Morphological changes in the visual pathway induced by experimental glaucoma in Japanese monkeys

Glaucoma, an optic neuropathy, is the leading cause of world blindness. In this condition, the damage extends from the retina to the visual center in the brain, although the primary region of damage is thought to be the optic nerve head (ONH), with the lateral geniculate nucleus (LGN) being secondarily affected. We investigated time-dependent alterations in the ONH, the optic nerve (ON), and the LGN after intraocular pressure (IOP) elevation in Japanese monkeys (a species more similar to humans than other macaque species). Nine Japanese monkeys, each with an experimental glaucomatous left eye, and two naive monkeys were studied. Ocular-testing sessions (including IOP measurement and fundus photography) were held weekly. Eyes and brains were enucleated at 2-48 weeks after IOP elevation, and alterations in ONs and LGN were evaluated. The IOP of the treated eyes was monitored periodically and found to be elevated continuously throughout the observation period in each monkey. The ONH of the glaucomatous eyes exhibited time-dependent deep cupping and thinning of the rim area from 2 weeks after the IOP elevation. Loss of axons and a decrease in the area of ON were first observed at 4 and 28 weeks, respectively. Neuronal loss was first observed at 2 weeks in layers 1 and 2 of LGN [magnocellular (M)-layer] and at 12 weeks in layers 3-6 of LGN [parvocellular (P)-layer]. Neuronal shrinkage was first observed at 2 weeks in all layers in LGN. These findings indicate that in Japanese monkeys, damage to neurons in LGN can be detected in the early phase (first few weeks) after an IOP elevation, as can damage to ONH.     

Traumatic subdural hygroma: pathology and meningeal enhancement on magnetic resonance imaging.

Five patients with traumatic subdural hygroma are reported with reference to its pathology and meningeal enhancement on magnetic resonance imaging. Hygromas showed initially iso- and, later, high intensity on both T1- and T2-weighted images compared with the intensity of the cerebrospinal fluid. In all cases of the thick hygromas, magnetic resonance imaging with gadolinium diethylene-triamine-pentaacetic acid showed meningeal enhancement. Intravenously injected radioisotope immediately flowed into the hygromas, but computed tomographic cisternography and gross inspection during the surgery showed no evidence of an influx of cerebrospinal fluid into the hygromas. Microscopic examination of the enhanced meninges revealed vascularized neomembrane with numerous fenestrations and pinocytosis underneath the dura mater. It is suggested from these data that the subdural neomembrane is associated with the development of the traumatic subdural hygromas. Meningeal enhancement would be useful to clarify the growing mechanism of traumatic subdural hygromas.     

Ultrastructural study of the final cerebrospinal fluid pathway in human arachnoid villi

Human arachnoid villi were studied ultrastructurally to clarify the mechanism of cerebrospinal fluid absorption. Arachnoid villi of humans showed quite different features from those of animals. The former were not always invested with endothelial linings as previously reported in the latter. Instead, there was a covering layer of arachnoid cells which consisted of both an electron-lucent outer zone and an electron-dense inner zone. The outer zone had less cytoplasmic filaments and desmosomes than the inner zone. The inner zone was basically indistinguishable from the arachnoid membrane and had numerous cytoplasmic filaments and a series of desosomes. Often, the covering layer was further encompassed by the thin fibrous capsule which reflected from the dura mater or sinus wall. Both the outer and inner zones were characterized by numerous extracellular cisterns which appeared, electron-optically, to be empty or contain a little ‘fuzzy’ material. In the villi affected by subarachnoid hemorrhage, extracellular cisterns were distended by intact of disintegrating erythrocytes which appeared to be natural tracers of cerebrospinal fluid. The size of these cisterns measured approximately 10 μm in the maximum diameter. It is suggested that extracellular cisterns may contribute to the bulk outflow of cerebrospinal fluid.     

The Japanese version of RBANS (Repeatable Battery for the Assessment of Neuropsychological Status)]

In Japan, neuropsychological assessment of dementing illnesses has been done mainly using Mini-Mental State Examination (MMSE) and a revised version of Hasegawa Dementia Scale (HDS-R). However, because of a lack of appropriately designed test domains, early detection of senile dementia and/or cognitive impairment is hardly possible, even if using these batteries. This paper is to introduce a Japanese Version of RBANS (Repeatable Battery for the Assessment of Neuropsychological Status) which was originally developed by Randolph and revised by us. The entire battery of Japanese Version RBANS took less than 30 minutes to administer, and yielded scaled scores for five cognitive domains such as immediate memory, visuospatial/constructional ability, language, attention, and delayed memory. On RBANS, abnormal cognitive decline in the older adult was much easily detected, being compared to MMSE and HDS-R: 52 normal volunteer subjects ranging from 24 to 80 years old showed a significant (p < 0.05 on t test) impairment of delayed and immediate memories due to ageing. The aged (60-79) subjects with average scores of MMSE and HDS-R being over 25, significantly showed impairment of both immediate memory (list and story learnings) and delayed memory (list, story and figure recalls). The present data suggest that the Japanese Version RBANS is useful for both detecting and characterizing early dementia, and should be widely utilized for a neuropsychological screening battery in the clinical practice throughout Japan.     

