do not permit egg donation. Careful counselling is required, however, because of the low probability of live births after IVF in middle-aged women.

When it is difficult to approach the brachial or femoral artery during endovascular surgery, an alternative approach is the direct puncture of the carotid artery. In this case of a giant cerebral aneurysm, we punctured the carotid artery directly and performed flow diverter stent placement and endosaccular coil embolization. Although the procedure required two thick access routes, it was performed after administering two antiplatelet drugs and an anticoagulant in order to achieve reliable hemostasis of the puncture sites after the operation. Direct common carotid artery puncture through a cervical skin incision is useful, because it ensures multiple access routes safely and provides secure hemostasis of the puncture sites.

Background Chronic subdural hematoma (CSDH) with cerebrospinal fluid hypovolemia syndrome (CHS) remains refractory to standard treatment with hematoma drainage by burr hole and irrigation and/or epidural blood patch. Previously, we reported the utility of middle meningeal artery (MMA) embolization for intractable CSDH. In this study, we present the usefulness of MMA embolization as a treatment for CSDHs with CHSs. Cases We present two cases of CSDHs with CHSs occurring in patients, 1 treated with burr hole craniotomy and irrigation, and the other treated with the epidural blood patch. Both patients exhibited similar-appearing bilateral relatively-thin hematomas, hyperplasia, and enhanced contrast effects in the dura mater, and extradural hygroma in the cervical portion on enhanced magnetic resonance imaging scans. Also, to reviewing prior literature and imaging findings, they had already undergone conventional treatment. We added MMA embolization treatment and they followed a good course. Results Despite the known intractable outcomes of patients with CSDHs with CHSs, MMA embolization worked well in the current case series. Conclusion MMA embolization might be considered as a preferred therapeutic option for CSDHs with CHSs in order to buy time before the epidural blood patch starts working.

To elucidate the differences in etiology of dyskinetic cerebral palsy (DCP) between term-born and preterm-born children and its relationship to functional outcomes.We determined the etiology of DCP based on the clinical course and brain MRI of 163 term-born and 136 preterm-born children. Information about genetic abnormality was also collected if available. Functional outcomes were compared between the two major etiologies in each group, i.e., hypoxic ischemic encephalopathy (HIE) and bilirubin encephalopathy (BE), using four standardized classification systems, i.e., Gross Motor Function Classification System (GMFCS), Manual Ability Classification System (MACS), Communication Function Classification System (CFCS), and Eating and Drinking Ability Classification System (EDACS).The most common etiologies were HIE (123/163) in term-born and BE (93/136) in preterm-born children. Genetic mutations were identified in 14 of 30 term-born children with no other known etiology. GMFCS levels of the preterm children with BE were significantly poorer than those of term children with HIE (p 0.01). Both the CFCS and EDACS levels were significantly better in preterm children with BE than in term children with HIE (p 0.01).The most common etiology of DCP is different between term-born and preterm-born children, and the distribution of functional impairment is significantly influenced by etiology and gestational age. The difference should be taken into consideration to allow the provision of adequate interventions.

STUDY OBJECTIVE To evaluate the efficacy of a nonsurgical treatment for cervical pregnancy (CP) and cesarean section scar pregnancy (CSP). DESIGN Retrospective clinical study (Canadian Task Force classification III). SETTING Private assisted reproductive technology practice. PATIENTS Nineteen women with CP (n = 16) or CSP (n = 3), including 6 patients with positive fetal heartbeat. INTERVENTION Transvaginal local injection of absolute ethanol (AE) into the hyperechoic ring (lacunar space) around the gestational sac under ultrasound guidance. MEASUREMENTS AND MAIN RESULTS Serum beta-human chorionic gonadotropin (β-hCG) was measured at frequent intervals, and ultrasound and/or magnetic resonance imaging was used to observe the gestational sac. In 9 patients, the serum β-hCG level was effectively reduced with a single AE injection at 2 hours. In the remaining 10 patients, the level decreased but then increased in 4 and slowly decreased in the other 6; all of these 10 patients required 2 to 5 repeat AE injections. In all patients, serum β-hCG level was reduced by 50% within 3 days and decreased to

PURPOSE: A microwell culture system that facilitates group culture, such as well-of-the-well (WOW), improves embryonic development in an individual culture. We examined the effect of WOW on embryonic development in vitro with commercially available human single culture media. METHODS: Using four different commercial human single culture media, in vitro development and imprinted gene expression of bovine embryos cultured in WOW were compared to droplet culture (one zygote per drop). To determine the effects of microwell and group culture on embryonic development, different numbers of embryos were cultured in droplet or WOW. Diffusion simulation of accumulating metabolites was conducted using the finite volume method. RESULTS: WOW had a positive effect on bovine embryonic development, regardless of the type of single culture media. Imprinted gene expression was not different between droplet- and WOW-derived blastocysts. The microwell and group cultures in WOW showed a significant positive effect on the rate of total blastocysts and the rate of development to the expanded and hatching blastocyst stages. The assumed cumulative metabolite concentration of WOW with one embryo was 1.47 times higher than that of droplet culture with one embryo. Furthermore, the concentration of WOW with three embryos was 1.54 times higher than that of WOW with one embryo. CONCLUSIONS: In using human single culture media, a microwell culture system that allows group culture could be a powerful clinical tool for improving the success of assisted reproductive technologies. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s10815-018-1252-z) contains supplementary material, which is available to authorized users.

