Primary intracranial malignant lymphomas with particular reference to their pathogenesis.

During the past 6 years we have experienced a total of 6 cases of malignant lymphomas, which originated primarily in the central nervous system. The most reliable diagnostic criteria will be a "perivascular cuffing" by silver impregnation with further spreading of tumor cells to the periphery, a "starry-sky" appearance consisting of numerous histiocytes with foamy cytoplasm intermingled with tumor cells, and cytological features of the imprint preparation. Since there is a close histologic similarity to extracerebral malignant lymphomas, we would like to propose that these tumors should be regarded as primary malignant lymphomas of the central nervous system instead of mere reticulum cell sarcoma-microglioma, and also would like to regard the brain to be not an exceptional site other than visceral lymphomas for occurrences of malignant lymphomas. For the pathogenesis of primary intracranial malignant lymphomas, the hypothesis, proposed by FEIGIN, of the possible existence of multipotential stem cells in the brain was discussed.     

Molecular approach in cancer epidemiology: early detection of carcinogen-induced mutations in a whole genome (Review)

Chronic exposure of organisms to endo- or exogenous genotoxic products results in the accumulation of mutations in the genome and eventually to the development of cancers. Early detection of these mutations would allow the identification of at risk individuals who present a high load of mutations either because of an occupational or environmental exposure, or because of less efficient DNA repair processes. However, highly specific and sensitive assays are required to allow the detection of point mutations in a whole genome. We review a long-term study on the mutagenesis induced in E.coli by an aromatic amide, the N-2-acetylaminofluorene. A major contribution of this work was to reveal the presence of specific mutation hot spot sequences. Taking advantage of this observation, we designed a specific, sensitive and semi-quantitative in vitro assay allowing the detection of carcinogen induced mutations. This assay has been validated in vivo and demonstrate the sensitivity of the technique in early detection of mutations and its usefullness in molecular epidemiology, early diagnostic and prognosis.     

A highly hydrophobic domain within hypervariable region 1 may be related to the entry of hepatitis C virus into cultured human hepatoma cells

Interaction of the envelope glycoprotein of hepatitis C virus (HCV) with a cellular receptor(s) is thought to be essential for the initial steps of HCV infection. However, the mechanisms of HCV infection remain unclear. The aim of the present study was to determine the features of HCV that enable efficient entry of the virus into human hepatocytes. Variations of hypervariable region 1 (HVR1) sequences in HCV inocula and in infected human hepatoblastoma HepG2 cells were examined. Immunofluorescence of inoculated HepG2 cells with anti-HCV core antibodies demonstrated that HCV structural proteins were expressed in the cytoplasm, and their entry into HepG2 cells was confirmed. When the HVR1 amino acid sequences were compared, HVR1 quasispecies in the inoculated cells showed more uniformity than those of the inocula. Although there were no statistically significant differences between the two groups, hydrophobic residues were observed more frequently in the HVR1 amino acids from inoculated cells than in the HVR1 amino acids from the inocula. Results of hydropathy analysis revealed that highly hydrophobic domains exist in the middle of HVR1 in the inoculated cells in 7 of 10 patients. The results suggest that limited HCV populations are able to enter HepG2 cells and that the highly hydrophobic domain existing within the HVR1 may play an important role in the entry of HCV into cells.     

The molecular basis of HbH disease in a Japanese girl

Hemoglobin H disease is often caused by deletion of three of the four alpha-globin genes (genotype: --/-alpha). We studied a Japanese girl who had microcytic hypochromic anemia, a decreased alpha/beta globin synthetic ratio and about 8% Hb H in her fresh hemolysate, by means of restriction endonuclease mapping of the alpha-like gene complex (5'-zeta-phi zeta-phi alpha 2-phi alpha 1-alpha 2-alpha 1-theta-3') with zeta- and alpha-specific probes. It was found that the defect of one chromosome was associated with the removal of about 18 kb of DNA, known as --SEA type alpha-thalassemia-1, including the deletion of the part of phi alpha 2, phi alpha 1, alpha 2, alpha 1, and theta globin genes, while the other one was associated with the removal of 3.7 kb of DNA, known as rightward deletion type alpha-thalassemia-2. The results of a family study demonstrated that the deletion haplotype --SEA was inherited from her father's side and the other -alpha 3.7 from her mother's side.     

