Clinicopathological Study on a Case of Neuro-Behçet's Disease: In Special Reference to MRI, SPECT and Neuropathological Findings

Abstract: A case of neuro-Behçet's disease with dementia and personality changes is described with magnetic resonance imaging (MRI), single photon emission tomography (SPECT) and neuropathological findings. MRI disclosed high signal areas in the cerebral white matter and the brain stem. SPECT showed a marked reduction of blood flow in the frontal cortex. Neuropathologically, multifocal necrotizing lesions with perivascular lymphocytic infiltration and glial proliferation were detected mainly in the brain stem, namely the midbrain and the pons. From these findings, it is suggested that mental disorders of neuro-Behçet's disease are related to the secondary dysfunction of the frontal cortex due to the damage of the subcortical structures, mainly the brain stem.     

Possible new assessment of patulous Eustachian tube function: audiometry for tones presented in the nasal cavity

OBJECTIVE: To assess the acoustic transfer function of the Eustachian tube by means of audiometric measurements in order to evaluate the severity of the patulous condition. MATERIAL AND METHODS: Detection thresholds for tones presented in the nasal cavity (at the nostril) were measured in subjects with a patulous Eustachian tube (PET) and in normal subjects. RESULTS: In typical cases, these thresholds were lower in the subjects with PET and were markedly elevated to the same level as those of normal subjects by the insufflation of Lugol's solution (iodine solution). The pre- versus post-insufflation threshold differences seemed to reflect the effects of a patulous tube on the acoustic characteristics via the Eustachian tube. Based on the obtained results, sound patency via a patulous tube appeared to be dominant in lower frequency tones. CONCLUSION: The present method seems to be another easy way to assess PET.     

Microglial tau undergoes phosphorylation-independent modification after ischemia

Tau2 is a phosphorylation-independent antibody that immunolabels neurofibrillary tangles (NFTs) of Alzheimer type and microglia around ischemic foci on formalin-fixed, paraffin-embedded sections. We found that copresence of polyethyleneglycol-p-isooctylphenyl ether (Triton X-100; TX) with tau2 abolished its immunoreactivity (IR) in these microglia but not its IR on NFTs. Tau2-immunoreactive bands, exclusively retrieved in Tris-soluble fraction of brain homogenates from ischemic foci, normal human and bovine brains, were of similar electrophoretic mobility, indicating that tau2 IR in these microglia is unrelated to hyperphosphorylation of tau. These tau2-immunoreactive bands except those from bovine brain were abolished in the copresence of TX. This was not due to washing out of tau, because similar immunoreactive bands were detectable with another antitau antibody even under a higher concentration of TX and because washing after TX exposure restored similar tau2 IR both on immunohistochemistry and immunoblot. These findings are explained if tau, modified after ischemia, undergoes a reversible conformational change on TX exposure. Because conformation at Ser101 of bovine tau is crucial for its affinity to tau2, this Ser-like conformation mimicked by its human counterpart Pro may represent pathological modification of tau shared by microglia around ischemic foci and NFTs. Relative resistance of tau2 epitope in NFTs to TX exposure suggests that tau woven into NFTs confers additional stability to this pathological modification on tau2 epitope. Susceptibility of tau2 epitope to TX, seen in these microglia, is shared with glial cytoplasmic inclusions and will show its conformational state to be different from that in NFTs.     

Adenoid glioblastoma arising in a patient with neurofibromatosis type-1

An unusual case of glioblastoma with adenoid structures arising in a 30-year-old Japanese woman with neurofibromatosis type-1 (NF1) is reported. The patient was admitted to University of Miyazaki Hospital, complaining of headache, nausea and vomiting. From the neuroradiological findings the patient was diagnosed as having glioblastoma, and the tumor was surgically resected. Histologically, the tumor consisted mainly of dark basophilic cells showing prominent tubular or glandular structures surrounded by large eosinophilic cells, in addition to the typical glioblastoma features in the periphery of the tumor. Both cells showed strong stainability with glial fibrillary acidic protein (GFAP) and S-100 protein immunohistochemically, so that the tumor was classified as adenoid glioblastoma. Several cases of glioblastoma have been reported to reveal the adenoid or epithelioid differentiation. The patients with NF1 are prone to develop malignant tumors including glioblastoma, but no cases representing adenoid glioblastoma associated with NF1 have been reported. This report is considered to be the first case of adenoid glioblastoma arising in a patient with NF1. The recognition of the existence of epithelial features of glioblastoma would be important in differential diagnosis of epithelioid tumors of the brain including metastatic carcinomas.     

Notch pathway regulates osimertinib drug-tolerant persistence in EGFR-mutated non–small-cell lung cancer

Osimertinib is a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) that has shown marked antitumor activity in patients with EGFR-mutated non–small-cell lung cancer (NSCLC). However, these effects are transient and most patients develop resistance. Reversible drug-tolerant persister (DTP) cells are defined as a small subpopulation of cells with markedly reduced sensitivity and non-genetic acquired resistance to EGFR-TKIs. Notch is a transmembrane receptor that plays an important role in tumorigenesis. We previously reported that there is significant crosstalk between the Notch and EGFR pathways in NSCLC. Moreover, the Notch pathway is associated with resistance to previous-generation EGFR-TKIs. However, the role of Notch in osimertinib resistance is not fully understood. In this study, we evaluated whether Notch is involved in osimertinib resistance. We show that NOTCH1 and Notch target genes are upregulated in osimertinib DTP cells, and that the addition of a γ-secretase inhibitor (GSI), a Notch inhibitor, impairs drug-tolerant persistence in vitro and in vivo. Compared with osimertinib, combined GSI and osimertinib suppress phospho-ERK partly by enhancing DUSP1 expression. Furthermore, Notch1 and HES1 were upregulated after EGFR-TKI treatment in half of human EGFR-mutated NSCLC tumor tissues. These results suggest that the combination of GSI and osimertinib may be a potential therapy for EGFR-mutated NSCLC.     