Baloxavir marboxil has been used for influenza treatment since March 2018 in Japan. After baloxavir treatment, the most frequently detected substitution is Ile38Thr in polymerase acidic protein (PA/I38T), and this substitution reduces baloxavir susceptibility in influenza A viruses. To rapidly investigate the frequency of PA/I38T in influenza A (H1N1)pdm09 and A (H3N2) viruses in clinical samples, we established a rapid real-time system to detect single nucleotide polymorphisms in PA, using cycling probe real-time PCR. We designed two sets of probes that were labeled with either 6-carboxyfluorescein (FAM) or 6-carboxy-X-rhodamine (ROX) to identify PA/I38 (wild type strain) or PA/I38T, respectively. The established cycling probe real-time PCR system showed a dynamic linear range of 101 to 106 copies with high sensitivity in plasmid DNA controls. This real-time PCR system discriminated between PA/I38T and wild type viruses well. During the 2018/19 season, 377 influenza A-positive clinical samples were collected in Japan before antiviral treatment. Using our cycling probe real-time PCR system, we detected no (0/129, 0.0%) influenza A (H1N1)pdm09 viruses with PA/I38T substitutions and four A (H3N2) (4/229, 1.7%) with PA/I38T substitution prior to treatment. In addition, we found PA/I38T variant in siblings who did not received baloxavir treatment during an infection caused by A (H3N2) that afflicted the entire family. Although human-to-human transmission of PA/I38T variant may have occurred in a closed environment, the prevalence of this variant in influenza A viruses was still limited. Our cycling probe-PCR system is thus useful for antiviral surveillance of influenza A viruses possessing PA/I38T.

Ndel1, a protein located at the subdistal appendage of mother centriole, functions as an upstream regulator of the trichoplein–Aurora A pathway that suppresses ciliogenesis in proliferating cells., Primary cilia protrude from the surface of quiescent cells and disassemble at cell cycle reentry. We previously showed that ciliary reassembly is suppressed by trichoplein-mediated Aurora A activation pathway in growing cells. Here, we report that Ndel1, a well-known modulator of dynein activity, localizes at the subdistal appendage of the mother centriole, which nucleates a primary cilium. In the presence of serum, Ndel1 depletion reduces trichoplein at the mother centriole and induces unscheduled primary cilia formation, which is reverted by forced trichoplein expression or coknockdown of KCTD17 (an E3 ligase component protein for trichoplein). Serum starvation induced transient Ndel1 degradation, subsequent to the disappearance of trichoplein at the mother centriole. Forced expression of Ndel1 suppressed trichoplein degradation and axonemal microtubule extension during ciliogenesis, similar to trichoplein induction or KCTD17 knockdown. Most importantly, the proportion of ciliated and quiescent cells was increased in the kidney tubular epithelia of newborn Ndel1-hypomorphic mice. Thus, Ndel1 acts as a novel upstream regulator of the trichoplein–Aurora A pathway to inhibit primary cilia assembly.

Objective A subset of patients with chronic subdural hematoma (CSDH) remains refractory to standard treatment with hematoma drainage by burr-hole craniotomy and irrigation. We recently reported the usefulness of middle meningeal artery (MMA) embolization for intractable CSDH in patients with multiple intractable risk factors. We present the midterm outcomes of MMA embolization in patients with intractable CSDHs. Methods and Results Seventeen consecutive patients (average age, 76.4 years; 12 men [71%]) underwent MMA embolization of CSDH from January 2014 to July 2017. Earlier interventions included embolization using N-butyl-2-cyanoacrylate (although trisacryl gelatin microspheres were used in recent cases), followed by burr-hole craniotomy and irrigation in all cases. None of the patients experienced perioperative complications or postoperative recurrence. The modified Rankin Scale scores, which were unfavorable at admission, improved significantly at discharge but were comparable to those at the time of hospitalization when measured during the follow-up period. Although the patients required rehospitalization at other departments for unrelated causes, none required rehospitalization in our department. Conclusions Despite the known unfavorable outcomes of patients with intractable CSDHs, MMA embolization was not associated with recurrent CSDH or rehospitalization in our department in the current case series. MMA embolization should be considered a preferred therapeutic option for intractable CSDHs.

This study compared privacy consciousness between Japanese (n = 211) and Taiwanese (n = 308) high school students, who responded to the Privacy Consciousness Scale. Results indicated that Taiwanese students had higher privacy consciousness for the self and others than Japanese students.

A series of 9-disubstituted N-(9H-fluorene-2-carbonyl)guanidine derivatives have been discovered as potent and orally active dual 5-HT(2B) and 5-HT(7) receptor antagonists. Upon screening several compounds, N-(diaminomethylene)-4',5'-dihydro-3'H-spiro[fluorene-9,2'-furan]-2-carboxamide (17) exhibited potent affinity for both 5-HT(2B) (Ki = 5.1 nM) and 5-HT(7) (K(i) = 1.7 nM) receptors with high selectivity over 5-HT(2A), 5-HT(2C), α(1), D(2) and M(1) receptors. Optical resolution of the intermediate carboxylic acid 16 via the formation of diastereomeric salts using chiral alkaloids gave the optically pure compounds (R)-17 and (S)-17. Both enantiomers suppressed 5-HT-induced dural protein extravasation in guinea pigs in a dose-dependent manner and the amount of leaked protein was suppressed to near normal levels when orally administrated at 10 mg/kg. (R)-17 and (S)-17 were therefore selected as candidates for human clinical trials.