Determination of HIV-1 infectivity by lymphocytic cell lines with integrated luciferase gene

We have established lymphocytic cell lines H9 and M8166 that contain integrated copy of luciferase gene under the control of human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR). While H9 is known to be non-permissive for or insensitive to some particular mutant strains of HIV/simian immunodeficiency virus (SIV), M8166 is one of the most susceptible lines to various HIV/SIVs. The luciferase gene driven by HIV-1 LTR was transfected into H9 and M8166 cells with the neo gene, and cell lines were selected by G418. The indicator cell lines thus obtained were designated H9/H1luc and M8166/H1luc, and monitored for their susceptibility to various HIV clones including in vitro-constructed mutants. Both cell lines, particularly M8166/H1luc, were found to be exquisitely sensitive to HIV-1 and HIV-2. Furthermore, they exhibited the response to infections by various viral clones exactly as expected from the characteristics of the original cell lines. These results indicated that our new indicator cell lines H9/H1luc and M8166/H1luc are eminently useful for a variety of molecular virological studies on HIV/SIV.     

Clinical Ethics Consultation: Examining how American and Japanese experts analyze an Alzheimer's case

Background  

Few comparative studies of clinical ethics consultation practices have been reported. The objective of this study was to explore how American and Japanese experts analyze an Alzheimer's case regarding ethics consultation.     

Effect of IL-6 polymorphism on risk of Alzheimer disease: genotype-phenotype association study in Japanese cases

Interleukin-6 (IL-6), an inflammatory cytokine might be involved in the pathophysiology of Alzheimer disease (AD); several studies have reported that the "C allele of IL-6 variable number of tandem repeat polymorphism" (IL-6vntr) delayed initial onset of AD and also decreased its risk per se. Another polymorphism, G/C allele of IL-6 gene promoter region (IL-6prom), is also a candidate because it has an influence on the regulation of plasma IL-6 concentration. We examined these IL-6 polymorphisms in 128 Japanese AD cases and 83 control cases using a PCR-RFLP method. The results showed the frequency of the IL-6prom G allele was significantly increased in AD, although IL-6vntr polymorphism was not. Plasma IL-6 concentration of the AD cases was also significantly higher than that of the control cases. Moreover, the IL-6prom G allele-positive AD patients showed a tendency to have higher IL-6 concentration in the AD group. These findings suggest that the IL-6prom G allele which may affect plasma IL-6 concentration might be a risk factor for sporadic AD in Japanese.     

Sites in the rabbit flocculus specifically related to eye blinking and neck muscle contraction

In alert rabbits, the cerebellar flocculus was mapped for effects of local stimuli delivered through glass microelectrodes. Triple-barreled glass microelectrodes were used, each barrel of which was filled with solution containing one of three different dyes (Fast Green FCF, Pontamine Sky Blue and Nigrosine) for differentially labeling the sites exhibiting different stimulus effects. In addition to eye movements reported earlier, eye blinking and contraction of dorsal neck muscles were elicited from limited areas of the flocculus. Eye blinking sites were concentrated rostroventrally and neck muscle contraction sites caudoventrally within the flocculus. The present results suggest that the rabbit flocculus contains specific sites devoted to the control of eye blinking and neck posture.     

A synthetic peptide which specifically inhibits heat-treated interleukin-8 binding and chemotaxis for neutrophils

Interleukin-8 (IL-8) is a peptide which is secreted by stimulated human monocytes and which is chemotactic for human neutrophils. We synthesized three overlapping peptides spanning the amino-terminal region of the IL-8 sequence. None of the peptides retained the chemotactic activity of the native molecule. One of the peptides, IL-8(_3–25), inhibited the neutrophil chemotactic activity of recombinant IL-8 (rIL-8) which had been preheated to 40°C but did not reduce neutrophil chemokinesis, or the chemotactic activity of unheated rIL-8, FMLP, C5a or LTB₄. Interleukin-8 exhibited similar binding kinetics and chemotaxis for neutrophils regardless of whether it had been pretreated at 40°C.In addition, IL-8(_3–25) was also able to decrease the binding of prehead IL-8 to neutrophils. IL-8(_3–25), which can self-associate, binds directly to receptors on the neutrophil. The data suggest that heat-treated, but not untreated, IL-8 causes the IL-8(_3–25) multimers to disaggregate, allowing the monomeric peptide to directly bind to the IL-8 receptor and thus inhibiting IL-8/receptor binding.