To 600 Da, penetrate only slowly both through porin channels 16 ; and through bilayer regions of the outer membrane 20 ; . In fact, we are not aware of any previous report that the NorA Bmr-type transporter activity could be significantly inhibited by reserpine or verapamil in gram-negative bacterial cells, with their outer membrane barrier. Several spontaneous mutants with increased resistance to norfloxacin were isolated by plating about 108 cells of ATCC 25285 on GAM agar plates containing 16 g of norfloxacin per ml. One of these single-step mutants, NFX06, appeared to be more resistant to other agents and was examined in detail by determining precise MICs with gradient plates 5 ; . As seen in Table 1, it became more resistant to ethidium bromide and puromycin, known substrates of the NorA Bmr multidrug efflux pump 13 ; , but the MICs of cefoxitin, tetracycline, and erythromycin remained essentially unchanged. Among fluoroquinolones, practically no change was seen with the more lipophilic sparfloxacin, again as reported for the NorA pump 23 ; , and the MIC of cetyltrimethylammonium bromide, a substrate of NorA Bmr 13 ; , showed a modest increase. These results are consistent with those of the inhibitor studies and suggest that at least some of the fluoroquinolone efflux in B. fragilis occurs through a pump with a specificity and inhibitor profile resembling that of NorA Bmr, an efflux pump with a more limited specificity than the AcrAB MexAB-type pumps. This conclusion is also consistent with the observation that many B. fragilis strains are susceptible, in spite of their poorly permeable outer membrane see reference 24 ; , to erythromycin, chloramphenicol, and tetracycline, all excellent substrates of the pumps of the latter type. We are currently trying to identify the gene s ; responsible for the drug efflux activity in B. fragilis through transposon mutagenesis. As far as we are aware, this is the first report of a drug efflux process in an obligate anaerobe, although such processes have been known for aerotolerant organisms with essentially anaerobic metabolism, such as wild-type strains of Enterococcus hirae 12 ; and Enterococcus faecalis 11 ; and drug-resistant mutants of Lactococcus lactis 3 ; and Streptococcus pneumoniae 2 ; . The possible efflux of other drugs should be examined for B. fragilis and other obligate anaerobes, many of which are known to be resistant, either intrinsically or in an acquired manner, to a wide range of antibiotics 7, 21. Blastomycosis has rarely been reported in AIDS. Therapeutic recommendations include amphotericin B for lifethreatening forms and itraconazole in other cases. Although, no definitive recommendation can be given, itraconazole is probably the best secondary prophylaxis for AIDS patients with blastomycosis.
Figure 1 Effect of infusion of tyramine into the right brachial artery on the hand blood flow HBF ; of a patient with Raynaud's phenomenon without pretreatment A ; , forty minutes after intra-arterial infusion of 0.5 mg of reserpine into the right brachial artery B ; , and after 5 weeks of oral administration of reserpine 1 mg day C.

FIG. 2 Effect of biocide concentration on fluorescence parameters Fo, Fm, Fv Fm ; in Coccomyxa ML 19. Data expressed as mean values SD cont control; du DCMU; nd Neo Desogen; m Metatin N58-10 101.

Tion factors, activation of signal transduction pathways, and alterations of growth factor receptors. If each type of genetic lesion found in AML involved a distinct process to cause leukemia, then "targeted" therapy directed at specific genetic lesions would be futile--quite simply, there would be too many potential targets. However, it appears that many of the pathways perturbed in leukemogenesis interact, so that a limited number of specific targets may be useful in a wide variety of AML cases. Indeed, if multiple genetic abnormalities are needed to cause and sustain AML, then the blunting of a single aberrant pathway may be enough to eliminate the proliferative advantage and curb the disease. In this short review we will examine the signaling pathways involved in leukemogenesis, with specific emphasis as to how these pathways can be utilized as targets for novel therapy. Normal Signal Transduction Signal transduction pathways are designed to translate extracelluar signals e.g., stimulation to respond to cytokine ligands, interferons ; into intracellular action proliferation, differentiation, survival ; . Perhaps the best understood pathway involves signaling utilizing the ras family of guanosine nucleotidases GTPases ; . A highly simplified cartoon of the ras signal transduction pathway is shown in Figure 4 see color page 541 ; . The most important components include the following: Receptor tyrosine kinase RTK ; : These ligand binding receptors include PDGF, Fms, c-kit, and Flt 3.1-4 In general their structure includes an extracellular ligand binding region consisting of 5 immunoglobulin-like domains, transmembrane and juxtamembrane domains, and an intracellular domain with kinase activity Figure 5; see color page 541 ; . Grb-2 and SOS: Grb-2 is an adaptor protein that functionally bridges the association of the RTK with ras. SOS is a guaninine nucleotide exchange protein that facilitates ras-GDPras-GTP exchange. Ras. Harvey H ; , Kirsten K ; , and N-ras are 21 kd GDP GTP-binding proteins that serve as the hub of signal transduction.5, 6 All three ras proteins are expressed in most tissues, but the constellation of muta and revlimid.