To identify potent dual 5-HT2B and 5-HT7 receptor antagonists, we synthesized a series of novel carbonyl guanidine derivatives and examined their structure-activity relationships. Among these compounds, N-(9-hydroxy-9H-fluorene-2-carbonyl)guanidine (10) had a good in vitro profile, that is, potent affinity for human 5-HT2B and 5-HT7 receptor subtypes (Ki=1.8 nM and Ki=17.6 nM, respectively) and high selectivity over 5-HT2A, 5-HT2C, α1, D2 and M1 receptors. Compound 10 also showed a suppressing effect on 5-HT-induced dural protein extravasation in guinea pigs when orally administered.

Human mutations in KATNB1 (p80) cause severe congenital cortical malformations, which encompass the clinical features of both microcephaly and lissencephaly. Although p80 plays critical roles during brain development, the underlying mechanisms remain predominately unknown. Here, we demonstrate that p80 regulates microtubule (MT) remodeling in combination with NuMA (nuclear mitotic apparatus protein) and cytoplasmic dynein. We show that p80 shuttles between the nucleus and spindle pole in synchrony with the cell cycle. Interestingly, this striking feature is shared with NuMA. Importantly, p80 is essential for aster formation and maintenance in vitro. siRNA-mediated depletion of p80 and/or NuMA induced abnormal mitotic phenotypes in cultured mouse embryonic fibroblasts and aberrant neurogenesis and neuronal migration in the mouse embryonic brain. Importantly, these results were confirmed in p80-mutant harboring patient-derived induced pluripotent stem cells and brain organoids. Taken together, our findings provide valuable insights into the pathogenesis of severe microlissencephaly, in which p80 and NuMA delineate a common pathway for neurogenesis and neuronal migration via MT organization at the centrosome/spindle pole.

Neuronal nitric oxide synthase is involved in diverse signaling cascades that regulate neuronal development and functions via S-Nitrosylation-mediated mechanism or the soluble guanylate cyclase (sGC)/cyclic guanosine monophosphate (cGMP) pathway activated by nitric oxide. Although it has been studied extensively in vitro and in invertebrate animals, effects on mammalian brain development and underlying mechanisms remain poorly understood. Here we report that genetic deletion of “Nos1” disrupts dendritic development, whereas pharmacological inhibition of the sGC/cGMP pathway does not alter dendritic growth during cerebral cortex development. Instead, nuclear distribution element-like (NDEL1), a protein that regulates dendritic development, is specifically S-nitrosylated at cysteine 203, thereby accelerating dendritic arborization. This post-translational modification is enhanced by N-methyl-D-aspartate receptor-mediated neuronal activity, the main regulator of dendritic formation. Notably, we found that disruption of S-Nitrosylation of NDEL1 mediates impaired dendritic maturation caused by developmental alcohol exposure, a model of developmental brain abnormalities resulting from maternal alcohol use. These results highlight S-Nitrosylation as a key activity-dependent mechanism underlying neonatal brain maturation and suggest that reduction of S-Nitrosylation of NDEL1 acts as a pathological factor mediating neurodevelopmental abnormalities caused by maternal alcohol exposure.

Selective attention can be improved under conditions in which a high perceptual load is assumed to exhaust cognitive resources, leaving scarce resources for distractor processing. The present study examined whether perceptual load and acute stress share common attentional resources by manipulating perceptual and stress loads. Participants identified a target within an array of nontargets that were flanked by compatible or incompatible distractors. Attentional selectivity was measured by longer reaction times in response to the incompatible than to the compatible distractors. Participants in the stress group participated in a speech test that increased anxiety and threatened self-esteem. The effect of perceptual load interacted with the stress manipulation in that participants in the control group demonstrated an interference effect under the low perceptual load condition, whereas such interference disappeared under the high perceptual load condition. Importantly, the stress group showed virtually no interference under the low perceptual load condition, whereas substantial interference occurred under the high perceptual load condition. These results suggest that perceptual and stress related demands consume the same attentional resources.

To clarify the molecular epidemiology of human metapneumovirus (HMPV) in Okinawa Prefecture, located in a subtropical region of Japan, we performed genetic analysis of the F gene in HMPV from patients with acute respiratory infection from January 2009 to December 2011. HMPV was detected in 18 of 485 throat swabs (3.7%). Phylogenetic analysis showed that 17 strains belonged to subgroup A2 and 1 strain belonged to subgroup B1. We did not observe seasonal prevalence of HMPV during the investigation period. A high level of sequence identity was observed in the strains belonging to subgroup A2 (95%), and no amino acid substitution was found compared with other strains detected in Japan and other countries. The pairwise distance values among the present strains belonging to subgroup A2 were short. Our results suggest that the predominant HMPV strains belonging to A2 are highly homologous and seasonal epidemics were not seen in Okinawa during the investigation period.

Antegrade recanalisation of a completely occluded internal carotid artery (ICA) via the vasa vasorum is extremely rare. Here, we report such a case after proximal endovascular coiling in a case of dissected (i.e. non-atherosclerotic) ICA. A 42-year-old man presented with thromboembolic stroke of the left frontal lobe owing to pseudo-occlusion of the left ICA manifesting as motor aphasia and right hemiparesis. There were abundant floating thrombi in the petrous portion of the left ICA. Because of good collateral flow in the left middle cerebral artery territory through the anterior communicating artery and external carotid artery system, endovascular coil embolisation of the left ICA was performed for prevention of further thromboembolic stroke. The patient showed progressive recovery following endovascular treatment, and was discharged with mild right hemiparesis 1 month later. He maintained a regimen of aspirin and physical rehabilitation. At follow-up, 38 months later, the patient was asymptomatic. Angiography demonstrated occlusion of the left ICA and multiple serpiginous vessels originating from the proximal internal and external carotid arteries and which filled the ICA distal to the occlusion. This case suggests that an ICA occluded by proximal coil embolisation—even in a non-atherosclerotic case—might be recanalised via the vasa vasorum.

