樋口 佳則

Apolipoprotein E (apoE) is a lipid binding protein that plays an important role in tissue repair following brain injury. In the present studies, we have investigated whether apoE affects the behavioral toxicity of high charge, high energy (HZE) particle radiation. METHODS: Sixteen male apoE knockout (KO) mice and sixteen genetically matched wild-type (WT) C57BL mice were used in this experiment. Half of the KO and half of the WT animals were irradiated with 600 MeV/amu iron particles (2Gy whole body). The effect of irradiation on motor coordination and stamina (Rotarod test), exploratory behavior (open field test), and spatial working and reference memory (Morris water maze) was assessed. ROTAROD TEST: Performance was adversely affected by radiation exposure in both KO and WT groups at 30 d after irradiation. By 60 d after radiation, the radiation effect was lost in WT, but still apparent in irradiated KO mice. OPEN FIELD TEST: Radiation reduced open field exploratory activity 14, 28, 56, 84, and 168 d after irradiation of KO mice, but had no effect on WT mice. MORRIS WATER MAZE: Radiation adversely affected spatial working memory in the KO mice, but had no discernible effect in the WT mice as assessed 180 d after irradiation. In contrast, irradiated WT mice showed marked impairment of spatial reference memory in comparison to non-irradiated mice, while no effect of radiation was observed in KO mice. CONCLUSIONS: These studies show that apoE expression influences the behavioral toxicity of HZE particle radiation and suggest that apoE plays a role in the repair/recovery from radiation injury of the CNS. ApoE deficiency may exacerbate the previously reported effects of HZE particle radiation in accelerating the brain aging process.

Background and Purpose-Subarachnoid hemorrhage (SAH) increases production of vascular extracellular superoxide anion (O-2(-)) We examined whether overexpression of murine extracellular superoxide dismutase (EC SOD) alters SAH induced cerebral vasospasm oxidative stress and neurological outcome Methods-Mice exhibiting a 2 fold increase in vascular EC SOD and wild type (WT) littermates were subjected to sham surgery or SAH by perforation of the right anterior cerebral artery Neurological deficits were scored 72 hours later Middle cerebral artery (MCA) diameter was measured or immunohistochemically stained for nitrotyrosine Results-MCA diameter (mean+/-SD) was greater in EC SOD versus WT mice after SAH but not sham surgery (EC SOD SAH=56+/-10 mum WT SAH=38+/-13 mum [P<0 01] EC SOD sham=99+/-16 μm WT sham=100+/-15 μm) SAH decreased median (range) neurological score (scoring scale 9 to 39 no deficit=39) versus shams but there was no difference between EC SOD and WT groups (EC SOD SAH=26 [23 to 30] WT SAH=23 [19 to 29] [P=0 27] EC SOD sham=39 [39] WT sham=39 [39]) Sensory motor deficits correlated with MCA diameter (P<0 001) but worsened primarily between 60 and 50 mum plateauing below this threshold The percentage of mice with MCA nitrotyrosine staining increased after SAH in WT (sham=29% SAH=100% [P<0 05]) but not EC SOD (sham=33% SAH=44% [P=0 80]) mice Conclusions-Endogenous overexpression of EC SOD attenuated vasospasm and oxidative stress but failed to reduce neurological deficits after SAH Extracellular O-2(-) likely plays a direct role in the etiology of vasospasm.

Short-inversion time inversion-recovery (STIR) imaging using a 3 tesla system was assessed to reveal the postcommissural fibres (PF) of the fornix, which have rarely been highlighted neuroradiologically in the clinical setting. We studied 27 normal subjects. Sequence parameters were TR/TE/TI 8000/52/ 150 ms. STIR was expected to take advantage of the high signal-to-noise ratio of a high-field system, due to the long repetition time. PF were identifiable in axial and coronal slices in all cases. They were bordered anteriorly and superiorly by the anterior commissure and posteriorly and inferiorly by the mamillary body. Behind the anterior commissure, they ran in an archshaped posterior and inferior course in the hypothalamic nuclei and joined the mamillary body anterolaterally. They usually extended through three 3-mm slices (with 1 mm interslice gap) in anteroposterior and vertical dimensions. Little variation was observed in their course or size. Demonstration of the PF would provide a more detailed correlation of human neuroanatomy to hypothalamic function and individualised understanding of hypothalamic pathology and influence therapy.

