Detailed Arterial Anatomy and Its Anastomoses of the Sphenoid Ridge and Olfactory Groove Meningiomas with Special Reference to the Recurrent Branches from the Ophthalmic Artery.

BACKGROUND AND PURPOSE: Detailed arterial anatomy of the sphenoid ridge and olfactory groove meningiomas is complicated due to the fine angioarchitecture and anastomoses between each feeder. Herein, we present details of the arterial anatomy and the relationships of feeders in these lesions. MATERIALS AND METHODS: This study included 20 patients admitted to our department between April 2015 and March 2020. Conditions of subjects consisted of 16 sphenoid ridge meningiomas and 4 olfactory groove meningiomas. We mainly analyzed arterial anatomy using 3D rotational angiography and slab MIP images of these lesions. We also analyzed the anastomoses of each feeder. RESULTS: We found that 19 (95%), 15 (75%), and 15 (75%) lesions had feeders from the ophthalmic, internal carotid, and external carotid arteries, respectively. As feeders from the ophthalmic artery, recurrent meningeal arteries were involved in 18 lesions (90%). Fifteen lesions (75%) had anastomoses between each feeder. CONCLUSIONS: Most of the meningiomas in the sphenoid ridge and olfactory groove had feeders from the ophthalmic and internal carotid arteries. There were various anastomoses between each feeder. This is the first report to demonstrate the detailed arterial anatomy and frequency of recurrent branches from the ophthalmic artery and their anastomoses using detailed imaging techniques.

Systemic administration of α-lipoic acid suppresses excitability of nociceptive wide-dynamic range neurons in rat spinal trigeminal nucleus caudalis.

Although a modulatory role has been reported for α-lipoic acid (LA) on T-type Ca2+ channels in the nervous system, the acute effects of LA in vivo, particularly on nociceptive transmission in the trigeminal system, remain to be determined. The aim of the present study was to investigate whether acute intravenous LA administration to rats attenuates the excitability of wide dynamic range (WDR) spinal trigeminal nucleus caudalis (SpVc) neurons in response to nociceptive and non-nociceptive mechanical stimulation in vivo. Extracellular single unit recordings were made from seventeen SpVc neurons in response to orofacial mechanical stimulation of pentobarbital-anesthetized rats. Responses to both non-noxious and noxious mechanical stimuli were analyzed in the present study. The mean firing frequency of SpVc WDR neurons in response to both non-noxious and noxious mechanical stimuli was significantly and dose-dependently inhibited by LA (1-100 mM, i.v.) and maximum inhibition of the discharge frequency of both non-noxious and noxious mechanical stimuli was seen within 5 min. These inhibitory effects lasted for approximately 10 min. These results suggest that acute intravenous LA administration suppresses trigeminal sensory transmission, including nociception, via possibly blocking T-type Ca2+ channels. LA may be used as a therapeutic agent for the treatment of trigeminal nociceptive pain.

A novel LSD1 inhibitor NCD38 ameliorates MDS-related leukemia with complex karyotype by attenuating leukemia programs via activating super-enhancers.

Lysine-specific demethylase 1 (LSD1) regulates gene expression by affecting histone modifications and is a promising target for acute myeloid leukemia (AML) with specific genetic abnormalities. Novel LSD1 inhibitors, NCD25 and NCD38, inhibited growth of MLL-AF9 leukemia as well as erythroleukemia, megakaryoblastic leukemia and myelodysplastic syndromes (MDSs) overt leukemia cells in the concentration range that normal hematopoiesis was spared. NCD25 and NCD38 invoked the myeloid development programs, hindered the MDS and AML oncogenic programs, and commonly upregulated 62 genes in several leukemia cells. NCD38 elevated H3K27ac level on enhancers of these LSD1 signature genes and newly activated ~500 super-enhancers. Upregulated genes with super-enhancer activation in erythroleukemia cells were enriched in leukocyte differentiation. Eleven genes including GFI1 and ERG, but not CEBPA, were identified as the LSD1 signature with super-enhancer activation. Super-enhancers of these genes were activated prior to induction of the transcripts and myeloid differentiation. Depletion of GFI1 attenuated myeloid differentiation by NCD38. Finally, a single administration of NCD38 causes the in vivo eradication of primary MDS-related leukemia cells with a complex karyotype. Together, NCD38 derepresses super-enhancers of hematopoietic regulators that are silenced abnormally by LSD1, attenuates leukemogenic programs and consequently exerts anti-leukemic effect against MDS-related leukemia with adverse outcome.

Activation of GABA(B) receptors potentiates inward rectifying potassium currents in satellite glial cells from rat trigeminal ganglia: in vivo patch-clamp analysis.