Lissencephaly is a severe human neuronal migration defect characterized by a smooth cerebral surface, mental retardation and seizures. The two most common genes mutated in patients with lissencephaly are LIS1 and DCX. LIS1 was the first gene cloned that was important for neuronal migration in any organism, and heterozygous mutations or deletions of LIS1 are found in the majority of patients with lissencephaly, while DCX mutations were found in males with X-linked lissencephaly. In this review, we will discuss how an understanding of the molecular and cellular pathways disrupted in model organisms with Lis1 and Dcx mutations or knock-down not only provide insights into the normal processes of neuronal migration, including neurogenesis, but they also may lead to potential novel therapeutic strategies for these severe cortical malformations.

Haploinsufficiency is a state of genetic disease, which is caused by hemizygous mutations of functional alleles. Lissencephaly is a typical example of haploinsufficiency disorders characterized by a smooth cerebral surface, thick cortex and dilated lateral ventricules associated with mental retardation and seizures due to defective neuronal migration. LIS1 was the first gene cloned in an organism, which was deleted or mutated in patients with lissencephaly in a heterozygous fashion. Series of studies uncovered that LIS1 is an essential regulator of cytoplasmic dynein. In particular, we reported that LIS1 is essential for dynein transport to the plus-end of microtubules by kinesin, which is essential for maintaining proper distribution of cytoplasmic dynein within the cell. Fortuitously, we found that a substantial fraction of LIS1 is degraded by the cystein protease, calpain after reaching the plus-end of microtubules. We further demonstrated that inhibition of calpain-mediated LIS1 degradation increased LIS1 level at the cortex of the cell, resulting in therapeutic benefit using genetic mouse models with reduced levels of LIS1. Our work might provide a potential therapeutic approach for the treatment of a fraction of haploinsufficiency disorders through augmenting reduced proteins by the targeting inhibition of degradation machinery.

Lissencephaly is a devastating neurological disorder caused by to defective neuronal migration. LIS1 (or PAFAH1B1), the gene mutated in lissencephaly patients and its binding protein NDEL1 were found to regulate cytoplasmic dynein function and localization. LIS1 and NDEL1 also play a pivotal role on a microtubule regulation and determination of cell polarity. For example, LIS1 is required for the precise control of mitotic spindle orientation in both neuroepithelial stem cells and radial glial progenitor cells. On the other hand, NDEL1 is essential for mitotic entry as an effector molecule of Aurora-A kinase. In addition, an atypical protein kinase C (aPKC)-Aurora-A-NDEL1 pathway is critical for the regulation of microtubule organization during neurite extension. These findings suggest that physiological functions of LIS1 and NDEL1 in neurons have been ascribed for proteins fundamentally required for cell cycle progression and control. In turn, cell cycle regulators may exert other functions during neurogenesis in a direct or an indirect fashion. Thus far, only a handful of cell cycle regulators have been shown to play physiological cell cycle-independent roles in neurons. Further identification of such proteins and elucidation of their underlying mechanisms of action will likely reveal novel concepts and/or patterns that provide a clear link between their seemingly distinct cell cycle and neuronal functions.

Aim: The present study was a 52-week, non-comparative, open-label study of flexible dose paroxetine (20–40 mg) in 52 Japanese post-traumatic stress disorder (PTSD) patients in order to obtain clinical experience regarding efficacy and safety in regular clinical practice. Methods: Efficacy was measured using the Clinician-Administered PTSD Scale One Week Symptom Status Version (CAPS-SX). Results: The mean change from baseline in CAPS-SX total score was −19.1, −22.8 and −32.3 at weeks 4, 12 and 52, respectively, and that in the Clinical Global Impression (CGI) Severity of Illness score was −1.1 at week 12 and −1.7 at week 52. A total of 46.9% were CGI responders at week 12, while 67.3% were improved on the CGI at week 52. Of 52 subjects who entered into the drug treatment, 25 completed the study. Only one patient withdrew from the study due to lack of efficacy. In patients who were rated as ‘moderately ill’ or less at baseline, the proportion of CGI responders at end-point was higher at a dose of 20 mg/day than at higher doses, whereas in patients rated as ‘markedly ill’ or more, it was higher at 30 and 40 mg/day, suggesting that severely ill patients could benefit from higher doses. Conclusion: Paroxetine appeared generally tolerated in short- and long-term use, and the safety profile in this study was consistent with international trials and other Japanese populations (i.e. patients suffering from depression, panic disorder or obsessive–compulsive disorder). Although the study was not conducted in double-blind fashion, the current findings suggest that paroxetine may contribute to clinically meaningful improvement that is maintained during long-term use and is generally well tolerated.

LIS1 was first identified as a gene mutated in human classical lissencephaly sequence. LIS1 is required for dynein activity, but the underlying mechanism is poorly understood. Here, we demonstrate that LIS1 suppresses the motility of cytoplasmic dynein on microtubules (MTs), whereas NDEL1 releases the blocking effect of LIS1 on cytoplasmic dynein. We demonstrate that LIS1, cytoplasmic dynein and MT fragments co-migrate anterogradely. When LIS1 function was suppressed by a blocking antibody, anterograde movement of cytoplasmic dynein was severely impaired. Immunoprecipitation assay indicated that cytoplasmic dynein forms a complex with LIS1, tubulins and kinesin-1. In contrast, immunoabsorption of LIS1 resulted in disappearance of co-precipitated tubulins and kinesin. Thus, we propose a novel model of the regulation of cytoplasmic dynein by LIS1, in which LIS1 mediates anterograde transport of cytoplasmic dynein to the plus end of cytoskeletal MTs as a dynein-LIS1 complex on transportable MTs, which is a possibility supported by our data.