Neurotoxicity of local administration of two nitrosoureas in malignant gliomas

The neurotoxicity of local administration of nitrosoureas in malignant gliomas was investigated clinicopathologically. Twenty patients were entered into this study: 13 were treated with 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU) and 7 with methyl 6-[3-(2-chloroethyl-3-nitrosoureido]-6-deoxy-alpha-D-glucopyranoside (MCNU). On the average, a single dose of 20 mg of ACNU was administered 15 times, for a total dose of 295 mg in each case, while a single dose of 11 mg of MCNU was given 2 times, for a total dose of 24 mg. These nitrosoureas provoked greater toxicity when the administration dose was larger or the indwelling multiperforated Silastic basket was in direct continuity with the ventricle or the basal cistern. Usually ACNU was well tolerated, whereas MCNU induced marked brain edema. Side effects consisted of headache, nuchal stiffness, vomiting, motor weakness, and cranial nerve palsy for ACNU, and headache, vomiting, abnormal respiration, and arrhythmia for MCNU. Pathological changes were represented by capsule formation, spongy degeneration and reactive gliosis of adjacent white matter, occlusion of neighboring arteries, and demyelination of cranial nerves in the patients treated with ACNU, while they were represented by focal brain necrosis in two patients treated with MCNU. The differences in neurotoxity of ACNU and MCNU conceivably derive from the different blood-brain delivery of these drugs.     

Immunohistochemical localization of cell adhesion molecule epithelial cadherin in human arachnoid villi and meningiomas.

Cadherins are a family of intercellular glycoproteins responsible for calcium-dependent cell adhesion and are currently divided into four types: epithelial (E), neuronal (N), placental (P), and vascular (V). Since cadherins are known to be indispensable for not only morphogenesis in the embryo but also maintenance of tumor cell nest, we examined the expression of E-cadherin in 31 meningiomas (11 syncytial, 12 transitional, 8 fibroblastic) and 3 arachnoid villi by immunoblot and immunohistochemical analyses. In the immunoblot analysis, E-cadherin was detected at the main band of Mr 124,000 in all of the arachnoid villi, as well as syncytial and transitional types of meningiomas, but not in the fibroblastic type. The immunohistochemical examination showed that E-cadherin was expressed at the cell borders of syncytial and transitional types, but the expression was absent in the fibroblastic type. Immunoelectron microscopy showed that E-cadherin was localized at the intermediate junctions in arachnoid villi, while it was detected diffusely at the cell surface in meningiomas. It is suggested from these data that the expression of E-cadherin might be closely related to the differentiation and organogenesis of meningioma cells.     

Calpain-dependent proteolysis of merlin occurs by oxidative stress in meningiomas: a novel hypothesis of tumorigenesis.

BACKGROUND: The purpose of this study is to indicate that oxidative stress may contribute to occurrence of meningiomas. Recently, it was reported that aside from the neurofibromatosis type 2 (NF2) gene mutations, the calpain-dependent proteolysis of the NF2 gene product, merlin might be closely related to the development of certain NF2-related tumors. Although meningiomas are well known to occur more frequently in aged persons, it still remains unknown why calpain activation occurs predominantly in them. Because the production of free radicals with aging might be one of the causes of calpain activation especially in leptomeningeal cells being devoid of blood supply, the authors examined the relations between mu-calpain activation and merlin proteolysis induced by the oxidative stress. METHODS: The authors examined 12 patient-derived sporadic meningiomas and their primary cultured cells. Malignant glioma cell line (U-251MG), which had no relation to NF2, was used as a control. They were exposed to hydrogen peroxide (H2O2) for 1 hour. After oxidative stress, they were examined by Western blot and immunofluorescence microscopic analyses. RESULTS: Despite the consistent expressions of activated mu-calpain in 11 of 12 meningioma tissues, this calpain activation completely disappeared after culture; instead the full-length merlin appeared again in 8 of 11 cases. The treatment of cultured cells with hydrogen peroxide induced both mu-calpain-dependent cleavage of merlin and reduction of an intrinsic calpain inhibitor calpastatin. Such proteolysis was significantly blocked by a specific calpain inhibitor, Z-LLal. The full-length merlin was immunocytochemically colocalized with activated mu-calpain at the plasma membrane, and, after mu-calpain activation, the fragment of merlin translocated to the perinuclear cytoplasm or into the nucleus. CONCLUSIONS: These findings suggest that oxidative stress-induced activation of mu-calpain causes proteolysis of merlin conceivably to impair cell adhesion and/or contact inhibition of meningioma cells.