In vitro activity of SCH-56592 and comparison with activities of amphotericin B and itraconazole against Aspergillus spp

In this study, we investigated the in vitro activity of SCH-56592 (SCH), a new triazole antifungal agent. We compared the activity of SCH with those of itraconazole (ITZ) and amphotericin B (AB) against 60 clinical isolates of Aspergillus spp. by using a microtiter format. Incubation was done at 37 degrees C for 48 h, and MIC endpoints (no growth) were read visually. The medium used for all of the drugs was RPMI 1640 buffered with morpholinepropanesulfonic acid (MOPS) and supplemented with 2% glucose. MICs and minimum fungicidal concentrations (MFCs; killing of > or = 99.99%) were measured for all isolates. The geometric mean (GM) MICs and ranges (in micrograms per milliliter) were as follows: SCH, 0.09 and < or = 0.01 to 1; ITZ, 0.25 and 0.06 to 32; AB, 1.46 and 0.25 to 32. Aspergillus terreus (n = 7) was markedly more susceptible to SCH (GM, 0.05 microg/ml) and ITZ (GM, 0.07 microg/ml) than to AB (GM, 8.8 microg/ml). For all isolates, the GM MFCs and ranges (in micrograms per milliliter) were as follows: SCH, 3.64 and 0.125 to 16; ITZ, 15.09 and 0.125 to 32; AB, 10.3 and 1 to 32. In the drug concentration range tested, 71, 32, and 64% of the isolates against which SCH, ITZ, and AB, respectively, were tested were killed. A reproducibility study was performed with 20% of the isolates; for 11 of the 12 isolates retested, the MIC was the same or within 1 well of the original MIC of each drug. Therefore, in vitro mould testing of SCH is feasible and reproducible. SCH was found to be very active against all species of Aspergillus and at lower concentrations than either ITZ or AB.     

Inorganic arsenic: a need and an opportunity to improve risk assessment

This paper presents views on the current status of (inorganic) arsenic risk assessment in the United States and recommends research needed to set standards for drinking water. The opinions are those of the Arsenic Task Force of the Society for Environmental Geochemistry and Health, which has met periodically since 1991 to study issues related to arsenic risk assessment and has held workshops and international conferences on arsenic. The topic of this paper is made timely by current scientific interest in exposure to and adverse health effects of arsenic in the United States and passage of the Safe Drinking Water Act Amendment of 1996, which has provisions for a research program on arsenic and a schedule mandating the EPA to revise the maximum contaminant level of arsenic in drinking water by the year 2001. Our central premise and recommendations are straightforward: the risk of adverse health effects associated with arsenic in drinking water is unknown for low arsenic concentrations found in the United States, such as at the current interim maximum contaminant level of 50 microg/l and below. Arsenic-related research should be directed at answering that question. New epidemiological studies are needed to provide data for reliable dose-response assessments of arsenic and for skin cancer, bladder cancer, or other endpoints to be used by the EPA for regulation. Further toxicological research, along with the observational data from epidemiology, is needed to determine if the dose-response relationship at low levels is more consistent with the current assumption of low-dose linearity or the existence of a practical threshold. Other recommendations include adding foodborne arsenic to the calculation of total arsenic intake, calculation of total arsenic intake, and encouraging cooperative research within the United States and between the United States and affected countries.     

Clinically silent microemboli in patients with artificial prosthetic aortic valves are predominantly gaseous and not solid

BACKGROUND AND PURPOSE: Microembolic signals (MES) are frequently observed by transcranial Doppler ultrasound after prosthetic heart valve implantation. Whether these MES are due to solid or gaseous particles is uncertain. We hypothesized that MES are gaseous and that if they are due to cavitation effects, their occurrence should respond to changes of dissolved oxygen concentration in the blood. METHODS: Transcranial monitoring of MES was performed in five patients with prosthetic aortic valves, who inspired 100% oxygen through a facial mask. In one patient 100% oxygen was administered under hyperbaric (2.5 kPa) conditions in a hyperbaric chamber. RESULTS: Inspiration of 100% oxygen reduced the total number of MES from 96/30 min to 2/30 min. Increasing the concentration of dissolved oxygen in the hyperbaric chamber led to an increase from 0.3 MES per minute (1.0 kPa) to 0.9 MES per minute (2.5 kPa). CONCLUSIONS: The dependence of occurrence of MES in patients with prosthetic cardiac valves on the oxygen partial pressure in blood provides strong evidence that these microemboli are gaseous.     

