K-ras activation and ras p21 expression in latent prostatic carcinoma in Japanese men.

Twenty-three clinically silent prostatic carcinomas discovered in Japanese men at autopsy were surveyed for ras proto-oncogene mutations by mutation-specific oligonucleotide probe hybridization after polymerase chain reaction (PCR) amplification from a section of formalin-fixed, paraffin-embedded tissue. Six of the 22 that were satisfactory amplified contained activating point mutations in codon 12 of K-ras, a significantly higher frequency than has been reported in patients with clinically advanced disease in the United States. Of the six cases with activating point mutations in codon 12 of K-ras, one had a GGT----GAT transition, four had GGT----GTT transversions, and one had both GGT----GAT and GGT----GTT mutations. Sections from the same tissues were immunohistochemically stained with an anti-ras p21 antibody. Carcinoma cells stained for ras p21 to some degree in 13 cases. Immunohistochemically detectable expression of p21 was always focal and was not necessarily associated with K-ras mutation. K-ras oncogene activation in prostatic carcinoma appears to merit additional study as a significant event in the pathogenesis of this neoplasm.     

The effect of FK506 on segmental pancreas allograft in mongrel dogs]

FK506 is a potent immunosuppressive agent on experimental and clinical organ transplantation. We studied the the effect of this agent on segmental pancreas allograft in mongrel dogs. Graft survival was prolonged significantly with continuous administration of FK506, 0.3mg/kg/day intramuscular and 1.0mg/kg/day orally. However such symptoms as loss of appetite, nausea and extreme emaciation were observed and caused death. While bolus therapy of FK506 (3 days administration with the dose of 1.0mg/kg i.m. from 4 to 6 day postoperatively) showed the same immunosuppressive effect as continuous therapy and less side effect. Furthermore it was suggested that FK506 plasma levels were concerned with the appearance of side effect. In conclusion, the administration of FK506 with plasma level monitoring was thought to be useful on pancreas transplantation.     

Innate immunity and its role against infections.

LEARNING OBJECTIVES: This article reviews current concepts of the innate immune system that offers protection against infections. It offers an overview for the readers to understand how innate immunity, consisting of different receptors, cells, and mediators recognizes pathogens and exerts protective function against pathogens. DATA SOURCES AND STUDY SELECTION: MEDLINE-search articles including original research papers, review articles, textbooks, and references identified from bibliographies of relevant articles. RESULTS AND CONCLUSIONS: The innate immune system is nonspecific immunity present since birth not requiring repeated exposure to pathogens. It is capable of differentiation between self and nonself. Because of its nonspecificity, it has a broad spectrum of resistance to infection. Further, it is thought to play an important role in the control of adaptive immunity by regulating co-stimulatory molecules and effector cytokines. Innate immunity includes pattern recognition molecules/receptors, antimicrobial peptides, the complement system, inflammatory mediators, and cytokines produced by immune cells. Pattern recognition molecules/receptors recognize pathogen-associated molecular patterns that are essential for microorganisms' survival and pathogenicity. Although innate immunity has recently gained increasing importance, further studies are necessary for a better understanding of its role.     

Self-disclosure and loneliness]

This study examined the relationship between self-disclosure and loneliness. The self-disclosure questionnaire (ESDQ) and the loneliness scale (LSO, consists of two subscales, U-scale and E-scale) were administered to 114 female subjects (junior college students). Results show that self-disclosure scores were negatively related to the U-scale of loneliness (whether or not they believe in mutual sympathy among human beings), but not to the E-scale of loneliness (whether or not they are conscious of individuality of each individual). The results suggest that we have to specify the quality of loneliness in question, when we examine the relationship between self-disclosure and loneliness.     

Characterization of chromosome aberrations induced by incubation at a restrictive temperature in the mouse temperature-sensitive mutant tsFT20 strain containing heat-labile DNA polymerase alpha

tsFT20 cells derived from a mouse mammary carcinoma cell line, FM3A, which has temperature-sensitive DNA polymerase alpha activity (Y. Murakami, H. Yasuda, H. Miyazawa, F. Hanaoka, and M. Yamada, Proc. Natl. Acad. Sci. USA, 82:1761-1765, 1985) were rapidly committed to death after temperature upshift to 39 degrees C. tsFT20 cells synchronized in S phase were more sensitive to the restrictive temperature than exponentially growing cells. In order to gain insight into the processes from the interruption of DNA synthesis to cell death, we analyzed chromosome aberrations induced in tsFT20 cells which had been incubated for 2 or 4 h at the restrictive temperature and then cultured at the permissive temperature. The majority of metaphase cells showed extensive chromosome aberrations such as chromatid gaps, breaks, and exchanges; chromosome pulverizations; their mixed types; and ring chromosomes. Analyses with the use of cell synchronization and autoradiography revealed that chromosome aberrations were induced only in the cells which synthesized DNA during incubation at 39 degrees C. We classified the chromosome aberrations into five types: gap or break type; exchange type; pulverization type; complex type; and ring type. The temporal order of the appearance of these types of chromosome aberrations was found to be the above described order. It was further found that cycloheximide dramatically repressed the induction of chromosome aberrations, and metaphases with many chromosome aberrations exhibited a large number of sister chromatid exchanges. These results indicate that abnormal cessation of DNA replication in tsFT20 cells at the restrictive temperature due to the inactivation of DNA polymerase alpha results in cell death via induction of double-strand breaks which lead to chromosome aberrations as well as sister chromatid exchanges.     

