Vertical distributions of bactena and viruses were Investigated in the oceanic stations located in subarctic (Stn A) and subtropical (Stn B) areas of the Paciflc using the direct count technique and transmission electron microscopy. Small DAPI-positive, virus-like particles (VLP) were found to be distributed throughout the water column down to 5000 m a t both of the stations. The abundance of VLP ranged from 38 X 10' ml-' a t 50 m depth to 0.6 X 10' ml-' at 5000 m depth a t Stn A. The ratio of VLP to bacteria-like particle (BLP) ranged from 1.1 to 7.4 a t Stn A and 1.0 to 8.7 at Stn B in the entire water column. The maximum ratio was recorded at Stn B from the deepest sample, collected at a depth of 5000 m. The electron microscopic investigation Indicated that the major proportion of VLP were probably viruses.

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Although the p53 tumor-suppressor gene product plays a critical role in apoptotic cell death induced by DNA-damaging chemotherapeutic agents, human glioma cells with functional p53 were more resistant to c-radiation than those with mutant p53. U-87 MG cells with wild-type p53 were resistant to c-radiation. U87-W E6 cells that lost functional p53, by the expression of type 16 human papillomavirus E6 oncoprotein, became susceptible to radiation-induced apoptosis. The formation of ceramide by acid sphingomyelinase (A-SMase), but not by neutral sphingomyelinase, was associated with p53-independent apoptosis. SR33557 (2-isopropyl-1-(4-[3-Nmethyl-N-(3,4-dimethoxybphenethyl)amino]propyloxy)benzene-sulfonyl) indolizine, an inhibitor of A-SMase, suppressed radiation-induced apoptotic cell death. In contrast, radiationinduced A-SMase activation was blocked in glioma cells with endogenous functional p53. The expression of acid ceramidase was induced by c-radiation, and was more evident in cells with functional p53. N-oleoylethanolamine, which is known to inhibit ceramidase activity, unexpectedly downregulated acid ceramidase and accelerated radiation-induced apoptosis in U87-W E6 cells. Moreover, cells with functional p53 could be sensitized to c-radiation by N-oleoylethanolamine, which suppressed radiation-induced acid ceramidase expression and then enhanced ceramide formation. Sensitization to cradiation was also observed in U87-MG cells depleted of functional p53 by retroviral expression of small interfering RNA. These results indicate that ceramide may function as a mediator of p53-independent apoptosis in human glioma cells in response to c-radiation, and suggest that p53-dependent expression of acid ceramidase and blockage of A-SMase activation play pivotal roles in protection from c-radiation of cells with endogenous functional p53.

Cytotoxic T lymphocyte antigen 4 (CTLA-4) is a T cell costimulation receptor that delivers inhibitory signals upon activation. Although the tyrosine-based motif (165YVKM) within its cytoplasmic tail has been shown to associate in vitro with Src homology 2 domain–containing tyrosine phosphatase (SHP-2) and phosphatidylinositol 3 kinase upon phosphorylation, the mechanism of negative signaling remains unclear. Here, we report a new mechanism of negative signaling based on the analysis of murine T cell clones transfected with various mutants of CTLA-4. Upon T cell activation by cross-linking with anti-CD3 and anti-CD28 antibodies, CTLA-4 engagement inhibited both proliferation and interleukin 2 production in tyrosine mutants as well as in wild-type CTLA-4 transfectants. Furthermore, the mutant CTLA-4 lacking most of the cytoplasmic region strongly suppressed interleukin 2 production as well. These data suggest that negative signals by CTLA-4 could be mediated through the membrane-proximal region of CTLA-4 but not through the YVKM motif and that the association of CTLA-4 with SHP-2 is not required for CTLA-4–mediated suppression of T cell activation.

To establish strategies for treatment of asymptomatic microscopic hematuria we conducted a prospective study of 1,034 patients with this disease. The patients were examined by cystoscopy, urine cytology, abdominal ultrasound and excretory urography. On initial examination 30 highly significant lesions, including 24 cases of urological malignancies, 195 moderately significant lesions and 246 insignificant lesions were detected. In the remaining 563 patients no underlying lesion could be found. Of the 246 patients with insignificant lesions and 563 with unexplained asymptomatic microscopic hematuria followup was done in 421 at 6-month intervals for more than 1 year. A diagnosis became clear within 3 years in 22 patients, including 3 cases of bladder carcinoma and 1 of prostatic carcinoma.