Oxatomide inhibits the release of chemical mediators from human lung tissues and from granulocytes

The effects of oxatomide on the release of histamine and leukotriene C4 (LTC4) from human lung fragments and granulocytes were examined and the findings compared with the effects of the antiallergic drugs ketotifen, azelastine and tranilast. Oxatomide inhibited the release of both histamine and LTC4 from human lung fragments in cases of passive sensitization with human IgE myeloma serum upon anti-epsilon stimulation. IC50 values for the release of LTC4 from human lung fragments were as follows: oxatomide, 2.35 x 10(-5) M; azelastine, 27.2 x 10(-5) M; ketotifen, 52.1 x 10(-5) M; tranilast, 62.9 x 10(-5) M. Oxatomide also inhibited the release of both histamine and LTC4 from human mixed leukocytes stimulated by the calcium ionophore A23187. IC50 values for the release of LTC4 from human mixed leukocytes were as follows: oxatomide, 1.67 x 10(-5) M; azelastine, 3.65 x 10(-5) M; ketotifen, 12.2 x 10(-5) M; tranilast, 15.1 x 10(-5) M. The effects of oxatomide on the release of LTC4 from purified human neutrophils and eosinophils were also given attention. Oxatomide inhibited the release of LTC4 from eosinophils more effectively than from neutrophils and mixed leukocytes. As there is evidence that eosinophils play an important role in the development of late asthmatic responses and/or in the aggravation of asthma, oxatomide is expected to be an effective treatment for such conditions.     

Human neutrophils express messenger RNA of vitamin D receptor and respond to 1alpha,25-dihydroxyvitamin D3

1Alpha,25-Dihydroxyvitamin D3 (1,25(OH)2D3) has been shown to modulate the production of various cytokines or the expression of certain differentiation markers in human T cells or monocytes. Its effects on neutrophils, however, are poorly understood. In this paper, we show several lines of evidence indicating that neutrophils express functional vitamin D receptors (VDR). Sort-purified neutrophils from human peripheral blood expressed VDR mRNA at a level comparable to that of monocytes. As reported to occur in monocytes, protein expression of CD14 on the cell surface of neutrophils was augmented when the cells were incubated with 1,25(OH)2D3. To investigate the physiological roles for VDR in neutrophils, we investigated possible modulating effects of 1,25(OH)2D3 on the expression of several genes in lipopolysaccharide-stimulated neutrophils by using differential display analysis. Of the genes we identified, trappin-2/elafin/SKALP, which was originally reported to be an inhibitor of elastase, was induced in neutrophils by lipopolysaccharide, but was suppressed significantly in the presence of 1,25(OH)2D3. Under the same conditions, interleukin-1beta expression was also inhibited. These findings suggest that 1,25(OH)2D3 has a potential to affect the inflammatory process by modulating the expression of neutrophil genes.     

The Role of Polymorphonuclear Leukocytes in Rat Chronic Serum Sickness-type Nephritis

In order to investigate the role of polymorphonuclear leukocytes (PMN) in the distribution of antigen in various organs and in the development of nephritis, chronic serum sickness type nephritis was induced in both anti rat PMN rabbit serum (APS) treated and normal rabbit serum (NRS) treated rats by preimmunization with bovine serum albumin (BSA) and subsequent daily intravenous administration of BSA for 4 weeks. Kinetic studies using radiolabeled BSA showed that accumulation of BSA after the first intravenous administration was reduced by APS treatment in the liver, lungs and spleen and increased in the circulation, but was not affected in the kidneys and glomeruli. Histological studies supported the above findings. After 4 weeks of BSA administration, the BSA accumulation in the kidneys and glomeruli was significantly less in APS treated rats than in NRS treated ones, while amounts of BSA in the circulation and other organs were not different between the two groups. Furthermore, APS treatment reduced proteinuria, PMN infiltration and IC deposition in the glomeruli. These observations indicate that PMN play a partial role in IC deposition in the glomerular capillary walls and subsequent destruction of glomerular permeability in chronic serum sickness-type nephritis. Acta Pathol Jpn 39 : 619-629, 1989.     

Details of an isolation method for hepatic lymphocytes in mice.

The liver comprises a unique lymphocyte population, i.e., extrathymic alpha beta T cells with TcR of intermediate intensity. In the present study, we attempted to determine what pretreatments were appropriate to isolate hepatic mononuclear cells (MNC) containing such intermediate alpha beta TcR cells in mice. Hepatic MNC were isolated from untreated mice and mice subjected to either bleeding or liver perfusion, and the intermediate alpha beta TcR cells in each preparation were identified. For reasons of simplicity, cell purity and cell yields, hepatic lymphocytes should be obtained from mice subjected to total bleeding. Additional information on extrathymic alpha beta T cells obtained by using the recommended method is also presented.     