A case of aseptic meningitis caused by relapsing polychondritis]

We report a patient of relapsing polychondritis (RP) with antecedent aseptic meningitis. A 65-year-old man has developed headache and fever. Neurological examination showed meningeal signs, and cerebrospinal fluid (CSF) examination revealed meningeal inflammation which contained 450 polymorphonuclear cells/microl, 302 mononuclear cells/microl, and 0 red cells/microl, with 79 mg protein/dl. Serologic testing for autoimmune disease as well as the culture and cytology of CSF were negative. He admitted our hospital as having aseptic meningitis and experienced antibiotic therapy. However, his pyrexia continued and he developed repeating visual and hearing impairment reacting to steroid. Three months later, he became behaviorally deaf, and bilateral auricular chondritis occurred with nonerosive seronegative inflammatory polyarthritis. The result of condral biopsy was consistent with the diagnosis of RP showing cartilage surrounded by an intense inflammatory cell response with a decreased number of chondrocytes. A clinical diagnosis was made and prednisolone 60 mg/day was begun with the result of resolution of the auricular chondritis, and slight improvement of his deafness. Aseptic meningitis is a rare complication of RP. Only one report detailed RP patient who had preceding meningitis. RP is a potentially lethal disease resulting from suffocation by airway collapse, the complications of a cardiac large vessel, and so on. For improvement of a life prognosis, an early diagnosis and treatment are indispensable. Although RP is a rare discovery, it is necessary that RP should be taken into consideration and be differentiated as a cause of relapsing aseptic meningitis.     

Independent association of antibodies against human papillomavirus type 16 and E7 proteins with cervical cancer

The E4 open reading frame (ORF) of human papillomaviruses (HPVs) is transcribed in abundant mRNAs encoding an fusion gene during the productive infection, and the HPV 16 E7 ORF encodes an oncoprotein detectable in the cell lines derived from cervical carcinoma. We examined 421 human sera, which included 108 samples from the patients with cervical carcinoma, for the presence of IgG antibodies against the HPV 16 E4 and E7 proteins by enzyme-linked immunosorbent assay. Bacterially expressed fusion protein lac- and nonfusion protein E7 were purified and used as antigens. All of the 22 serum samples positive for anti-E7 antibody and the 11 out of 15 samples positive for anti- antibody were from the patients with cervical carcinoma, but only one sample was found to contain both anti- and anti-E7 antibodies. These findings show specific and independent association of these antibodies with cervical carcinoma.     

Conditions of Alzheimer-type dementia in the old-old and oldest-old patients with special reference to extreme conditions of brain aging

A neuropathological study on 1540 consecutive autopsy brains ranging from 60 to 107 years of age revealed the following points. (1) Of the of the demented cases of the plaque-predominant type, 93% were complicated with multiple tiny cortical infarcts. They showed a tendency for dementia to develop before or after the appearance or worsening of a systemic disorder such as cardiovascular disease, respiratory infection and cancer. However, there was no case showing Alzheimer-type dementia (ATD). (2) The plaque-predominant type might be an extreme condition of brain aging in terms of senile plaques (SP). It is likely that although the pathological appearance of SP alone is not responsible for dementia, its coexistence with multiple cortical infarcts could be the cause of dementia. Therefore, this type should be distinguished from ATD. (3) Primary hippocampal degeneration could also be an extreme condition of brain aging in terms of neurofibrillary tangles. This condition was different pathologically from the hippocampal lesion in ATD. (4) Several characteristics of old-old and oldest-old patients were clarified.     

Antagonistic effects of selective alpha1-adrenoceptor antagonists MDL73005EF and tamsulosin and partial agonists clonidine and tizanidine in rat thoracic aorta and rabbit iliac artery

The antagonistic effects of MDL73005EF and tamsulosin and partial agonists clonidine and tizanidine at rat thoracic aorta and rabbit iliac artery alpha1-adrenoceptors were investigated in this study. Selective alpha1-adrenoceptor antagonists MDL73005EF and tamsulosin dose-dependently shifted the concentration-response curves for noradrenaline to the right. Schild plots of the results obtained from the inhibition by MDL73005EF (pA2 8.30 +/- 0.04) and tamsulosin (pA2 10.51 +/- 0.06) of noradrenaline yielded a straight line with a slope of unity in rat thoracic aorta. The slopes of Schild plots obtained from the inhibition by MDL73005EF and tamsulosin of noradrenaline were significantly different from unity in rabbit iliac artery. Schild plots of the results obtained from the inhibition by clonidine and tizanidine of noradrenaline yielded a straight line with a slope of unity in rat thoracic aorta (pA2 7.08 +/- 0.04 and 7.32 +/- 0.04, respectively). These results suggest that alpha1D-adrenoceptors play a significant role in the alpha1-adrenoceptor-agonist-induced contraction of rat thoracic aorta and rabbit iliac artery, and that clonidine and tizanidine interact with the alpha1D-adrenoceptor subtype as competitive antagonists in rat thoracic aorta.     

Pivotal function for cytoplasmic protein FROUNT in CCR2-mediated monocyte chemotaxis

Ligation of the chemokine receptor CCR2 on monocytes and macrophages with its ligand CCL2 results in activation of the cascade consisting of phosphatidylinositol-3-OH kinase (PI(3)K), the small G protein Rac and lamellipodium protrusion. We show here that a unique clathrin heavy-chain repeat homology protein, FROUNT, directly bound activated CCR2 and formed clusters at the cell front during chemotaxis. Overexpression of FROUNT amplified the chemokine-elicited PI(3)K-Rac-lamellipodium protrusion cascade and subsequent chemotaxis. Blocking FROUNT function by using a truncated mutant or antisense strategy substantially diminished signaling via CCR2. In a mouse peritonitis model, suppression of endogenous FROUNT markedly prevented macrophage infiltration. Thus, FROUNT links activated CCR2 to the PI(3)K-Rac-lamellipodium protrusion cascade and could be a therapeutic target in chronic inflammatory immune diseases associated with macrophage infiltration.