In a previous study, we demonstrated that inflammation suppressed inward rectifying K(+) (Kir) currents in satellite glial cells (SGCs) from the trigeminal ganglia (TRGs) and that this impairment of glial potassium homeostasis in the trigeminal ganglion (TRG) contributed to trigeminal pain. The aim of the present study was to investigate whether activation of GABAB receptors modulates the Kir current in SGCs using in vivo patch-clamp and immunohistochemical techniques. Immunohistochemically, we found that immunoreactivity for glial-specific Kir channel subunit Kir4.1 and the GABAB receptor was co-expressed in SGCs from the TRGs. In vivo whole-cell recordings were made using SGCs from the TRGs of urethane-anesthetized rats. Application of baclofen, a GABAB receptor agonist, significantly increased the mean peak amplitude of Kir currents in a concentration-dependent and reversible manner. Baclofen-induced potentiation of the Kir current was abolished by co-application of 3-amino-2-(4-chlorophenyl)-2-hydroxyprophylsulfonic acid (saclofen). In addition, baclofen significantly potentiated the density of the Ba(2+)-sensitive Kir current, and resulted in hyperpolarization of the mean membrane potential. These results suggest that activation of GABAB receptors potentiates the Kir current in SGCs and that GABA released from the TRG neuronal soma could contribute to buffering of extracellular K(+) concentrations following excitation of TRG neurons during the processing of sensory information, including the transmission of noxious stimuli.

Integrin antagonist augments the therapeutic effect of adenovirus-mediated REIC/Dkk-3 gene therapy for malignant glioma.

Reduced expression in immortalized cells/Dickkopf-3 (REIC/Dkk-3) was identified as a gene whose expression is reduced in many human cancers. REIC/Dkk-3 expression is also downregulated in malignant glioma and regulates cell growth through caspase-dependent apoptosis. cRGD (EMD121974), an antagonist of integrins, has demonstrated preclinical efficacy against malignant glioma. In this study, we investigated the antiglioma effect of combination therapy using an adenovirus vector carrying REIC/Dkk-3 (Ad-REIC) and cRGD. Quantitative real-time reverse-transcription PCR revealed the reduction of REIC/Dkk-3 mRNA levels in malignant glioma cell lines. The reduction of REIC/Dkk-3 protein expression in malignant glioma cell lines was also confirmed with western blot analysis. After treatment with Ad-REIC and cRGD, the proliferative rate of malignant glioma cells was significantly reduced in a time-dependent manner. In vivo, there was a statistically significant increase in the survival of mice treated with Ad-REIC and cRGD combination therapy compared with Ad-REIC monotherapy. We identified an apoptotic effect following monotherapy with Ad-REIC. Moreover, cRGD augmented the antiglioma efficacy of Ad-REIC. These results may lead to a promising new approach for the treatment of malignant glioma.

The integrin inhibitor cilengitide enhances the anti-glioma efficacy of vasculostatin-expressing oncolytic virus.

Oncolytic viral (OV) therapy has been considered as a promising treatment modality for brain tumors. Vasculostatin, the fragment of brain-specific angiogenesis inhibitor-1, shows anti-angiogenic activity against malignant gliomas. Previously, a vasculostatin-expressing oncolytic herpes simplex virus-1, Rapid Antiangiogenesis Mediated By Oncolytic virus (RAMBO), was reported to have a potent antitumor effect. Here, we investigated the therapeutic efficacy of RAMBO and cilengitide, an integrin inhibitor, combination therapy for malignant glioma. In vitro, tube formation was significantly decreased in RAMBO and cilengitide combination treatment compared with RAMBO or cilengitide monotherapy. Moreover, combination treatment induced a synergistic suppressive effect on endothelial cell migration compared with the control virus. RAMBO, combined with cilengitide, induced synergistic cytotoxicity on glioma cells. In the caspase-8 and -9 assays, the relative absorption of U87ΔEGFR cell clusters treated with cilengitide and with RAMBO was significantly higher than that of those treated with control. In addition, the activity of caspase 3/7 was significantly increased with combination therapy. In vivo, there was a significant increase in the survival of mice treated with combination therapy compared with RAMBO or cilengitide monotherapy. These results indicate that cilengitide enhanced vasculostatin-expressing OV therapy for malignant glioma and provide a rationale for designing future clinical trials combining these two agents.

Human herpesvirus-6 encephalitis during hematopoietic stem cell transplantation leads to poor prognosis.

INTRODUCTION: Indications for the application of hematopoietic stem cell transplantation (HSCT) from alternative donors have remarkably broadened in scope; however, the incidence of infections that lead to failure of HSCT, such as human herpesvirus-6 (HHV-6) encephalitis, has also increased. METHODS: We analyzed risk factors for symptomatic HHV-6 reactivation and the development of HHV-6 encephalitis in 140 consecutive adult patients who received allogeneic HSCT at our institution. Stem cell sources for the recipients were as follows: related-donor bone marrow in 40, related-donor peripheral blood in 5, unrelated bone marrow in 67, and unrelated cord blood in 28. RESULTS: Symptomatic HHV-6 reactivation occurred in 22 patients (16%), and 11 patients manifested encephalitis. Multivariate Cox proportional hazards regression analysis identified cord blood cell transplantation (CBT) as an independent predictor of HHV-6 reactivation (P = 0.008). Hyponatremia or hypernatremia at the time of HHV-6 reactivation was detected before the development of HHV-6 encephalitis in 2 or 4 patients, respectively. Two patients died of HHV-6 encephalitis and 6 patients died of relapse of underlying diseases. Survival analysis identified higher risk of the disease (P = 0.021) and HHV-6 encephalitis (P = 0.003) as independent risk factors for reduced overall survival. CONCLUSION: In cases involving CBT or unrelated-donor transplantation, patients should be carefully monitored for the symptomatic reactivation of HHV-6.

