Airway responsiveness and airway remodeling after chronic exposure to procaterol and fenoterol in guinea pigs in vivo

BACKGROUND: Chronic exposure to fenoterol (FEN), a beta(2)-adrenergic receptor (beta(2)-AR) agonist, was shown to induce both airway hyperresponsiveness and airway remodeling in experimental animals. OBJECTIVE: We wanted to know the effects of chronic exposure to procaterol (PRO), a beta(2)-AR agonist, on airway function and structure, because this agent is widely used as a bronchodilator in Japan. For comparison, the effects of FEN were also examined. METHODS: Aerosolized PRO (0.1 or 1 mg/ml), FEN (1 mg/ml) or vehicle (0.9% NaCl) was given to guinea pigs 3 times a day for 6 weeks. Sublaryngeal deposition of these agents was calculated using radioisotopes. At 72 h after the last inhalation of PRO, FEN or vehicle, the dose-response relationship between lung resistance (R(L)) and intravenously administered acetylcholine (ACh) was measured. After measuring R(L), histological changes in noncartilaginous airway dimensions were evaluated. RESULTS: The amount of sublaryngeal deposition of 0.1 mg/ml PRO in the present study was speculated to be 100 times larger than that of therapeutic dose. ACh concentrations causing 2-fold, 10-fold and maximal increases in R(L) were not different in 4 groups tested. In the smaller membranous airways (<0.4 mm in diameter), but not the larger ones, thickening of adventitial areas was significantly greater in animals treated with beta(2)-AR agonists than in control animals (23 and 25, and 96% higher in animals treated with 0.1 and 1 mg/ml PRO or 1 mg/ml FEN, respectively). The degree of the increase was significantly less in PRO-treated animals than in FEN-treated animals (p < 0.01). CONCLUSION: Our results did not provide any evidence that regular inhalation of PRO at the therapeutic dose might induce bronchial hyperresponsiveness. In addition, huge amounts of PRO only caused a mild thickening of the adventitial areas, suggesting that PRO may be a weak inducer of airway remodeling compared with FEN.     

Lymph Node Mesenchymal and Endothelial Stromal Cells Cooperate via the RANK-RANKL Cytokine Axis to Shape the Sinusoidal Macrophage Niche

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Melanocytes and melanosis of the oesophagus in Japanese subjects — analysis of factors effecting their increase

Summary Normal oesophagus specimens taken from 65 autopsy cases and surgical specimens from 127 oesophageal carcinoma cases were examined histopathologically to determine melanocyte incidence and distribution. Melanocytes were found in the epithelio-stromal junction in 7.7% of normal oesophagus specimens examined at autopsy, and in 29.9% of surgical cases with oesophageal carcinoma. Positive specimens in the latter groups, especially from pre-operatively irradiated individuals, showed a more remarkable increase of melanocytes than was evident in any of the normal oesophageal samples. There were no significant differences in incidence between males and females, or between age groups. In cases where the cancer invaded into deeper stroma, the melanocytes were mainly observed in the normal epithelium around the carcinomas. Epithelial and stromal elements of the melanotic mucosa commonly showed hyperplastic changes such as acanthosis or basal cell hyperplasia, and chronic oesophagitis. Melanocytes were observed most commonly in the lower part of the oesophagus, the site where malignant melanoma of the oesophagus, most often originates. These results strongly suggest that the melanocyte increase observed in areas of hyperplastic epithelium and chronic oesophagitis may play an important role as a precursor lesion for malignant melanoma in the oesophagus.     

RMRP mutations in Japanese patients with cartilage-hair hypoplasia

We examined 12 Japanese patients with metaphyseal chondrodysplasia (MCD) for mutations in the ribonuclease mitochondrial RNA processing gene (RMRP), and identified four novel mutations in two patients with typical and atypical cartilage-hair hypoplasia (CHH), a form of MCD characterized by extra-skeletal manifestations including hypoplastic hair and defective immunity. A patient with typical CHH had a 17-bp duplication at +3 and a de novo 182G > A. The other patient with atypical CHH had a 17-bp insertion at -20 and a 218A > G. Expression analysis revealed that the allele with this insertion mutation in the promoter region silenced the gene. Spectrum analysis of the mutations and polymorphisms in RMRP showed marked difference between the Japanese and other ethnic groups. Such ethnic and phenotypic difference should be taken into account in mutation analysis of the gene.     