Protein phosphatase 4 catalytic subunit (PP4c) is a PP2A-related protein serine/threonine phosphatase with important functions in a variety of cellular processes, including microtubule (MT) growth/organization, apoptosis, and tumor necrosis factor signaling. In this study, we report that NDEL1 is a substrate of PP4c, and PP4c selectively dephosphorylates NDEL1 at Cdk1 sites. We also demonstrate that PP4c negatively regulates Cdk1 activity at the centrosome. Targeted disruption of PP4c reveals disorganization of MTs and disorganized MT array. Loss of PP4c leads to an unscheduled activation of Cdk1 in interphase, which results in the abnormal phosphorylation of NDEL1. In addition, abnormal NDEL1 phosphorylation facilitates excessive recruitment of katanin p60 to the centrosome, suggesting that MT defects may be attributed to katanin p60 in excess. Inhibition of Cdk1, NDEL1, or katanin p60 rescues the defective MT organization caused by PP4 inhibition. Our work uncovers a unique regulatory mechanism of MT organization by PP4c through its targets Cdk1 and NDEL1 via regulation of katanin p60 distribution.

Although many reports support stimulated in vitro fertilization, several patients do not respond to it well. Furthermore, stimulated treatment could be associated with reduced ovarian response. We describe three successful cases involving patients of advanced age from whom dominant follicles were retrieved during the natural cycle.All patients had failed to bear children through stimulated in vitro fertilization. In case 1, a follicle was retrieved after a gonadotropin-releasing hormone agonist was used to induce luteinizing hormone surge. In cases 2 and 3, pregnancy was achieved via completely natural cycles.One embryo was transferred every 16 cycles. Ongoing pregnancy--defined as pregnancy progressing beyond gestation week 9--was established in three cycles. The patients successfully delivered and had uneventful neonatal courses.Mature oocyte retrieval followed by natural rather than stimulated in vitro fertilization might be a potential treatment for patients of advanced age when stimulated in vitro fertilization has been repeatedly unsuccessful.

The effects of anonymity on self-disclosure were investigated in a CMC (computer-mediated communication) situation by separately manipulating the anonymity of the self and the other. It was hypothesized that anonymity of the self would enhance disclosure, whereas anonymity of the other would decrease it. Female undergraduate students (n = 60) were randomly assigned to a 2 (self: anonymous or non-anonymous) x 2 (other: anonymous or non-anonymous) experimental design. The anonymity of the self and the other was manipulated in the profile, such as the photo, name, and sex of the self or the other, on the computer screen. The results indicated that anonymity of the self decreased the feeling of anxiety, but had no effect on disclosure, whereas anonymity of the other decreased the feeling of closeness and decreased the intimacy of disclosure.

NDEL1 is a binding partner of LIS1 that participates in the regulation of cytoplasmic dynein function and microtubule organization during mitotic cell division and neuronal migration. NDEL1 preferentially localizes to the centrosome and is a likely target for cell cycle-activated kinases, including CDK1. In particular, NDEL1 phosphorylation by CDK1 facilitates katanin p60 recruitment to the centrosome and triggers microtubule remodeling. Here, we show that Aurora-A phosphorylates NDEL1 at Ser251 at the beginning of mitotic entry. Interestingly, NDEL1 phosphorylated by Aurora-A was rapidly downregulated thereafter by ubiquitination-mediated protein degradation. In addition, NDEL1 is required for centrosome targeting of TACC3 through the interaction with TACC3. The expression of Aurora-A phosphorylation-mimetic mutants of NDEL1 efficiently rescued the defects of centrosomal maturation and separation which are characteristic of Aurora-A-depleted cells. Our findings suggest that Aurora-A-mediated phosphorylation of NDEL1 is essential for centrosomal separation and centrosomal maturation and for mitotic entry.

During endovascular neurosurgery, various devices, such as catheters, are passed through the intracranial arteries to access target vessels; the arteries can thereby be perforated. Even though such incidents are serious and should be dealt with appropriately, few case reports or standard procedures have been published. Herein, we report two cases of arterial perforation that occurred recently in our hospital. In the first case, the patient had been treated preoperatively using feeder occlusion of an arteriovenous malformation; the microcatheter perforated the feeder, which branched from the middle cerebral artery. The feeder and perforation site were occluded by injection of n-butyl 2-cyanoacrylate (NBCA) through the same microcatheter, and complete hemostasis was thereby achieved. The second case occurred during an embolization of the middle meningeal artery (MMA) to treat a refractory chronic subdural hematoma;the microcatheter perforated a branch of the MMA. Both the perforation and the artery were embolized using platinum coils and by injecting NBCA, and hemostasis was achieved. Considering the anatomical and pathological properties of the injured vessels, favorable results were achieved with appropriate intervention.