Rates of spontaneous mutation in an archaeon from geothermal environments

To estimate the efficacy of mechanisms which may prevent or repair thermal damage to DNA in thermophilic archaea, a quantitative assay of forward mutation at extremely high temperature was developed for Sulfolobus acidocaldarius, based on the selection of pyrimidine-requiring mutants resistant to 5-fluoro-orotic acid. Maximum-likelihood analysis of spontaneous mutant distributions in wild-type cultures yielded maximal estimates of (2.8 +/- 0.7) x 10(-7) and (1.5 +/- 0.6) x 10(-7) mutational events per cell per division cycle for the pyrE and pyrF loci, respectively. To our knowledge, these results provide the first accurate measurement of the genetic fidelity maintained by archaea that populate geothermal environments. The measured rates of forward mutation at the pyrE and pyrF loci in S. acidocaldarius are close to corresponding rates reported for protein-encoding genes of Escherichia coli. The normal rate of spontaneous mutation in E. coli at 37 degrees C is known to require the functioning of several enzyme systems that repair spontaneous damage in DNA. Our results provide indirect evidence that S. acidocaldarius has cellular mechanisms, as yet unidentified, which effectively compensate for the higher chemical instability of DNA at the temperatures and pHs that prevail within growing Sulfolobus cells.     

Inhalation teratology and reproduction studies with 1,1-dichloro-2,2,2-trifluoroethane (HCFC-123)

HCFC 123 is one of the chemicals being developed as a replacement for CFC 11 in refrigerant and solvent applications. Supplementing earlier rat teratology studies, a rabbit inhalation teratology study was conducted. In addition, one-generation and two-generation inhalation reproduction studies were conducted. In the teratology study, the pregnant rabbits were exposed to levels of 0 (control), 500, 1500, and 5000 ppm, 6 hr per day from Days 6 through 18 of gestation. Slight body weight losses and reduced food consumption were seen in does in all three exposure level groups. This response followed an exposure-related pattern. There were no other signs of maternal toxicity. There was also no evidence of treatment-related effects on the kits. A probe one-generation reproduction study was conducted. In this study four groups of 12 male and 12 female rats were exposed to vapors of HCFC 123 6 hr per day, 7 days per week from 4 weeks prior to mating through weaning of their offspring. The exposure levels for this study were 0 (control), 300, 1000, and 5000 ppm. There were no effects on mating and fertility, or on pup survival or birth weight. A two-generation study was subsequently conducted. In this study, five groups of 32 male and female rats were exposed to HCFC 123 from 6 weeks of age through weaning. From the offspring of these animals, groups of 28 males and females were selected for the F1 generation. These animals were exposed to HCFC 123 from weaning (4 weeks of age) through weaning of the F1 generation. All exposures were 6 hr per day, 7 days per week. The exposure levels for this study were 0 (control), 30, 100, 300, and 1000 ppm. There were no effects on any of the fertility or reproductive indices measured. As with prior studies, decreases in serum triglyceride levels were seen. Pup survival and birth weight were unaffected by treatment. Pup body weight gain was lower in all treatment groups during nursing, following an exposure-related pattern. Since weight gain for the F1 animals was normal following weaning, this depression of body weight gain may be related to the depression of serum triglycerides. In addition, liver weights of the adult rats exposed to levels of 100 ppm and higher of HCFC 123 were higher than controls, histological examination revealed only hepatic enlargement and vacuolation. It was concluded that exposure to HCFC 123 did not cause reproductive effects although it did effect the body weight gain of the offspring during lactation.     

