Specific inhibition of viral ribonucleic acid replication by Gliotoxin.

Gliotoxin inhibits intracellular replication of poliovirus in HeLa cells at a stage subsequent to adsorption and penetration of virus. The sensitive step is synthesis of viral RNA: synthesis of viral protein is unaffected except as a consequence of blockade of RNA synthesis. Concentrations of gliotoxin sufficient to block viral RNA synthesis completely do not affect cellular RNA synthesis.

Effects of species composition, land surface cover, CO2 concentration and climate on isoprene emissions from European forests.

Emissions of isoprene from terrestrial vegetation are known to affect atmospheric chemical properties, like its oxidation capacity or the concentration of tropospheric ozone. The latter is of concern, since besides being a potent greenhouse gas, O(3) is toxic for humans, animals, and plants even at relatively low concentrations. Isoprene-emitting forests in the vicinity of NO(x) pollution sources (like cities) can contribute considerably to O(3) formation, and to the peak concentrations observed during hot summer weather. The biogenic contribution to O(3) concentrations is generally thought to increase in a future, warmer climate--pushing values beyond health thresholds possibly even more frequently and over larger areas--given that emissions of isoprene are highly temperature-dependent but also because of the CO(2) fertilisation of forest productivity and leaf growth. Most projections of future emissions, however, do not include the possible CO(2)-inhibition of leaf isoprene metabolism. We explore the regional distribution of emissions from European woody vegetation, using a mechanistic isoprene-dynamic vegetation model framework. We investigate the interactive effects of climate and CO(2) concentration on forest productivity, species composition, and isoprene emissions for the periods 1981-2000 and 2081-2100. Our projection of future emissions includes a direct CO(2)-isoprene inhibition. Across the model domain, we show that this direct effect has the potential to offset the stimulation of emissions that could be expected from warmer temperatures and from the increased productivity and leaf area of emitting vegetation. Changes in forest species composition that may result from climate change can play a substantial additional role in a region's future emissions. Changes in forest area or area planted in woody biofuels in general are not noticeable in the overall European forest isoprene budget, but--as was the case for changes in species composition--may substantially affect future projections in some regions of the continent.

Role of plasminogen activator in the morphological alterations induced by derivatives of adenosine cyclic 3':5'-monophosphate in hepatoma tissue culture cells.

We have reported previously that derivatives of adenosine cyclic 3':5'-monophosphate dramatically stimulate the activity of plasminogen activator (PA), an arginine-specific serine protease, in HTC rat hepatoma cells. We report here that these derivatives also cause striking alterations in hepatoma tissue culture cell morphology. Because PA has been shown to alter cell morphology in other cell lines, we investigated whether the morphological changes induced by cyclic nucleotides were mediated by the stimulation of PA activity. Alterations in PA activity, measured by the plasminogen-dependent solubilization of 125I-labeled fibrin, and in cell morphology, detected by evaluation of cell flattening and process extension with phase-contrast microscopy, were assessed in the same cultures under various experimental conditions. Several lines of evidence clearly dissociate these two adenosine cyclic 3':5'-monophosphate-mediated phenomena. (a) The morphological changes precede increases in either cell-associated or extracellular PA activity. (b) Upon removal of the effectors, the morphological effects are completely reversed at a time when PA activity is still considerably elevated. (c) when protein synthesis is inhibited by the addition of cycloheximide, the stimulation of PA activity by cyclic nucleotides is blocked completely, whereas the induction of morphological alterations still occurs. (d) An exogenous PA, urokinase, does not elicit the characteristic changes in cell shape. We conclude that the morphological alterations induced by adenosine cyclic 3':5'-monophosphate derivatives in HTC cells are not mediated by the stimulation of PA activity and that these two membrane-associated properties are regulated independently.

Differential modulation of gene induction by glucocorticoids and antiglucocorticoids in rat hepatoma tissue culture cells.

Studies of glucocorticoid and antiglucocorticoid induction of tyrosine aminotransferase (TAT) in two rat hepatoma cell lines (Fu5-5 and HTC) are described. These studies revealed several phenomena that are not consistent with the current models of steroid hormone action: (a) TAT induction occurred at glucocorticoid levels below those required for comparable receptor occupancy in Fu5-5, but not in HTC, cells; (b) the ability of antiglucocorticoids to induce TAT is higher in Fu5-5 than in HTC cells; (c) the values of the amount of TAT agonist activity with the antiglucocorticoid dexamethasone 21-mesylate and of log10 of the dexamethasone concentration required for half-maximal induction of TAT were not constant over time but varied in a linear, reciprocal manner. This modulation was seen for several glucocorticoids and antiglucocorticoids at the level of both TAT enzyme and mRNA but not for two other glucocorticoid inducible genes in the same cells. These results, plus the fact that a similar difference in the concentration required for half-maximal TAT induction in Fu5-5 cells was seen for both glucocorticoids and cyclic AMP, argue that the modulation occurs at some point distal to receptor-steroid complex binding to the biologically active nuclear sites but proximal to translation of TAT mRNA. In order to explain these results, it is pointed out that models involving second messengers are entirely appropriate for steroid hormone action. The participation of a modulated trans-acting factor in such a model may explain the above results.