Phenotypic analysis of a novel chordin mutant in medaka.

We have isolated and characterized a ventralized mutant in medaka (the Japanese killifish; Oryzias latipes), which turned out to have a mutation in the chordin gene. The mutant exhibits ventralization of the body axis, malformation of axial bones, over-bifurcation of yolk sac blood vessels, and laterality defects in internal organs. The mutant exhibits variability of phenotypes, depending on the culture temperature, from embryos with a slightly ventralized phenotype to those without any head and trunk structures. Taking advantages of these variable and severe phenotypes, we analyzed the role of Chordin-dependent tissues such as the notochord and Kupffer's vesicle (KV) in the establishment of left-right axis in fish. The results demonstrate that, in the absence of the notochord and KV, the medaka lateral plate mesoderm autonomously and bilaterally expresses spaw gene in a default state.     

Cranial nonmetric variation of Yayoi people in the Kyushu District

The Yayoi people in Kyushu and Yamaguchi area are generally classified by metrical analyses mainly into the Yayoi people in the northern Kyushu and Yamaguchi area who are regarded as migrants from the Asian Continent and their posterity and the Yayoi people in the northwestern Kyushu who are regarded as having inherited the characteristics of the Jomon people. Such classification is verified by the analysis with the 22 traits in the cranial nonmetric variation. Of the 22 traits, supraorbital foramen, transverse zygomatic suture vestige, biasterionic suture vestige, jugular foramen bridging, hypoglossal foramen bridging, pterygospinous foramen, mylohyoid bridging and tympanic dehiscence are particularly important as the traits to classify two types of Yayoi peoples. The analysis by the C. A. B. Smith's Mean Measure of Divergence (MMD) suggests that out of the migrant Yayoi peoples, the very Yayoi people who are closely related to the formation of the modern Japanese are the ones in the northern Kyushu area, not the ones in the Doigahama site. Also, it is assumed that the appearance and disappearance of cranial nonmetric variations is affected by genetic elements, because the incidencies of cranial nonmetric variations is largely different between two types of Yayoi peoples in infants like in adults. Lastly the cranial nonmetric variation in the people of the period equivalent to Jomon and Yayoi in the Okinawa district, and in the Kofun people in southern Kyushu area, was briefly introduced.     

A neuroprotective agent, T-817MA (1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl} azetidin-3-ol maleate), prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity in mice

T-817MA (1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl} azetidin-3-ol maleate) is a candidate therapeutic agent for Alzheimer's disease that inhibits oxidative stress and nitric oxide-induced neurotoxicity and acts as a neurotrophic factor. The present study examines the effect of T-817MA on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity in C57BL/6J mice. MPTP treatment (10mg/kg, s.c.x4 at 2-h intervals) impaired rotarod performance, and T-817MA improved this deficit. MPTP treatment also decreased dopamine levels and tyrosine hydroxylase immunostaining in the substantia nigra (SNc) and striatum. Pretreatment with T-817MA (10 and 30mg/kg as T-817, p.o.) attenuated these decreases in dopamine levels and tyrosine hydroxylase immunoreactivity, but did not affect brain levels of 1-methyl-4-phenylpyridinium ion, an active metabolite of MPTP. The protective effect was almost complete in the SNc, but only partial in the striatum. MPTP increased levels of the lipid peroxidation product, thiobarbituric acid reactive substance, only in the midbrain, which could be blocked by T-817MA. MPTP caused microglial activation both in the SNc and striatum, but T-817MA did not affect the activation of microglia. These results suggest that T-817MA protects against MPTP-induced neurotoxicity by blocking lipid peroxidation in the SNc, and imply that this compound may be useful for treating neurodegenerative disorders related to oxidative stress, such as Parkinson's disease.     

Habitual sniffing and postoperative configuration of the posterior meatal wall reconstructed with soft tissue

CONCLUSIONS: Habitual sniffing is a significant contributing factor to the development of postoperative retraction of the reconstructed posterior meatal wall and tympanic membrane, although it still seems a multifactorial event. OBJECTIVE: To examine the possible contribution of habitual sniffing to retraction-type middle ear pathology in a more direct way than previous reports. PATIENTS AND METHODS: The correlation between habitual sniffing and the postoperative configuration of the posterior meatal wall was examined in 58 patients with cholesteatoma who underwent tympanoplasty with reconstruction of the soft meatal wall. RESULTS: The postoperative configuration of the posterior meatal wall showed severe retraction in 7 of 8 patients with habitual sniffing, but only 22 of 47 without habitual sniffing. Habitual sniffing was significantly associated with postoperative severe retraction (Fisher's exact test, p<0.05).