Molecular epidemiology of subgenus F adenoviruses associated with pediatric gastroenteritis during eight years in Hiroshima Prefecture as a limited area.

We have studied the prevalence of the subgenus F adenoviruses and the molecular characteristics of adenovirus type 41 in Hiroshima Prefecture, Japan, as a limited area during the period of 1997-2004. Subgenus F adenoviruses were detected in 30 (3.4%) of 892 fecal specimens by enzyme immunoassay (EIA), and 80.0% (24 of 30) of positive patients were <36 months old. One (3.3%) and 29 (96.7%) of the 30 EIA-positive specimens were adenoviruses type 40 (Ad40) and 41 (Ad41), respectively. The genomes of Ad41 strains amplified by PCR were divided into two genomic type clusters (GTC1 and GTC2) based on the hexon gene as described by Li et al. (J Clin Microbiol 42: 4032-4039, 2004.). Twenty-one (95.5%) of 22 Ad41 strains detected between 2000 and 2004 belonged to GTC1, whereas all seven strains detected between 1997 and 1999 belonged to GTC2. These genomic typings were the same for the hexon and fiber genes except for one strain. This strain contained a hexon gene belonging to GTC1 and a fiber gene belonging to GTC2 and was considered to be a recombinant between adenoviruses of these types.

[A case of ovarian cancer with metastatic tumor in the liver with paclitaxel and carboplatin systemic chemotherapy was very effective].

An 82-year-old woman was admitted to the Dept. of Obstetrics and Gynecology, Yamanashi Medical University to try to identify the origin of a liver metastatic tumor. CT examination revealed a small tumor located adjacent to the uterine cervix in a cul-de-sac. With biopsy using MR, it was clearly shown histologically that the origin of the tumor was the ovary. Systemic chemotherapy with paclitaxel and carboplatin was selected as the most reasonable treatment for this case because of the patient's age. After 6 courses of this chemotherapy, the tumor in the cul-de-sac disappeared and the tumor in the liver decreased markedly. Furthermore, no severe side effects were seen during this treatment. This result indicated that systemic chemotherapy with paclitaxel and carboplatin is effective and safe in cases of advanced ovarian cancer.

The DD genotype of angiotensin converting enzyme polymorphism is a risk factor for coronary artery disease and coronary stent restenosis in Japanese patients.

Stent implantation has decreased the incidence of restenosis after coronary intervention, but has not eliminated it. The contribution of the angiotensin-converting enzyme (ACE) genotype to the development of coronary artery disease and restenosis after coronary stenting was investigated in 67 Japanese patients in whom 103 lesions in which stents had been successfully implanted were assessed by quantitative coronary angiography, before, immediately after coronary stenting, and during follow-up. The distribution of the patients with the DD, ID, and II genotypes was 13%, 54%, and 33%, respectively. The prevalence of multivessel disease in the DD genotype was significantly higher (DD genotype: 78%; ID genotype: 58%; II genotype: 27%, chi2=8.13, p=0.016) and the late loss in the DD genotype (1.43+/-0.96 mm) was significantly greater (ID genotype: 0.78+/-0.98 mm and II genotype: 0.79+/-0.88 mm, p<0.05 vs DD genotype). However, there was no significant difference in the restenosis rate among the 3 genotypes. The present study in Japanese patients indicates that the DD genotype is associated with more extensive coronary artery disease and progression of the inward remodeling within the stented lesion, which is primarily caused by neointimal hyperplasia.

Sexual dimorphism of porcine amelogenins: male-specific amelogenins have strong adsorption properties onto apatite crystals.

The present studies were undertaken to investigate the sexual dimorphism of porcine amelogenins and to gain information as to whether excesses of male amelogenins, if any, possess functional significance in protein-crystal interactions. Enamel proteins, including the intact full-length amelogenins and their degraded polypeptides, were isolated from the secretory enamel of male and female pigs. To identify the amelogenins among the separated pools of male- and female-matrix proteins, rabbit anti-C13 and C25 peptide sera were used, which reacted specifically with the conserved C-terminal domain. Immunoblotting showed that a few extra members of the amelogenins, sharing common epitopes at the C-terminus, were recognized in male products. The apparent yield of the male amelogenins was only marginal, on the basis of their stained intensities on the gel, but the secreted male amelogenins demonstrated selective (probably the strongest among the amelogenins) adsorption properties onto apatite crystals. Reflecting the general symmetric electrophoretic profiles of the male- and female-enamel proteins in toto, there were no sex-linked differences in the protein-crystal interaction and the resulting regulatory function of crystal precipitation.