Cerebrospinal fluid leaks following spinal surgery are relatively common complications. However, subdural hematomas are uncommon, and infratentorial subdural hemorrhages are extremely rare. An 80-year-old man who had a history of myocardial infarction and was being treated with antiplatelet drugs underwent excision of a nerve sheath tumor of the upper cervical spine. Postoperatively, the patient developed headache and experienced weakness in both lower extremities 1 week after the surgery. In addition, he developed vomiting 2 weeks later. Magnetic resonance imaging revealed cerebrospinal fluid retention behind the upper cervical spine, subdural hematomas in the right supra- and infra-tentorial regions, and subdural hygromas in the left supra- and infra-tentorial regions. The chronic subdural hematoma in the right supratentorial region was evacuated through a burr hole. Marked cerebellar ptosis and hydrocephalus developed postoperatively. Thereafter, cerebellar symptoms appeared. The infratentorial subdural hematoma and hygromas diminished in size;however, a posterior fossa cyst was found behind the fourth ventricle. Ten weeks after the burr hole surgery, a ventriculoperitoneal(VP)shunt was installed to decrease the cerebrospinal fluid retention behind the fourth ventricle and to cure the liquorrhea by reducing cerebrospinal fluid flow into the subarachnoid space of the posterior cranial fossa and the spinal canal. The patient's postoperative course was satisfactory, and the liquorrhea disappeared.

Dear Editor: Surgery is not indicated for mild trigonocephaly, as clearly described in the introduction of Dr. Shimoji’s newest paper [1]. The introduction also specifically says Bthe use of surgical interventions is not generally accepted for children with mild trigonocephaly complicated by clinical manifestations^ [1]. Indeed, reference 15 in the paper supports Shimoji’s significant finding that individuals with a very mild form of trigonocephaly can have developmental problems, but the conclusion of the reference is that Bthe frequency of these problems is not related to the severity of the trigonocephaly^ [2]. In Shimoji’s cases, the intraoperative intracranial pressure (ICP) values were not correlated with the level of postoperative clinical changes [1]. Every neurosurgeon knows that these facts are themain reasons for the general consensus that Bneither the neurological findings nor the severity of deformity nor the intracranial pressure provide any arguments favoring a mechanical cause of brain dysfunction^ in isolated trigonocephaly cases [3, 4]. Therefore, the continuous implementation of this unaccepted surgical procedure as a therapeutic intervention is underpinned by ethical fallacies, tricky ambiguities, and the misinterpretation of the outcomes. Most of the following points had already repeatedly been presented [5–9].

Ingestion of a foreign body is not uncommon, but rarely results in perforation of the gastrointestinal tract. The most common sites of perforation are reportedly the narrowest parts of the bowel, and perforation of the right side of the colon is rare. We report herein the case of a 69-year-old man who presented with an 8-week history of right upper abdominal pain. Laboratory data revealed inflammation at the first hospital visit. Computed tomography revealed a hypodense lesion containing a hyperdense foreign body in the abdomen. Intra-abdominal abscess caused by foreign body perforation was diagnosed. After administering antibiotics for 2 weeks, surgery was performed. Symptoms had resulted from perforation of the ascending colon by a fish bone.

A 24-year-old woman underwent craniotomy for falx meningioma (5 cm in diameter) on October 24, 1995. The deepest part of the tumor was located in the anterior horn of the lateral ventricle, which was not resected. The histology was clear cell meningioma (CCM), aggressive in nature. The MIB-1 labeling index was high (11%). She underwent gamma knife (GK) radiosurgery for the residual tumor with an irradiation dose of 16 Gy at the tumor periphery on May 24, 1996. The postradiosurgical course was uneventful. The residual intraventricular tumor gradually decreased in size, but the peripheral portion gradually grew into the diencephalic region. The patient remained in good condition for 5 years until September 2001, when she exhibited memory disturbance and lethargy. Magnetic resonance imaging demonstrated a large tumor (4.5 cm in diameter) in the diencephalon, compressing the optic nerves and fornix. The calculated tumor doubling time was 120 days. A second craniotomy was performed on October 9, 2001. The tumor was totally resected through the anterior transcallosal approach. The histology and the MIB-1 labeling index of the tissue from the second operation did not differ markedly from those of the first operation. Neither tumor recurrence nor metastasis has been observed to date. GK radiosurgery contributed to control of the residual intraventricular tumor, but the peripheral portion of the tumor, which received a relatively low radiation dose (16 Gy), grew rapidly. This suggests that a marginal dose of 16 Gy may not be sufficient for control of CCM.

Autosomal dominant polycystic kidney disease is a systemic disorder that primary affects the kidney which is characterized by the formation of fluid-filled cysts in both kidneys that leads to progressive renal failure. Mutated genes, polycystin-1 and polycystin-2, are identified, and evidence has emerged that polycystins are ion channels or regulators of ion channels. In spite of extensive characterization of polycystins, how polycystin channel signaling may be involved in cyst formation in ADPKD is still unclear. We found a mutant mouse which exhibits polycystic kidney and bone deformity in the course of making a transgenic mouse carrying the Drosophila sex-lethal gene. We identified a mutated gene Makorin1 by positional cloning. Makorin1 carries a typical RING-finger motif, suggesting that Makorin1 belongs to ubiquitinase E3 family. Makorin1 would open a new avenue to understand pathogenesis of polycystic kidney, and become a new therapeutic target of polycystic kidney.