Decreased risk of subsequent colonic cancer in patients undergoing polypectomy after barium enema: analysis based on data from the preendoscopic era

OBJECTIVE: Published data from the Mayo Clinic gathered during the preendoscopic era were analyzed to show that the risk of subsequent colonic carcinoma is reduced in patients with benign-appearing polyps that are revealed by radiology who then undergo polypectomy. MATERIALS AND METHODS: Data from the Mayo Clinic gathered during a 6-year period before the availability of endoscopy were used to determine the effect on the subsequent risk of colonic carcinoma if the benign-appearing polyps initially revealed by radiology had been removed rather than left in place and followed up by serial barium enemas. Data were from 226 patients with benign-appearing polypoid lesions of the colon that were 1 cm in diameter or larger and had been followed up by periodic barium enemas. The period of radiologic surveillance was 12-229 months (mean, 68 months). Between two and 17 barium enemas (mean, 5.2) were performed on each patient. The clinical follow-up period was 12-242 months (mean, 140 months). RESULTS: Twenty-one adenocarcinomas developed at the site of the index polypoid lesion as found on follow-up barium enema examinations of these patients. Eleven additional adenocarcinomas of the colon were found at sites remote from that of the index lesion. If the index polyp had been removed when initially diagnosed radiologically, 66% fewer subsequent carcinomas would have occurred in these patients during the average of 11 years of clinical follow-up. CONCLUSION: Excision of benign-appearing polyps found on initial barium enema examinations would result in a significant decrease in the subsequent risk of colonic adenocarcinoma.     

Modulation of the Rev-RRE interaction by aromatic heterocyclic compounds

The HIV-1 Rev protein regulates the nucleocytoplasmic distribution of viral precursor RNAs that encode HIV-1 structural proteins. Rev-mediated viral RNA expression requires a sequence-specific interaction between Rev and a viral RNA sequence, the Rev responsive element (RRE). Because the Rev-RRE interaction is essential for HIV-1 replication, anti-viral agents that selectively block this interaction may be effective anti-HIV-1 therapeutics. Here, we show that certain aromatic heterocyclic compounds, in particular, a tetracationic diphenylfuran, AK.A, can block binding of Rev to its high-affinity viral RNA binding site. AK.A abolishes Rev-RRE interactions at concentrations as low as 0.1 microM. Inhibition appears to be selective and results from competitive binding of the drug to a discrete region within the Rev binding site. Interestingly, the molecular basis for the AK.A-RNA interaction, as well as the mode of RNA binding differs from previously described aminoglycoside Rev inhibitors. Analysis of a variety of aromatic heterocyclic compounds and their derivatives reveals stereo-specific features required for the inhibition. Our results further demonstrate the feasibility of identifying and designing small molecules that selectively block viral RNA-protein interactions.     

Mean energy, energy-range relationships and depth-scaling factors for clinical electron beams