Chromosome 1q terminal deletion resulting fromde novo translocation with an acrocentric chromosome

Summary Distal deletion of chromosome 1q has been reported in nearly 30 patients, all being associated with a deletion ranging from the 1q42 or q43 band to 1qter region. Here, we describe a girl with 1q terminal deletion resulting from an unbalancedde novo translocation t(1;D or G)(q44; p11), as revealed by the presence of a satellited feature and an NOR-stained region at the tip of 1q. We suggest that most of the phenotypic abnormalities seen in patients with 1q distal deletion are attributable to the monosomy for band 1q44.     

NECROSIS OF PORTAL TUMOR EMBOLUS OF HEPATOCELLULAR CARCINOMA BY LIPIODOL TRANSCATHETER CHEMO-EMBOLIZATION. A Case Report

We describe a case of hepatocellular carcinoma in which a tumor embolus in the portal vein and 3 of 4 intrahepatic metastases were necrosed completely by Lipiodol transcatheter chemo-embolization (Lipiodol-TCE). Tumor emboli in the portal vein and intrahepatic metastases usually cannot be necrosed by conventional transcatheter chemo-embolization alone, because small nodules such as intrahepatic metastases and tumor emboli in the portal vein are supplied blood from the portal vein. However, in this case, Lipiodol-TCE was effective against tumor emboli in the portal vein and intrahepatic metastases. ACTA PATHOL JPN 38: 1363-1367, 1988.     

Immunopharmacological study of CCA (Lobenzarit disodium), an anti-arthritis agent--I. Abrogation of IL 1 secretion by LPS-stimulated human monocytes and induction of gamma-interferon production with CCA

In vitro effects of CCA, an anti-arthritis agent, were studied upon autologous mixed lymphocyte reaction (AMLR), lymphocyte mitogenesis, IL 1 and IL 2 production, immunoglobulin production and gamma-interferon (IFN) production. CCA at 50 micrograms/ml, which was not toxic to cells, blocked AMLR, IL 1 production and immunoglobulin production (IgM and IgG) significantly, while CCA at the same dose did not affect IL 2 production and lymphocyte mitogenic responses to Staphylococcus aureus Cowan I(SAC) and pokeweed mitogen(PWM). CCA at both 20 ng/ml and 20 micrograms/ml induced human gamma/IFN. Addition of IL 1 and/or IL 2 reversed inhibitory effect of CCA on AMLR. These data suggest that CCA exerts its actions by mainly affecting T cells and monocytes and can be used as an immunomodulator.     

Peptide-binding motifs of the mixed haplotype Abetaz/Aalphad major histocompatibility complex class II molecule: a restriction element for auto-reactive T cells in (NZBxNZW)F1 mice.

We previously showed that the mixed haplotype Abetaz/Aalphad major histocompatibility complex (MHC) class II molecules function as restricting element for autoreactive T-cell clones derived from autoimmune prone (NZBxNZW)F1 (B/WF1) mice. Subsequent analysis revealed that some of these Abetaz/Aalphad-restricted autoreactive T-cell clones were pathogenic upon transfer to pre-autoimmune B/WF1 mice. In this paper, we analysed the peptide-binding motif of Abetaz/Aalphad class II molecules. Amino acid-sequencing analysis of peptides eluted from purified Abetaz/Aalphad molecules revealed several sequences, including one that corresponds to murine l-plastin 588-601. Synthetic 18-mer l-plastin 588-605 peptide (SMARKIGARVYALPEDLV, as described by the amino acid single letter code) was demonstrated to bind to Abetaz/Aalphad MHC class II molecules on transfectant B lymphoma cells (TAbetaz). A competitive binding inhibition assay using truncation peptides revealed the core sequence for binding resides in 591Arg to 601Pro. Binding inhibition assay using substitution peptides, each having substitution to the other 19 residues at positions from 590Ala to 601Pro, revealed four major anchor sites 592Lys (p1), 594Gly (p3), 595Ala (p4), 597Val (p6) and one minor anchor site 600Leu (p9). Positively charged residues are not allowed at p3 and negatively charged residues are not allowed at p4 and p6. Relatively large hydrophobic residues (Leu, Ile) are not tolerated at p3 and p4. Met and Trp are not tolerated at p6. Based on these findings, the characteristics of peptides recognized by autoreactive T cells in B/WF1 mice are discussed.