Aim Severe neurogenic pulmonary edema (NPE) can occur in a variety of brain insults, including subarachnoid hemorrhage (SAH), and severe case of NPE can cause devastating consequences. But the literature on the treatment strategy about aneurysmal SAH with NPE is very scant. We present that SAH patients with severe NPE, who were treated first by embolization of aneurysm followed by insertion of lumbar spinal drainage, had comparatively good outcome. Material and methods We present 12 consecutive cases of aneurysmal SAH with NPE in the acute stage, which were treated by endovascular treatment between April 2002 and December 2012. We classified the patients according to the Hunt and Hess grading system as follows: grade-3 (1 patient), grade-4 (4 patients), and grade-5 (7 patients). All patients needed respiratory management, with the assistance of a ventilator, and underwent endovascular treatment for the ruptured aneurysms within 72 hours from onset. For all the patients, immediately after the endovascular treatment, we performed lumbar spinal drainage. Results The pulmonary edema disappeared rapidly after respiratory management and endovascular treatment. The outcomes were as follows: good recovery (GR; 3 patients), moderate disability (MD; 4 patients), severe disability (SD; 3 patients), and death (D; 2 patients). Five patients (42%) developed pneumonia, and we postponed extubation until recovery from pneumonia. The cause for severe disability and death was symptomatic vasospasm and primary brain damage. No patients had rebleeding from ruptured aneurysms. Conclusion Endovascular treatment for ruptured aneurysm and placement of lumbar spinal drainage is an excellent treatment option for severe SAH with NPE.

Introduction. Gliosarcoma in infant is a very rare entity. Case report. The authors present a case of gliosarcoma in a 23-month-old boy. The patient was admitted to our hospital with persistent headache and frequent vomiting. MR imaging demonstrated a large frontal well-circumscribed lesion with a heterogeneous gadolinium enhancement. Although macroscopically the tumor was totally extirpated, the boy died of rapid tumor regrowth 2 months after surgery. The surgical specimens obtained from the tumor showed an admixture of two distinctive neoplastic tissues. One was a malignant mesenchymal feature. Its fibrosarcomatous nature was characterized by spindle-shaped cells with fine fibers that were deeply stained in silver preparations for reticulin. The other was gliomatous tissue forming islands surrounded by the sarcomatous tissues. Its glioblastomatous nature was obvious, as it was characterized by endothelial proliferation and perinecrotic pseudopalisading. Both tissues were histologically malignant, as evidenced by mitotic figure, high cellularity, atypical features, and variability. Discussion. The literature concerning gliosarcomatous tumors is reviewed, and pathological and clinical features of the tumor are briefly discussed.

Ischemic stroke of the anterior choroidal artery(AChA)is the most common and serious complication after AChA aneurysm treatment. The purpose of this study was to retrospectively evaluate and compare the treatment-related ischemic complications after surgical clipping and endovascular coiling of AChA aneurysms.br/Between June 2006 and March 2013, 32 patients with 34 AChA aneurysms were treated in our hospital by surgical clipping or endovascular coiling. There were 12 cases of ruptured aneurysms, seven cases of unruptured aneurysms, and 15 cases of incidentally identified unruptured aneurysms. Of the 34 aneurysms, 19 were managed with surgical clipping and 15 were managed with endovascular coiling. No rebleeding or retreatment occurred in any case during 4-84 months(median, 25 months)of follow-up, and no significant differences in clinical outcome were seen between clipping and coiling cases. Although there were four cases(11.8%;surgical clipping in three;endovascular coiling in one)of postoperative AChA infarction, we believe that we preserved the blood flow of the AChA during the procedure. The occurrence of subarachnoid hemorrhage and premature rupture during surgical clipping were significantly correlated with AChA infarction.

Background It is important to evaluate the likelihood of fatality in patients with acute primary pontine hemorrhage (PPH) in emergency departments. We aimed to evaluate the clinical symptoms and computed tomography findings of PPH to develop a simple grading scale for predicting the mortality of PPH. Methods Records of 101 consecutive patients admitted to our hospital with acute PPH between June 1, 2006, and January 31, 2014, were retrospectively reviewed. Independent predictors of 30-day mortality were identified by univariate and multivariate logistic regression analyses. A simple and easy clinical score (PPH score) was developed from independent factors to predict mortality in acute PPH. The PPH score was compared with the established intracerebral hemorrhage (ICH) score, which served as the reference scoring system. Results Overall mortality rate 30 days after onset was 58.4% (59 of 101). Factors independently associated with 30-day mortality were Glasgow Coma Scale (GCS) score of 6 or less (P = .0051), absence of pupillary light reflex (P = .0003), and blood glucose of 180 mg/dL or greater (P = .0312). The PPH score was the sum of independent factors, which were assigned 1 point each. The area under the receiver operating characteristic curve for predicting 30-day mortality was .90 (95% confidence interval [CI], .84-.95) for PPH score and .86 (95% CI, .78-.93) for ICH score. Conclusions GCS score of 6 or less, absence of pupillary light reflex, and plasma glucose of 10 mmol/L or greater are independent mortality predictors of PPH. The PPH score is a simple and reliable clinical grading scale for predicting 30-day mortality.

Intraductal papillary mucinous neoplasm of the bile duct (IPNB) is recognized as a precancerous lesion; however, both its pathogenesis and progression remain unclear. We present here a case of IPNB arising from the gallbladder accompanied by bile duct tumor thrombus in a 79-year-old female. The resected specimen revealed a tubulopapillary adenoma with no malignant cells. This case suggests that even in the absence of malignant cells, these tumors can behave as malignant tumors requiring aggressive treatment. Even if no malignant cells are present, intraepithelial neoplasms occurring in the ampullopancreatobiliary tract can behave as malignant tumors.

Cytoplasmic dynein acts as a motor for the intracellular retrograde motility of vesicles and organelles along microtubules. However, the regulatory mechanism underlying release of dynactin bound cargoes from dynein motor remains largely unknown. Here we report that ADP-ribosylation factor-like 3 (Arl3) and dynein light chain LC8 induce dissociation of dynactin from dynein. Immunoprecipitation and microtubule pull-down assays revealed that Arl3(Q71L) and LC8 facilitated detachment of dynactin from dynein. We also demonstrated Arl3(Q71L) or LC8-mediated dynactin release from a dynein-dynactin complex through trace experiments using quantum dot (Qdot)-conjugated proteins. Furthermore, we disclosed interactions of Arl3 and LC8 with dynactin and dynein, respectively, by live-cell imaging. Finally, knockdown (KD) of Arl3 and LC8 by siRNA induced abnormal localizations of dynein, dynactin and related organelles. Our findings uncovered the surprising functional relevance of GTP-bound Arl3 and LC8 for the unloading regulation of dynactin-bound cargo from dynein motor.