Nucleophosmin (NPM) is a major nuclear matrix protein associated with neoplastic: growth in various cell types. We recently suggested that expression of the NPM gene is involved in an increased resistance to UV irradiation in human cells against the cell-killing effects of UV (mainly 254nm wavelength far-ultraviolet ray) [Y. Higuchi, K. Kita, H. Nakanishi, X-L. Wang, S. Sugaya, H. Tanzawa, H. Yamamori, K. Sugita, A. Yamaura, N. Suzuki, Biochem. Biophys. Res. Commun. 248 (1998) 597-602]. In the present study, expression levels of the NPM gene were examined in human cell lines with a high sensitivity to UV cell-killing. Cockayne syndrome patient-derived cell lines, CSAI and CSBI, and the Xeroderma pigmentosum patient-derived cell line, XP20S(SV), XP13KY, XP3KA, XP6BE(SV), XP101OS and XP3BR(SV), have been investigated for their NPM mRNA expression with Northern blotting analysis. All of these UV-sensitive cells demonstrated lower expression levels compared with those of normal fibroblast cells. FF, or an UV-resistant cell line, UHr-10; quite a lower level of expression in XP205(SV) cells after UV irradiation in contrast to a distinguishable increase in the expression in UVr- cells. These results confirmed an intimate correlation between degree of UV sensitivity and expression levels of the NPM gene in human cells. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.

Purpose Surgical removal of growth hormone-producing pituitary adenomas (GHomas) becomes difficult when they invade the cavernous sinus (CS). We investigated the relation among tumor proliferative potential, tumor volume and invasion of GHomas to CS. Materials & Methods 15 patients with GHoma aged 20-59 years were enrolled. The volumes of the adenomas were calculated from MR images and the extension to CS was classified into 5 grades according to Knosp's grading system. The immuno-hisochemical staining for anti-Ki-67 monoclonal antibody (MIB-1) was performed and the proliferative potential of GHomas was determined as the percentage of MIB-1 labeled nuclei (MIB-1 index). The volume, MIB-1 index and pre-operative growth hormone (GH) level were compared with CS invasion by single and multiple regression analyses. Results With single regression analyses, CS invasion was significantly correlated with both the volume (r=0.69, p<0.01) and MIB-1 index (r=0.73, p<0.01), but not with the GH level (r=0.42, p=0.12). The volume and MIB-1 index showed a weak correlation but it was not significant (r=0.52, p=0.06). With multiple regression analysis, CS invasion was well explained by the volume and MIB-1 index of GHomas (r=0.82, p<0.01). About 66% of CS invasion was explained by these two factors. Conclusions In view of these results, not only the volume but also the speed of growth are important for GHomas to invade CS. GHomas with a high MIB-1 index may, even if they are small, more readily invade CS and need closer post-operative hormonal and neuroimaging studies.

Purpose: In order to numerically compare the morphological differences of the nasal cavity and nasal sinus between acromegalics and non-acromegalics, bone window CT scans sliced parallel to the transsphenoidal surgical route were performed. Material and cases: Acromegalic patients had small or large macroadenomas and were 13 (7 men and 6 women) in number, aged 53.2+/-16.1 years. Non-acromegalic patients had pituitary tumors and were 44 (21 men and 23 women) in number, aged 52.1+/-12.5 years. Results The results of acromegalics are described in comparison to non-acromegalics in parentheses. a) The width of the surgical corridor: piriform aperture, 27.6+/-2.7 (25.9+/-2.6) mm; origin of inferior nasal concha, 29.4+/-9.4 (26.6+/-4.0) mm; and origin of middle nasal concha, 29.8+/-3.2 (26.2 mm+/-4.2) mm. b) The depth of the surgical corridor: the upper lip thickness, 18.1+/-2.7 (13.3+/-1.4) mm; the distances between piriform aperture and sphenoid wall, 52.9+/-4.6 (49+/-4.2) mm; sphenoid wall and sellar floor, 17.3+/-4.1 (18.7+/-4.1)mm; and sellar floor to dorsum sellae, 17.6+/-3.4 (15.6+/-4.0)mm. c) Marked carotid prominence: 7/13=53.4% (8/44=18.25%). d) Sinusitis: 8/13=61.5% (12/44=27.3%). Discussion d; conclusion The data presented above show that morphological differences in bony nasal cavity and soft tissue may be responsible for a deeper and narrower surgical field for acromegalics. Acromegalics had a marked carotid prominence more frequently, which needs special attention to avoid carotid injury, when enlarging the surgical field. Knowing these morphological differences will provide useful information for peri-and intra-operative care.

