Grafting of neural stem and progenitor cells to the hippocampus of young, irradiated mice causes gliosis and disrupts the granule cell layer.

Ionizing radiation persistently reduces the pool of neural stem and progenitor cells (NSPCs) in the dentate gyrus (DG) of the hippocampus, which may explain some of the learning deficits observed in patients treated with radiotherapy, particularly pediatric patients. A single dose of 8 Gy irradiation (IR) was administered to the brains of postnatal day 14 (P14) C57BL/6 mice and 1.0 × 10(5) bromodeoxyuridine-labeled, syngeneic NSPCs were injected into the hippocampus 1 day, 1 week or 6 weeks after IR. Cell survival and phenotype were evaluated 5 weeks after grafting. When grafted 1 day post-IR, survival and neuronal differentiation of the transplanted NSPCs were lower in irradiated brains, whereas the survival and cell fate of grafted cells were not significantly different between irradiated and control brains when transplantation was performed 1 or 6 weeks after IR. A young recipient brain favored neuronal development of grafted cells, whereas the older recipient brains displayed an increasing number of cells developing into astrocytes or unidentified cells. Injection of NSPCs, but not vehicle, induced astrogliosis and reduced thickness of the dorsal blade of the GCL after 5 months. In summary, we demonstrate that age and interval between IR and grafting can affect survival and differentiation of grafted NSPCs. The observed long-term gliosis and degeneration warrant caution in the context of NSPC grafting for therapeutical purposes.

Apoptosis-inducing factor deficiency decreases the proliferation rate and protects the subventricular zone against ionizing radiation.

Cranial radiotherapy in children often leads to progressive cognitive decline. We have established a rodent model of irradiation-induced injury to the young brain. A single dose of 8 Gy was administered to the left hemisphere of postnatal day 10 (P10) mice. Harlequin (Hq) mice, carrying the hypomorphic apoptosis-inducing factor AIF(Hq) mutation, express 60% less AIF at P10 and displayed significantly fewer dying cells in the subventricular zone (SVZ) 6 h after IR, compared with wild type (Wt) littermates. Irradiated cyclophilin A-deficient (CypA(-/-)) mice confirmed that CypA has an essential role in AIF-induced apoptosis after IR. Hq mice displayed no reduction in SVZ size 7 days after IR, whereas 48% of the SVZ was lost in Wt mice. The proliferation rate was lower in the SVZ of Hq mice. Cultured neural precursor cells from the SVZ of Hq mice displayed a slower proliferation rate and were more resistant to IR. IR preferentially kills proliferating cells, and the slower proliferation rate in the SVZ of Hq mice may, at least partly, explain the protective effect of the Hq mutation. Together, these results indicate that targeting AIF may provide a fruitful strategy for protection of normal brain tissue against the detrimental side effects of IR.

Neuroradiological characteristics of pineocytoma and pineoblastoma.

We reviewed neuroradiological images in two histologically proven cases of pineocytoma and three of pineoblastoma to delineate the characteristic features of these rare tumours. CT revealed isodense or slightly hyperdense masses with central or peripheral calcification; enhancement with contrast medium tended to be homogeneous in pineocytomas and heterogeneous in pineoblastomas. In the pineocytomas, T1-weighted images revealed rounded, sometimes or slightly lobulated low-signal masses with strong, homogeneous contrast enhancement. Their margin was clear, without invasion of adjacent structures. In the pineoblastomas, however, T1-weighted images revealed multilobulated tumours with heterogeneous contrast enhancement. All three pineoblastomas had poorly defined margins with adjacent structures such as the posterior thalamus or corpus callosum, suggesting a more invasive nature. T2-weighted images revealed nonspecific high signal lesions in all five cases.

Toxoplasmic encephalitis in patients with acquired immunodeficiency syndrome--four case reports.

Four patients, all males aged 40-64 years, presented with toxoplasmic encephalitis associated with human immunodeficiency virus (HIV) infection manifesting as nonspecific neurological deficits such as epilepsy or hemiparesis. Magnetic resonance imaging showed single or multiple lesions with ring enhancement, mimicking metastatic brain tumor or brain abscess. Marked eosinophilia was noted in three patients. Two patients who received anti-toxoplasma chemotherapy in the early stage had a good outcome. However, the other two patients suffered rapid neurological deterioration and needed decompressive surgery, resulting in a poor outcome. Toxoplasma diffusely infects the whole central nervous system from the early stage. The outcome for patients who needed emergency surgery was poor. Therefore, this rare but increasingly common infectious disease must be considered in the differential diagnosis of a patient with neuroimaging findings similar to those of metastatic tumor or brain abscess. Appropriate chemotherapy should be started immediately after HIV-positive reaction is identified in patients with single or multiple mass lesions with ring enhancement.

Gamma knife treatment for multiple metastatic brain tumors compared with whole-brain radiation therapy.