Using Monte Carlo simulations we have studied the electron mean energy, Eo, and the most probable energy, Eo,p, at the phantom surface and their relationships with half-value depth, R50, and the practical range, Rp, for a variety of beams from five commercial medical accelerators with an energy range of 5-50 MeV. It is difficult to obtain a relation between R50 and Eo for all electrons at the surface because the number of scattered lower-energy electrons varies with the machine design. However, using only direct electrons to calculate Eo, there is a relationship which is in close agreement with that calculated using monoenergetic beams by Rogers and Bielajew [Med. Phys. 13, 687-694 (1986)]. We show that the empirical formula Eo,p = 0.22 + 1.98Rp + 0.0025R2p describes accurately the relationship between Rp and Eo,p for clinical beams of energies from 5 to 50 MeV with an accuracy of 3%. The electron mean energy, Ed, is calculated as a function of depth in water as well as plastic phantoms and is compared both with the relation, Ed = Eo (1-d/Rp), employed in AAPM protocols and with values in the IAEA Code of Practice. The conventional relations generally overestimate Ed over the entire therapeutic depth, e.g., the AAPM and IAEA overestimate Ed at dmax by up to 20% for an 18 MeV beam from a Clinac 2100C. It is also found that at all depths mean energies are 1%-3% higher near the field edges than at the central axis. We calculated depth-scaling factors for plastic phantoms by scaling the depth in plastics to the water-equivalent depth where the mean energies are equal. The depth-scaling factor is constant with depth in a given beam but there is a small variation ( < 1.5%) depending on the incident beam energies. Depth-scaling factors as a function of R50 in plastic or water are presented for clear polystyrene, white polystyrene and PMMA phantom materials. The calculated depth-scaling factor is found to be equal to R50water/R50plastic. This is just the AAPM definition of effective density but there are up to 2% discrepancies between our calculated values and those recommended by the AAPM and the IAEA protocols. We find that the depth-scaling factors obtained by using the ratio of continuous-slowing-down ranges are inaccurate and overestimate our calculated values by 1%-2% in all cases. We also find that for accurate work, it is incorrect to use a simple 1/r2 correction to convert from parallel beam depth-dose curves to point source depth-dose curves, especially for high-energy beams.     

Genetically transferred central and peripheral immune tolerance via retroviral-mediated expression of immunogenic epitopes in hematopoietic progenitors or peripheral B lymphocytes

BACKGROUND: Based on the hypothesis that IgGs are potent tolerogens and that immature lymphohematopoietic antigen-presenting cells (APC), and even mature peripheral B cells, may be effective APC for tolerance induction, we designed an immunoglobulin fusion protein retroviral expression vector to test the role of B cells in a novel gene therapy strategy for the transfer of immune tolerance. METHODS: An immunodominant epitope (residues 12-26 of the lambda repressor cI protein) was fused in frame to an IgG heavy chain in a retroviral vector, which was used to infect either bone marrow cells or activated peripheral B lymphocytes. These cells were transferred into syngeneic recipients, who were subsequently challenged with the 12-26 peptide in adjuvant. RESULTS: Bone marrow (BM) chimeras generated with retrovirally transduced bone marrow were shown to be profoundly unresponsive to the 12-26 peptide at both the humoral and cellular levels, but were competent to respond to an unrelated protein (lysozyme or PPD). Importantly, we also show that immunocompetent adult recipients infused with transduced mature, activated B lymphocytes, are rendered unresponsive by this treatment. Surprisingly, lymphoid-deficient BM progenitors from syngeneic SCID donors could also be transduced to produce tolerogenic APC. CONCLUSIONS: Our data suggest that activated B cells are sufficient to be effective tolerogenic APC in immunocompetent adult mice, but that nonlymphoid cells may also induce tolerance in reconstituted hosts. This approach for gene-transferred tolerogenesis has the potential to be maintained indefinitely, and it requires only knowledge of cDNA sequences of target antigens.     

Featural evaluation, integration, and judgment of facial affect

The paradigm of the fuzzy logical model of perception (FLMP) is extended to the domain of perception and recognition of facial affect. Two experiments were performed using a highly realistic computer-generated face varying on 2 features of facial affect. Each experiment used the same expanded factorial design, with 5 levels of brow deflection crossed with 5 levels of mouth deflection, as well as their corresponding half-face conditions, for a total stimulus set of 35 faces. Experiment 1 used a 2-alternative, forced-choice paradigm (either happy or angry), whereas Experiment 2 used 9 rating steps from happy to angry. Results indicate that participants evaluated and integrated information from both features to perceive affective expressions. Both choice probabilities and ratings showed that the influence of 1 feature was greater to the extent that the other feature was ambiguous. The FLMP fit the judgments from both experiments significantly better than an additive model. Our results question previous claims of categorical and holistic perception of affect.