Purpose Although routine mechanical nasal packing after transsphenoidal surgery (TS) is thought to increase respiratory disorders during sleep, there has been little in the literature about the pre-and post-operative airway assessment of acromegalics with sleep apnea. (SA) We describe 4 acromegalic patients with SA, who underwent transsphenoidal surgery. Methods and cases The patients were all men, aged from 47 to 59 years. The pre-and post-operative sleep study consisted with a computer calculated oximetry parameter of oxygen desaturation index (ODI), which was defined as the number/hour of oxygen desaturation episodes exceeding 4% from the base line (normal range<15). The postoperative (postop.) sleep study was carried out from the Ist postop. day to the 8th day, for 1 to 8 days, varying for each patient. Results Only the worst postop. result is shown. Patient 1 had 2 operations, 2 years apart. ODI was 39.6 before the Ist operation and 45.9 postop.. In the second operation ODI was 21.8 preoperatively (preop.) and 57.9 postop.. Preop. and postop. ODI was 18.1 and 22.2 in patient 2, 21.6 and 22.5 in patient 3 and 45.5 and 18.9 in patient 4, respectively. ODI of patient 4 was 39.6, 3 weeks later. Conclusion Our data showed that the postop. oxymetric study commonly showed worse results in acromegalics with nasal packing. The better result of patient 4 was probably due to a postop. sleepless state. REM sleep usually increases in the first several postop. days, when cardiopulmonary complications are more likely to occur. Since acromegalics with severe SA and postop. nasal packing may more readily suffer from cardiopulmonary complications, postoperative meticulous respiratory monitoring and care should be mandatory.

Purpose: GH replacement therapy is required in the majority of children with GH deficiency after treatment of sellar and suprasellar tumors. Owing to the high cell proliferative ability of human GH (hGH), its influence on tumor recurrence has been debated. We retrospectively studied the immunohistochemical expression of the GH receptor in various tumor tissues, in order to investigate the relation between tumor recurrence and hGH replacement. Methods: GH replacement therapy was performed in 25 patients (8 boys and 17 girls) after the treatment. Tumor recurrence was noted in 4 patients (craniopharyngioma: 2 patients, pilocytic astrocytoma and germinoma: 1 each). Immunohistochemical study of GH receptor in tumor tissue was carried out in those recurrent and recurrence-free cases, by using MAb 263 as a primary antibody. Results: Two patients with recurrent craniopharyngioma were positive for MAb 263, but 1 recurrence-free patient was negative. Patients with pilocytic astrocytoma (recurrent and recurrence-free: 1 each) were all positive. Five patients with germinoma (1 with recurrence and 4 without recurrence) were all negative. Conclusion: In the patients with craniopharyngioma treated with GH, a positive immunohistochemical expression of GH receptor in tumor tissue may indicate a high probability of recurrence. In our cases, GH receptor was positive in astrocytomas and negative in germinomas, with or without recurrence. It is therefore speculated that each brain tumor may have its specificity in GH receptor expression.

Neoplasms may be one of the systemic complications to which we attribute high mortality in acromegaly. The present study was designed to investigate the incidence of malignant tumors in patients with acromegaly in the Japanese population. In this report, 44 patients (25 men and 19 women) with biochemically proven acromegaly were studied retrospectively and had a total 670 patient years of the duration of acromegaly. We investigated the incidence of malignant tumors. There were 5 patients with malignant tumors (5 in men) in this study (11%). Male patients with acromegaly had nearly a 3.5 times higher ratio of malignancy than expected and this increased cancer incidence was considered significant (P=0.01). There was no significant increase in cancer incidence of either the total patient population or female patients. The malignant tumors were two thyroid cancers and one colon, one gastric and one bladder cancer. It is of note that the colon cancer of one patient was diagnosed 2 years after transsphenoidal surgery even though the levels of serum GH and insulin-like growth factor (IGF-1) were reduced to normal after operation. This preliminary study has suggested that male patients with acromegaly might have a high risk of malignancy and that careful screening for tumors is needed both before and after surgical and medical treatment, even in patients with normalized serum GH and IGF-1 levels.

