Down-regulation of β-adrenergic receptor following long-term monocular deprivation in cat visual cortex

To examine how adrenergic receptor binding is modified by experimental manipulation of sensory afferent, we carried out binding experiments (membrane fraction and in vitro autoradiography) for both ₂- and β-adrenergic receptors in the brain of cats which had been deprived of vision in one eye. In the cerebral cortex of control animals, β-adrenergic receptor (β-AR) binding was found to be higher in the occipital regions than in other regions, while ₂-AR binding was relatively uniform. Monocular deprivation throughout the postnatal sensitive period (1–7 month of age) significantly decreased β-AR binding in the visual cortex and lateral geniculate nucleus. Scatchard plot analysis in the visual cortex showed ca. 50% reduction in B_max and little change in K_d No significant difference was found in ₂-AR binding following monocular deprivation. Similar extent of down-regulation in β-AR binding was confirmed in all layers of visual cortex using autoradiography.     

Comparative dose-response study on the pulmonary carcinogenicity of 1, 6-dinitropyrene and benzo[a]pyrene in F344 rats

The dose dependencies of the lung carcinogenicity of 1, 6-dinitropyrene(1, 6-DNP) and benzo[a]pyrene (BaP) were examined by directinjections of these compounds into rat lungs. A total of 276male F344 rats were divided into 10 groups and given variousdoses of 1, 6-DNP or BaP, or no drug (control group). Both chemicalswere injected into the lung, as suspensions in beeswax-tricaprylinand the animals were then observed for 104 weeks. The incidencesof lung cancer were 0/39 (0%), 4/30 (13%), 13/31 (42%), 22/26(85%) and 6/9 (67%) in groups treated with 0.003, 0.01, 0.03,0.1 and 0.15 mg of 1, 6-DNP respectively, and 1/29 (3%), 7/30(23%) 22/29 (76%) and 9/13 (69%) in those treated with 0.03,0.1, 0.3 and 1.0 mg of BaP respectively. No lung cancer wasfound in control rats. Thus the incidences of lung cancer inducedby 1, 6-DNP and BaP showed significant dose dependence. At equaldoses, the incidence of lung cancer was much higher with 1,6-DNP than with BaP, and the induction of cancer by 1, 6-DNPwas higher even at one-third the dose of BaP. Histologically,most tumours induced by 1, 6-DNP were undifferentiated neoplasms,whereas most of those induced by BaP were well-differentiatedsquamous cell carcinomas.     

Evidence for different sites of monoamine oxidase and catechol-O-methyltransferase in the striatum

Wistar rats were implanted with a probe for brain microdialysis in the striatum, and measured for two major dopamine metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). Intraperitoneal chlorpromazine (5 mg/kg) increased the concentrations of both metabolites in the dialysate when the determinations were carried out before 90 min after the administration. An apparent difference between the declines in concentrations of DOPAC and HVA was observed. Although the concentration of HVA maintained higher levels for over 6 h after the administration, DOPAC underwent a decrease in its concentration after the maximum level, which occurred at 90 min after the administration. These results are discussed in terms of the different distributions of two enzymes related to the metabolism of dopamine, catechol-O-methyltransferase and monoamine oxidase.     

Metabolism of Tegafur in Rat Liver Observed by in vivo 19F Magnetic Resonance Spectroscopy and Chromatography

Metabolism of tegafur in the rat liver was observed by in-vivo ¹⁹F magnetic resonance spectroscopy (MRS). After MRS observation, tegafur and q-fluorouracil (S-FU) in the liver were determined by a shromatographic method for comparison with the results of ¹⁹F-MRS. Rats were divided into 3 groups: 1) CCl4-induced liver injury group, 2) uracil combined group, 3) control group. Catabolism to fluoro-β-alanine was suppressed in both the liver injury group and the uracil combined group. Low peaks of 5-FU and fluoronucleotides could be found only in the uracil combined group. The result of ¹⁹F MRS observation of each group was in agreement with the result of determination of tegafur and 5-FU by chromatography. This showed that substances which could be observed by ¹⁹F-MRS were in proportion to all intracelluar fluoro-containing substances. ¹⁹F-MRS can provide direct information on the metabolism of fluoropyimidines non-invasivey and it might be a useful aid in choosing suitable shemotherapy for patients.     