Polymeric chiral crown ethers, 4. Substituent effects of methyl and phenyl groups in the 3,3′-positions on chiral recognition of poly(crown ether)s synthesized by cyclopolymerization of divinyl ethers derived from 1,1′-bi-2-naphthol

Chiral poly(crown ether)s were synthesized by cationic cyclopolymerization of (S)-2,2′-bis(2-vinyloxyethoxy)-3,3′-dimethyl-1,1′-binaphthyl [(S)- 1b ] and (R)-2,2′-bis[2-(2-vinyloxyethoxy)-ethoxy]-3,3′-dimethyl (or 3,3′-diphenyl)-1,1′-binaphthyl [(R)- 3b or (R)- 3c ]. The substituents in the 3,3′-positions of binaphthyl moiety disturb the intramolecular cyclization in the polymerization of monomer (S)- 1b , but have no influence on the cyclopolymerization tendency of monomers (R)- 3b and (R)- 3c . The polymers from (R)- 3b and (R)- 3c [(R)- 4b and (R)- 4c ] have a higher ability of chiral recognition towards a-amino acids, such as phenylglycine, phenylalanine, valine, and methionine, than the polymer from (R)- 3a [(R)- 4a ], which has no substituent in 3,3′-positions. The methyl and the phenyl substituents in the 3,3′-positions undoubtedly act as additional barrier causing an increase in the ability of chiral recognition, though the effect is less than expected from the result of model crown ethers.     

BOVINE SERUM ALBUMIN (BSA) NEPHRITIS IN RATS IV. A SEQUENTIAL EVALUATION OF MONONUCLEAR PHAGOCYTE SYSTEM (MPS) FUNCTION

A clearance kinetic study of intravenously administered ¹²⁵I-labeled aggregated human IgG (¹²⁵I-AHIgG) from the circulation and its distribution in various organs was performed weekly during the course in a model of experimental immune complex glomerulonephritis which was induced in rats immunized 8 weeks previously with 6 times a week administration of 2 mg of bovine serum albumin (BSA) for 4 weeks from week 8 to 12. The removal rates of the injected ¹²⁵I-AHIgG from the circulation were retarded in nonproteinuric rats of week 9 and 10, at almost every checked point (p-value was <0.01). The clearance in those rats with severe proteinuria returned to the level of the control and of rats in week 8. The distribution of ¹²⁵I-AHIgG in the liver 4 hours after the administration revealed a considerable decrease in non-overt proteinuric rats of weeks 9, 10, and 11. A similar tendency of decreasing depositions of the radioactivity was shown in the spleen at each 4 hours. In contrast, the uptakes in the kidney and lung at the final week of 12 were larger. Delayed clearance from the circulation and a decreasing handle of the injected macromolecule in the liver and possibly in the spleen may suggest the presence of some impairment of the MPS function in the course of this experimental glomerulonephritis.     

Intravesical chemotherapy with 4′-epi-Adriamycin in patients with superficial bladder tumors

Summary We evaluated the effects of 4-epi-Adriamycin (EPI), a derivative of Adriamycin (ADR), in intravesical instillation chemotherapy. The patients received two courses of three daily instillations of 50–80 mg EPI dissolved in 30 ml physiological saline on 3 consecutive days, with an interval of 4 days between courses. Full evaluation was possible in 33 of 35 patients with superficial bladder tumors treated with EPI. Complete response was observed in 4 cases and partial response in 14 cases, giving a response rate of 55%. Side effects such as pollakiuria and pain on micturition occurred in 9 cases. EPI appears to be an effective agent for intravesical instillation chemotherapy in patients with superficial bladder tumors.     

Hereditary Apolipoprotein A-1 Amyloidosis With Glu34Lys Mutation Treated by Liver Transplantation: A Case Report

Hereditary apolipoprotein A-1 (ApoA-1) amyloidosis is a rare disease characterized by progressive deposition of amyloid fibrils in the kidney, heart, and liver. We observed a 45-year-old male patient with liver failure. Liver dysfunction was detected at 30 years of age during an annual health check-up. At 35 years of age, renal dysfunction was also found. At 40 years of age, the pathologic findings of the liver revealed amyloid deposition. A testis biopsy specimen taken at 42 years of age to identify the cause of male infertility showed amyloid accumulation. At 43 years of age, the amyloid results and genetic profile led to a definitive diagnosis of hereditary ApoA-1 amyloidosis caused by Glu34Lys mutation. A family history was absent. Liver failure showed Budd-Chiari–like formation, including enlargement of the caudate lobe and liver congestion. Although the patient showed end-stage liver cirrhosis and renal failure, only liver transplant was performed considering the burden for a living donor. The enlarged liver (4.9 kg) showed amyloid deposition in parenchyma and the space of Disse. Amyloid also accumulated in the giant spleen. The APOA1 mutation Glu34Lys is extremely rare, and in this case hepatic failure was successfully treated by liver transplant to both replace organ function and reduce production of the amyloidogenic ApoA-1–variant protein. Careful observation for reaccumulation of amyloidosis in the organ is required.