Comparison of glucocorticoid receptors in two rat hepatoma cell lines with different sensitivities to glucocorticoids and antiglucocorticoids.

Two independently derived rat hepatoma cell lines, HTC and Fu5-5, differ in their sensitivities to both glucocorticoids and antiglucocorticoids, despite virtually identical number and affinity of glucocorticoid receptors. The present study further examined both receptors for differences that could account for the nonidentical responses of the two cell lines. HTC and Fu5-5 cell receptors that were covalently labeled with [3H] dexamethasone 21-mesylate ([3H]DM) had the same mol wt of about 97,000 on sodium dodecyl sulfate-polyacrylamide gel electrophoresis and the same isoelectric point of about 6.4 by nonequilibrium pH gradient electrophoresis. Limited proteolysis of receptor-[3H]DM complexes with three different proteases generated identical protease-specific digestion patterns regardless of the cellular origin of the receptors. Receptor-[3H]dexamethasone complexes prepared from either Fu5-5 or HTC cells bound calf thymus DNA with the same affinity in vitro. In intact cells, the intracellular distribution of receptor-dexamethasone or receptor-DM complexes at equilibrium was almost identical in the two cell lines. Thus, we detected no differences in the size, sequence, or net charge of Fu5-5 or HTC cell receptors; additionally, there were no significant differences in steroid uptake, receptor binding, or activation, translocation, and nuclear binding of receptor-steroid complexes. However, the DM labeling efficiency, calculated as the percentage of total receptors covalently labeled by DM, was higher in HTC cells (65.9 +/- 12.9%; n = 5) than in Fu5-5 cells (39.3 +/- 7.7%; n = 5). The labeling efficiency of DM correlated inversely with its ability to induce tyrosine aminotransferase activity, suggesting that DM forms noncovalent, as well as covalent, complexes in vivo which mediate the glucocorticoid and antiglucocorticoid activities of DM, respectively. Further research is required to identify the factor(s) that influences DM labeling efficiency, thereby affecting the amount of DM agonist activity and, possibly, the sensitivity of the cells to glucocorticoids.

Selenium and acute alcoholism.

Selenium status was investigated in nine inebriated alcoholic subjects by collecting serial samples of blood and urine during hospitalization for alcohol detoxification. The selenium content of various alcoholic beverages and samples of hospital diets was also determined. Mean plasma selenium level and mean urinary excretion of selenium were both significantly lower (p less than 0.01) in alcoholic subjects as compared to the control subjects at the time of admission. Furthermore, the daily dietary intake of selenium before hospitalization was estimated to be below the recommended safe and adequate range in the majority of the alcoholic subjects. The selenium content of various alcoholic beverages was determined to be very low (0.1 to 0.8 microgram/dl). These data suggest that selenium depletion does occur in alcoholic subjects most likely due to poor dietary intake. Selenium depletion in this group of patients is corrected by cessation of ethanol ingestion and adequate dietary intake without additional selenium supplementation.

Design and biological activity of (S)-4-(5-([1-(3-chlorobenzyl)-2-oxopyrrolidin-3-ylamino]methyl)imidazol-1-ylmethyl)benzonitrile, a 3-aminopyrrolidinone farnesyltransferase inhibitor with excellent cell potency.

The synthesis, structure-activity relationships, and biological properties of a novel series of imidazole-containing inhibitors of farnesyltransferase are described. Starting from a 3-aminopyrrolidinone core, a systematic series of modifications provided 5h, a non-thiol, non-peptide farnesyltransferase inhibitor with excellent bioavailability in dogs. Compound 5h was found to have an unusually favorable ratio of cell potency to intrinsic potency, compared with other known FTIs. It exhibited excellent potency against a range of tumor cell lines in vitro and showed full efficacy in the K-rasB transgenic mouse model.

Children's bicycle helmet attitudes and use. Association with parental rules. The Pediatric Practice Research Group.