Mouse-Human Chimeric Antibody MH171 against the Multidrug Transporter P-Glycoprotein

We have developed a mouse-human chimeric antibody MH171, in which the antigen-recognizing variable regions of the mouse monoclonal antibody MRK17 are joined with the constant regions of human IgG1 antibodies. The MRK17 recognizes specifically the multidrug transporter P-glycoprotein and inhibits the growth of human multidrug resistant (MDR) tumor cells in vitro and in the xenograft nude mouse model system. The established chimeric MH171 antibody forms an apparently intact IgG composed of heavy and light chains covalently assembled via disulfide bonds in sodium dodecyl sulfate polyacrylamide gel electrophoresis analysis and is specific to MDR cell lines with a similar affinity to the original mouse MRK17. MH171 also displays strong antibody-dependent cell-mediated cytotoxicity to the target cells in vitro , when human mononuclear cells are used as effector cells. The chimeric antibody against P-glycoprotein, MH171, should be a useful agent in the treatment of human drug-resistant tumors.     

Prevalence of neurological complications in Japanese patients with AIDS after the introduction of HAART.

We investigated trends in neurological complications of infection with human immunodeficiency virus (HIV) in Japan after the introduction of highly active antiretroviral therapy (HAART). Two questionnaire surveys were performed in hospitals treating acquired immunodeficiency syndrome (AIDS) to compare two periods: immediately after the introduction of HAART (1999-2001); and a few years later (2002-3). Neurological complications accompanied 15.9% in 1999-2001 and 9.8% in 2002-3. Neurological complications developed without HAART in about 80% of cases. Neurological complications developed as the first AIDS-defining disease for 8.3% of AIDS patients in 1999-2001 and for 5.4% in 2002-3. Prevalences of HIV encephalopathy and myelopathy decreased markedly over the study period, as reported in other developed nations. However, prevalences of cytomegalovirus encephalitis, PML and primary brain lymphoma did not decrease. PML and primary brain lymphoma occurred in patients who received HAART and whose CD4 counts were relatively high during the study period. This is probably related to the extended survival of HIV-infected individuals after the introduction of HAART as a worldwide therapy, and the reactivation of viremia or latent infection persisting within the central nervous system.     

Human Monoclonal Antibodies against Cytokeratin 18 Generated from Patients with Gastric Cancer

By co-culturing regional lymph node B-cells and HAT-sensitive mutant cells obtained from RPMI-1788 cells, no less than 20,000 Epstein-Barr (EB)-transformed colonies were obtained from 32 patients with gastric cancer. From B-cell cultures generating antibodies reactive with gastric cancer tissues as well as cultured gastric cancer cells, two EB-transformed cell clones termed C418–59 and C1218–39 were isolated. Both of them produced human IgM-class antibodies, termed Mab418–59 and Mab 1218–39, respectively. Both antibodies reacted with an antigen with a molecular weight of 45 kd existing in gastric cancer MKN-45, MKN-1, and Kato-III cells, and also with all of 4 adenocarcinomas of the stomach in paraffin sections. The antigen recognized by both antibodies was identified as a kind of cytoskeletal protein, cytokeratin 18, In this study, it was confirmed that B-cell clones generating autoantibodies against cytokeratin 18 were present in some patients with gastric cancer.     

Dopaminergic Innervation of the Monkey Caudal Nucleus Accumbens

Previous studies have shown that the monkey (Macaca fuscata) caudal nucleus accumbens is neurochemically subdivided into three subdivisions, the medial, dorsolateral, and ventral subdivisions. In this study, dopaminergic innervation of these three subdivisions was studied in detail for the first time by light microscopic immunocytochemistry using a monoclonal antibody against dopamine. The patterns of dopamine fiber distribution were heterogeneous even within each subdivision. The medial subdivision showed extremely dense accumulation of thick dopamine-immunoreactive varicose fibers. Some areas with densely packed cells in Nissl-stained sections corresponded to dopamine-poor areas, while another area with concentrated cells corresponded to a dopamine-rich area. There were also areas with sparse cells that contained a few dopamine-immunoreactive fibers. In the dorsolateral subdivision thick dopamine-immunoreactive varicose fibers were found sparsely among diffuse puncta. The ventral subdivision exhibited similar profiles to those in the dorsolateral one, and there were also many characteristic spiral dopamine-immunoreactive fibers of passage. The present study indicates that the dopaminergic structures of the monkey nucleus accumbens differ according to the subterritories, and are morphologically different from those in the caudate-putamen.