OBJECT: The purpose of this retrospective study was to compare the effectiveness of gamma knife radiosurgery (GKS) for multiple cerebral metastases with that of whole-brain radiation therapy (WBRT). METHODS: Ninety-six consecutive patients with cerebral metastases from nonsmall cell lung cancer were treated between 1990 and 1999. The entry criteria were the presence of between one and 10 multiple brain lesions at initial diagnosis, no surgically inaccessible tumors with more than a 30-mm diameter, no carcinomatous meningitis, and more than 2 months of life expectancy. The patients were divided into two groups: the GKS group (62 patients) and the WBRT group (34 patients). In the GKS group, large lesions (> 30 mm) were removed surgically and all other small lesions (< or = 30 mm) were treated by GKS. New distant lesions were treated by repeated GKS without prophylactic WBRT. In the WBRT group, the patients were treated by the traditional combined therapy of WBRT and surgery. In both groups, chemotherapy was administered according to the primary physician's protocol. The two groups did not differ in terms of age, sex, initial Karnofsky Performance Scale (KPS) score, type, lesion number, and size of lesion, systemic control, and chemotherapy. Neurological survival and qualitative survival of the GKS group were longer than those of the WBRT group. In multivariate analysis, significant poor prognostic factors were systemically uncontrolled patients, WBRT group, and poor initial KPS score. CONCLUSIONS: Gamma knife radiosurgery without prophylactic WBRT could be a primary choice of treatment for patients with as many as 10 cerebral metastases from nonsmall cell cancer.

Proliferation, vascular endothelial growth factor expression and cavernous sinus invasion in growth hormone secreting pituitary adenomas.

Surgical cure of growth hormone producing pituitary adenomas (GHomas) becomes difficult when they invade the cavernous sinus (CS). Tumour proliferative activity and angiogenesis are thought to be required for tumour growth and invasion, and vascular endothelial growth factor (VEGF) activates neovascularization around tumours. In this study, the mechanism and clinical significance of CS invasion is analysed. In 25 surgically treated GHomas, the extent of CS invasion was classified as high (Knosp's grade 3 and 4), and low (grade 0, 1 and 2) MR grades, and the MR grades were compared with tumour proliferative potential (Ki-67 expression), angiogenetic demand (VEGF expression), volume of adenomas and serum hormone levels. The Ki-67 index of high MR grade adenomas (1.17 +/- 0.62%) was significantly higher than that of low MR grade adenomas (0.55 +/- 0.42%, p = 0.027), whereas VEGF expression showed no significant correlation with MR grades (p > 0.999). Tumour volume also showed a significant correlation with MR grade (p = 0.002). VEGF expression was not correlated with serum hormone level and volume, but was correlated with tumour proliferative potential. Proliferative potential and tumour volume were two independent factors related to CS invasion. Although VEGF expression was not a direct factor related to CS invasion, it may indirectly play a role in activation of tumour aggressiveness, which is required in CS invasion. Our results show that high MR grade adenomas have higher proliferative ability. In order to improve the surgical outcome, preoperative medical debulking is indicated, particularly, in such adenomas.

[Critical path; overview and its development process in the UOEH Hospital].

Critical Path (CP) is a kind of time-task matrix format. The first CP was developed by Karen Zander, an American nurse. The principal purpose of CP development was to improve the efficiency of hospital services under financial constraint caused by the introduction of DRG/PPS (Diagnosis Related Groups/Prospective payment system). Actually, the Japanese government is also discussing the possibility of introducing the DRG/PPS into the hospital financing scheme. In order to maintain, and even to improve the quality of hospital care, it is necessary to standardize care in the hospital. Thus it is necessary to develop a series of CPs in each hospital. In the spring of 1999, Prof. Osato, Director of the University Hospital, University of Occupational and Environmental Health, organized a task force team for CP development. Since then, this task force has been in charge of developing CP in our University Hospital. We have already developed several CPs and some of them are now in the process of field testing in each ward in order to check their applicability and problems to be corrected. In order to facilitate the use of CP in the hospital, doctors, nurses, pharmacists, and other health professionals must become more aware of the benefits of CP.

Topographical analysis of proliferating cells in meningiomas. Regional heterogeneity of the ability of tumors to proliferate.

Regional heterogeneity of the ability of tumors to proliferate has been pointed out, but its topographical analysis has not been studied in detail. To evaluate the distribution of highly proliferating cells in totally resected meningiomas, seven cases (including one recurrent case) were investigated in this study. Immunostaining of PCNA was performed on the sections crossing the equator of the tumors. These sections were divided into multi-squares with sides of 500 micrometers. The proliferating potential was determined as the PCNA positive cell count in each square. By painting those squares in eight kinds of color corresponding to the value of the PCNA positive cell count, maps of proliferative ability were made. To predict the localization of proliferating cells, we studied these maps in relation to the following: MR image, calcification, distance from the dural attachment and distance from the tumor capsule. Maps of the PCNA positive cell count showed the intra-tumoral heterogeneity of proliferative ability in all cases. Most of the cases showed homogeneous enhancement on MRIs and these images could not be a predicting factor of the highly proliferating area. There was no significant relationship between the calcification and the PCNA positive cell count. Although the proliferating ability was not correlated with the distance from the dural attachment, inner regions distant from the capsule showed higher proliferative ability in all cases. From these results, one should be aware that the information from the samples of meningiomas do not reflect the proliferating ability of the whole tumor.

