We isolated an imipenem-resistant strain, GN17203, of Pseudomonas aeruginosa. The strain produced a I8-lactamase that hydrolyzed imipenem. The I-lactamase was encoded by a 31-MDa plasmid, pMS350, which belongs to incompatibility group P-9. The plasmid conferred resistance to f8-lactams, gentamicin, and sulfonamide and was transferable by conjugation to P. aeruginosa but not to Escherichia coli. The molecular weight of the purified enzyme was estimated to be 28,000, and the isoelectric point was 9.0. The enzyme showed a broad substrate profile, hydrolyzing imipenem, oxyiminocephalosporins, 7-methoxycephalosporins, and penicillins. The enzyme activity was inhibited by EDTA, iodine, p-chloromercuribenzoate, CuS04, and HgCl2 but not by clavulanic acid or sulbactam.

We studied the effects of high intensity resistance exercise training on bone metabolism in 17 young adult Oriental males (23-31 years) by measuring sensitive biomarkers of bone formation and resorption. The subjects were assigned to a training group and a sedentary group. The training group followed a weight training program three times per week for 4 months. In the training group, serum osteocalcin concentration and serum bone-specific alkaline phosphatase activity were significantly increased within the first month after the beginning of resistance exercise training, and the elevated levels remained throughout the training period, while there was no significant change in plasma procollagen type-I C-terminal concentration. Urinary deoxypyridinoline excretion was transiently suppressed and returned to the initial value but was never stimulated during the 4 months. These results suggest that the resistance exercise training enhanced bone formation without prior bone resorption. In the sedentary group, there was no significant difference in bone metabolic markers except plasma procollagen type-I C-terminal, which continuously decreased during the experimental period. There were no significant changes in total and regional bone mineral density in either group. In conclusion, (1) resistance exercise training increased markers of bone formation, while it transiently suppressed a marker of bone resorption, and (2) such adaptive changes of bone metabolism to resistance exercise training occurred during the early period of the training, before changes in bone density were observable through densitometry. (J Bone Miner Res 1997;12:656-662)

The ATP-binding cassette (ABC) transporter ABCG2 has been implicated to play a significant role in the response of patients to medication and/or the risk of diseases. To clarify the possible physiological or pathological relevance of ABCG2 polymorphisms, we have functionally validated single nucleotide polymorphisms (SNP) of ABCG2. In the present study, based on the currently available data on SNPs and acquired mutations, we have created a total of 18 variant forms of ABCG2 (V12M,

High levels of granulocyte/macrophagecolony-stimulating factor (GM-CSF) autoantibodies are thought to cause pulmonary alveolar proteinosis (PAP), a rare syndrome characterized by myeloid dysfunction resulting in pulmonary surfactant accumulation and respiratory failure. Paradoxically, GM-CSF autoantibodies have been reported to occur rarely in healthy people and routinely in pharmaceutical intravenous immunoglobulin (IVIG) purified from serum pooled from healthy subjects. These findings suggest that either GM-CSF autoantibodies are normally present in healthy people at low levels that are difficult to detect or that serum pooled for IVIG purification may include asymptomatic persons with high levels of GM-CSF autoantibodies. Using several experimental approaches, GM-CSF autoantibodies were detected in all healthy subjects evaluated (n ‫؍‬ 72) at low levels sufficient to rheostatically regulate multiple myeloid functions. Serum GM-CSF was more abundant than previously reported, but more than 99% was bound and neutralized by GM-CSF autoantibody. The critical threshold of GM-CSF autoantibodies associated with the development of PAP was determined. Results demonstrate that free serum GM-CSF is tightly maintained at low levels, identify a novel potential mechanism of innate immune regulation, help define the therapeutic window for potential clinical use of GM-CSF autoantibodies to treat inflammatory and autoimmune diseases, and have implications for the pathogenesis of PAP. IntroductionGranulocyte/macrophage-colony-stimulating factor (GM-CSF) is a pleiotropic cytokine regulator of myeloid and other immune and nonimmune cells that is required for terminal differentiation of alveolar macrophages in the lungs and regulates the basal functional capacity of circulating neutrophils in mice and humans. [1][2][3][4][5][6][7] The paracrine, 3,8 autocrine, 9 and endocrine 10 effects of GM-CSF are mediated via heterologous cell-surface receptors 11 reported to stimulate myeloid cell survival at low GM-CSF concentrations, and survival, proliferation, differentiation, and antimicrobial functions at high concentrations. 12 Normally, GM-CSF is present at very low or undetectable levels in the serum and tissues in both mice and humans. 5,13 Nonetheless, these low levels are critical because GM-CSF-deficient mice have impaired myeloid cell functions, increased mortality from microbial infections, and a lung phenotype characterized by progressive surfactant accumulation as a result of impaired alveolar macrophage surfactant catabolism. 3,5,[14][15][16][17] Autoimmune pulmonary alveolar proteinosis (PAP) is a human disease characterized by high levels of GM-CSF autoantibodies and respiratory insufficiency as a result of pulmonary surfactant accumulation 4,18,19 with features similar in nearly every respect to those seen in GM-CSF knockout mice. 3 Disease pathogenesis is thought to be mediated by GM-CSF autoantibodies, which eliminate GM-CSF bioactivity 20 and impair GM-CSF-dependent myeloid cell functions. 5 Sustained elevation of GM-...

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