Aims Bile acid binding resin (BAR) improves glycaemic control in patients with type 2 diabetes. Although the mechanism is hypothesised to involve the clearance of excess hepatic triglyceride, this hypothesis has not been examined in appropriately designed studies. Therefore, we investigated whether reduced hepatic triglyceride deposition is involved in BAR-mediated improvements in glycaemic control in spontaneous fatty liver diabetic mice without dietary interventions. Methods Male 6-week-old fatty liver Shionogi (FLS) mice were fed a standard diet without or with 1.5% BAR (colestilan) for 6 weeks. Glucose tolerance, insulin sensitivity, hepatic lipid content, and gene expression were assessed. A liver X receptor (LXR) agonist was also administered to activate the LXR pathway. We also retrospectively analysed the medical records of 21 outpatients with type 2 diabetes who were treated with colestilan for ≥6 months. Results BAR enhanced glucose tolerance and insulin sensitivity in FLS mice without altering fat mass. BAR improved hepatic insulin sensitivity, increased IRS2 expression, and decreased SREBP expression. BAR reduced hepatic cholesterol levels but not hepatic triglyceride levels. BAR also reduced the expression of LXR target genes, and LXR activation abolished the BAR-mediated improvements in glycaemic control. Colestilan significantly lowered serum cholesterol levels and improved glycaemic control in patients with type 2 diabetes. Conclusions BAR improved hepatic insulin resistance in FLS mice by reducing hepatic cholesterol without affecting hepatic triglyceride levels or body fat distribution. Our study revealed that BAR improves glycaemic control at least in part by downregulating the hepatic cholesterol–LXR–IRS2 pathway.

We previously reported that the novel dual 5-HT₂B and 5-HT7 receptor antagonist N-(9-hydroxy-9H-fluorene-2-carbonyl)guanidine (4) exerted a suppressing effect on 5-HT-induced dural protein extravasation in guinea pigs. To develop a synthetic strategy, we performed docking studies of lead compound 4 bound to 5-HT₂B and 5-HT₇ receptors, and observed that the carbonyl guanidine group forms a tight interaction network with an active center Asp (D135:5-HT2B, D162:5-HT₇), Tyr (Y370:5-HT₂B, Y374:5-HT₇) and aromatic residue (W131:5-HT2B, F158:5-HT₇). Based on molecular modeling results, we optimized the substituents at the 5- to 8-position and 9-position of the fluorene ring and identified N-(diaminomethylene)-9-hydroxy-9-methyl-9H-fluorene-2-carboxamide (24a) exhibits potent affinity for 5-HT₂B (Ki=4.3 nM) and 5-HT7 receptor (Ki=4.3 nM) with high selectivity over 5-HT₂A, 5-HT₂C, α₁, D₂ and M₁ receptors. Compound 24a reversed the hypothermic effect of 5-carboxamidotryptamine (5-CT) in mice and also showed a suppressing effect on 5-HT-induced dural protein extravasation in guinea pigs when orally administered at 30 mg/kg. Compound 24a is therefore a promising candidate for a novel class of anti-migraine agent without any adverse effects.

The isolation frequency of pathogenic bacteria for acute respiratory infection (ARI) in the pharynx and nasal vestivulum was investigated. Age group-matched children with or without ARI including 109 individuals in each group were examined. Any of the organisms, which are widely regarded as the pathogens causing ARI such as Haemophilus influenzae, Streptococcus pneumoniae, beta-haemolytic Streptococcus, Staphylococcus aureus, and Moraxella catarrhalis, were isolated from 91% of the patient group and from 77% of the healthy group. The isolation frequency of S. pneumoniae in the nasal vestivulum of the patient group was outstanding. The healthy carrier rates of S. pneumoniae in the pharynx and nasal vestivulum were 9% and 8%, respectively. Whereas the isolation frequencies from the patient group were 7% and 28%, respectively. alpha-haemolytic Streptococci except S. pneumoniae revealed different tendency from S. pneumoniae. These organisms were almost always isolated from their pharynx but rarely isolated from the nasal vestivulum. The isolation frequency of H. influenzae from the pharynx of the patient group was 41%, which was slightly higher than 34% in the healthy group, but the difference was statistically not significant. H. influenzae was not isolated from the nasal vestivulum of the healthy group, nevertheless it was isolated from 25% of the patient group. The isolation of H. influenzae from the nasal vestivulum may have some important information about ARI. S. aureus was isolated from the pharynx with higher rate than the nasal vestivulum in both groups, and moreover, the isolation frequency of S. aureus in the healthy group was higher than the patient group. It means that the diagnosis of staphylococcal infection should be made very carefully. Considering the results of this study, it could be said that bacteriologic examination of the specimens from nasal vestivulum is valuable to determine S. pneumoniae and H. influenzae as the etiologic agents of ARI.

Here, we present a case of an unusual variant of a persistent primitive hypoglossal artery, which was found incidentally during an examination for a hypertensive thalamic haemorrhage. The anastomotic vessel arose from the external carotid artery and joined the vertebral artery through the hypoglossal canal. The embryology of the anomaly is briefly discussed.