Glucose and methionine uptake and proliferative activity in meningiomas.

Despite similar benign histological appearances, proliferative activity of meningiomas varies tumor to tumor, and even region to region in a tumor. To predict proliferative potential before surgery, we compared regional uptake of 2-[18F]fluoro-2-deoxyglucose ([18F]FDG) and L-[methyl-11C]methionine ([11C]MET) with histological indices of tumor proliferative activity in 17 specimens from six patients with meningioma obtained by PET guided stereotactic biopsies. Uptake of [11C]MET, an index of protein synthesis rate, significantly correlated not only with the count of nucleolar organizer regions (NORs), a histological index of protein synthesis, but also with Ki-67 index, a histological index of proliferative activity. On the other hand, [18F]FDG uptake showed no significant correlation with Ki-67 index or clinical malignancy. These results suggest that [11C]MET-PET is a useful tool for predicting tumor proliferative potential in meningiomas.

[Experimental studies on endocrine therapy for rat hepatocellular carcinoma].

Androgen receptor (AnR) and estrogen receptor (ER) are known to exist in human hepatocellular carcinoma (HCC), but the low binding capacity casts doubts on the efficacy of endocrinotherapy. However, we focussed on the favorable dissociation constant and displacement of AnR and ER. Efficacy of endocrinotherapy for HCC was investigated using rat HCC cell line (AH66F) resembling the properties of human HCC and sex hormone receptors. In rat HCC AH66F, we confirmed that the AnR and ER were both positive and were mentioned binding capacity, dissociation constant and displacement resembled those of human HCC. In rat HCC AH66F, administrations of Tamoxifen converted AnR and ER responses to negative. Rat HCC AH66F was transplanted intraperitoneally to Donryu rats, various endocrinotherapies administered and the number of survival days compared with a control group. In male and female rats, the number of survival days was both in the orchidectomied (p < 0.01) and the Tamoxifen treated (p < 0.001) group significantly prolonged. However, in the group treated with medroxyprogesterone acetate no significant differences were observed. Also, in experiments with AnR (-) and ER (-) rat HCC cell line AH60C all endocrinotherapies were ineffective. Above results confirmed the efficacy of endocrinotherapy for rat HCC with positive sex hormone receptors.

The prozone phenomenon in secondary syphilis.

We describe a 37-year-old woman with secondary syphilis, in whom the prozone phenomenon (false-negative test in undiluted specimens) occurred. The patient had been maintained on cyclosporine and prednisolone after renal transplantation. B-cell dysfunction induced by continuous immunosuppression may lead to higher non-treponemal serological titers. Non-treponemal testing should be repeated using serum dilutions to prevent missing the diagnosis of syphilis.

[False positives and false negatives seen in anti-HIV-1 antibody tests].

From September 1986 to December 1993 31059 anti-HIV antibody tests were performed on the samples from our clinic, from 29 health centers and their branches of Osaka Prefecture, from a hospital and from high risk groups. Enzyme immune assay (EIA) was used up to 1988 and from 1989 particle agglutination (PA) has been employed. The indeterminates of Western blot (WB) were seen in 5 EIA positives and in 2 PA positives. False positive rate of EIA was 0.235% (11/467) and that of PA was 0.011% (2/17922). Two false negative cases of anti-HIV-1 antibody test due to window period were documented and the importance of co-use of antigen test at the time of confirmative antibody tests was discussed.

Latex agglutination test for detecting antibodies to Treponema pallidum.

We have developed an automated latex agglutination test for Treponema pallidum (TPLA) for measurement of the concentration of treponemal antibodies in syphilitic sera. The assay needs neither a complicated pretreatment of the sera nor special techniques. Intra- and interassay precision studies showed high reproducibility. Potentially interfering substances, such as bilirubin, hemoglobin, triglycerides, and rheumatoid factor, did not affect the results. The results obtained with the TPLA test showed a strong correlation with those from conventional methods. This test for antibodies to T. pallidum may be useful for the mass screening of syphilitic infections.

Electro-optic focusing system for a high-density optical disk.

We have developed an electro-optic cell as a fine-adjustment focusing system for an optical disk. The cell is fabricated from transparent lead lanthanum zirconate titanate ceramic and has concentric-patterned indium tin oxide electrodes. The electro-optic cell can generate a relative phase shift in the pupil function. We have confirmed, theoretically and experimentally, that the phase shift induces a change in focal position that is as much as twice the focal depth without degrading the region near the main lobe of the point-spread function.

[Treatment of gonococcal urethritis].

Results of the treatment of 5 cases of males with uncomplicated gonoccocal urethritis using levofloxacin (LVFX, DR-3355), the L-type optical isomer of ofloxacin (OFLX), were compared with those treated with OFLX itself. Three hundred mg/day of LVFX or 600 mg/day of OFLX was given to each patient for 5 days. Both drugs showed excellent clinical results in all the patients. When MICs of the 2 drugs were compared against 57 isolated strains of Neisseria gonorrhoeae including 3 penicillinase-producing N. gonorrhoeae, it was found that MICs of LVFX were approximately one half of those of OFLX.