Purpose. The plethysmographic wave of pulse oximetry reflects arterial pulsation at the fingertip. Since arterial pressure and the pulsatile component of the arterial cross section represent the input and output of the fingertip arterial system, respectively, arterial wall mechanics may be delineated from their relationship. We aimed to construct a mathematical model of the fingertip arterial wall from the relationship between the plethysmographic wave and arterial pressure. Methods. The pulse oximetric plethysmograpic signal at the forefinger and pressure at the ipsilateral radial artery were measured. Employing the data, simple mathematical models with one to four mechanical elements were tested in terms of the goodness of fit and the physiological implications. The determined model was applied to the data obtained during administration of vasoactive agents in anesthetized patients. Results. The mathematical model suited for describing arterial wall mechanics was a four-element, two-compartment model. The two compartments represent passive mechanical and active contractile properties, respectively. In the application of the model to the anesthetized patients, the vasoactive agents produced changes in the model parameters that implied mechanical alterations in the arterial wall. Conclusion. These findings suggest the benefit of the four-element, two-compartment model in analyzing peripheral vascular wall mechanics influenced by various stimuli in intensive care and anesthesia.

Human interferon-beta (HuIFN-beta) confers UV-refractoriness in association with increased DNA repair capacity to human cells. We examined the modulation of XPG gene expression by HuIFN-beta in UV-sensitive cells from Cockayne syndrome complementation B (CSB), xeroderma pigmentosum complementation A (XPA) and normal control cells. Northern blot analysis revealed that XPG mRNA was more extensively transcribed in CSB cells treated with HuIFN-beta than in those without HuIFN-beta treatment. XPG mRNA from XPA cells and normal control cells was not markedly transcribed by HuIFN-beta treatment compared to that from CSB cells. The findings suggested that different mechanisms of UV-refractoriness by HuIFN-beta exist between CS and XP.

Using PCR-differential display, we have searched for genes expressed specially in human interferon (HuIFN)-beta-treated Cockayne syndrome (CS) fibroblast cells. Eighteen expressed genes induced by HuIFN-beta were identified, the sequences of seven of which were highly homologous to previously cloned sequences. The cDNAs of six of these seven clones were similar to expression tagged sequences from unknown genes in databases and the remaining one was identical to the cDNA of the xeroderma pigmentosum XPG gene. These results, together with our previous finding of increased resistance to ultraviolet (UV) cell-killing of CS cells pretreated with HuIFN-beta prior to UV irradiation suggest that XPG might be one of the genes possibly involved in the HuIFN-beta-induced UV-resistance. (C) 1998 Elsevier Science B.V. All rights reserved.

UVr-10 UV-resistant cells were established from UV-sensitive human RSb cells. We searched here for genes expressed differentially between UVr-10 and RSb cells using a differential display method to elucidate the molecular mechanisms underlying the W-resistance, Thirteen candidate cDNA fragments were obtained from 514 mRNA species first screened. Among the cDNA fragments, 3 revealed increased mRNA expression in UVr-10 cells compared with RSb cells by Northern analysis. Nucleotide sequence analysis identified 2 of the 3 cDNA fragments as encoding nucleophosmin (NPM) and T-plastin, The expression of NPM mRNA was induced after UV irradiation in UVr-10 cells but not in RSb cells, whereas irradiation did not affect the expression of T-plastin mRNA, UVr-10 cells transfected with antisense cDNA for NPM mRNA were partially sensitized to UV cell-killing. Thus, NPM and possibly T-plastin genes may contribute to the increased resistance to UV cell-killing, at least in the human cells tested. (C) 1998 Academic Press.

An attempt was made to apply functional magnetic resonance imaging (fMRI) to reveal cortical areas activated upon presentation of two groups of Chinese characters in six normal right-handed, male, Japanese subjects. Presentation of the characters representing 'abstract concepts' activated the bilateral occipital region without a significant difference between the bilateral occipital and temporal regions. Presentation of the characters representing 'concrete objects' resulted in significantly stronger activation in the left occipital and temporal regions. These results suggest that recognition of concrete characters involves a stronger initial process in the left occipital temporal cortices than recognition of abstract characters. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.