BACKGROUND: Previous studies have assessed the attitudes of parents and children toward bicycle helmet ownership and use in various settings, but they have not addressed the role of parental rules in promoting bicycle helmet use by children. OBJECTIVES: To further explore the attitudes of parents and children at pediatric practices toward bicycle helmet ownership and use by children and to assess the role of parental rules in promoting bicycle helmet use by children. DESIGN: One hundred sixty-nine 5- to 14-year-old children who owned bicycles and their parents were surveyed during well-child visits at 5 general pediatric practices in the Chicago, Ill, area. One hundred twenty-nine families were represented. Of the children, 60% were aged 5 to 9 years, and 50% were girls. RESULTS: Forty-eight children (28%) reported helmet ownership. Of the helmet owners, 21 (45%) reported helmet use; thus, the overall percentage of helmet use was 12%. Helmet ownership by children was significantly (P < .05) related to parental characteristics: educational level, race, perceived effectiveness of bicycle helmets, seat belt use, and parental helmet ownership. The most common reasons parents gave for lack of helmet ownership by children were "never thought about purchasing" a helmet (35%), "never got around to purchasing" a helmet (29%), "child wouldn't wear it anyway" (26%), and the bicycle helmet was "too expensive" (16%). Only 33% of the parents reported hearing about helmets from their children's pediatrician, but 40% of these parents regarded pediatricians as their most important information source. Of the children who did not own helmets, 64% said they would wear a bicycle helmet if they had one, a more frequent comment for 5- to 9-year-old children than 10- to 14-year-old children (76% vs 49%, P < .01). The most common reasons for not wearing a helmet among owners were as follows: forgot or lost it and not needed. The most common reasons for not wearing a helmet among nonowners were as follows: uncomfortable and appearance or perception of others. Children who owned helmets and whose parents had a strict rule about wearing helmets were more likely to always wear their helmets than helmet owners whose parents had a partial rule or no rule (88% vs 19%, P < .001). CONCLUSIONS: Parental rules are associated with bicycle helmet use by children. Pediatricians may increase helmet use rates by promoting strict parental helmet rules as part of their anticipatory guidance regarding bicycle safety. More research about the effectiveness of this strategy is needed.

Relation of sympathy and personal distress to prosocial behavior: a multimethod study.

Assessed sympathy and personal distress with facial and physiological indexes (heart rate) as well as self-report indexes and examined the relations of these various indexes to prosocial behavior for children and adults in an easy escape condition. Heart rate deceleration during exposure to the needy others was associated with increased willingness to help. In addition, adults' reports of sympathy, as well as facial sadness and concerned attention, were positively related to their intention to assist. For children, there was some indication that report of positive affect and facial distress were negatively related to prosocial intentions and behavior, whereas facial concern was positively related to the indexes of prosocial behavior. These findings are interpreted as providing additional, convergent support for the notion that sympathy and personal distress are differentially related to prosocial behavior.

Early results of right ventricular-pulmonary artery conduits in patients under 1 year of age.

OBJECTIVES: Management strategies for the repair of many complex heart defects require the implantation of a valved conduit between the right ventricle (RV) and the pulmonary artery (PA), often using aortic or pulmonary homograft valves. Their limited availability, however, has led to the development and use of new conduits. We retrospectively compared our experience with small homografts in patients of less than 1 year of age with the TissueMed bioprosthetic valved conduit. METHODS: From March 1994 to November 1997 29 patients in their first year of life underwent conduit implantation for complex heart defects. These were retrospectively reviewed in order to determine the incidence of death or conduit stenosis. Seventeen patients received homografts and 12 TissueMed conduits. RESULTS: Diagnoses and operative details including conduit size were similar in the two groups and in all cases complete repair of the underlying defect was carried out. Early post-operative mortality was 4/17 (23.5%) in the homograft group and 3/12 (25%) in the TissueMed group. Echo Doppler evaluation within 1 month of operation showed no right ventricular outflow tract (RVOT) obstruction in any of the survivors. In the TissueMed group 8/9 (77%) survivors have gone on to develop significant RVOT obstruction within 12 months of operation. There have been three late deaths in this group all related to severe RVOT obstruction. Two patients died during an attempt at balloon dilatation and one patient died of progressive right heart failure. Five patients had successful replacement of the TissueMed conduit. One child remains well with no evidence of RVOT obstruction. At operation to replace conduit, or at autopsy, the stenoses were related to the deposition of fibrous tissue at the anastomotic suture lines. In the homograft group none of the survivors developed RVOT obstruction during the first 12 months post-operatively. There was one late death (non-cardiac in origin) and one child is awaiting conduit replacement 40 months after initial implantation for obstruction. CONCLUSIONS: The homograft is a satisfactory conduit for re-establishment of RV-PA continuity in infancy. Further work needs to be undertaken in order to elucidate the mechanisms of early graft failure in bioprosthetic conduits if these are to be a suitable alternative for RV outflow reconstruction in infants.

Feedback inhibition of the synthesis of an antibiotic: aurodox (X-5108).

The effect of aurodox on its own biosynthesis by Streptomyces goldiniensis was studied. It was found that addition of exogenous aurodox inhibits further accumulation of aurodox by the antibiotic-producing culture. Both long term fermentation studies with aurodox-14C and precursor incorporation studies over short time periods indicated that aurodox synthesis was regulated by feedback inhibition. The concentration of aurodox required to completely block further synthesis of the antibiotic was about 400 microng/ml. This is the same as the maximum concentration of aurodox normally accumulated by the culture used in this study. Antibiotic synthesis was inhibited not only by aurodox but also by some structural analogs of aurodox including several having no antibacterial activity. This effect was immediate and readily reversible, indicating that it could be due to inhibition of an enzyme(s) involved in the biosynthesis of aurodox.

Induction of resistance to aurodox by aurodox in the antibiotic-producing culture, Streptomyces goldiniensis.

The sensitivity of protein and aurodox synthesis to aurodox was examined in relationship to the development of resistance to aurodix on Streptomyces goldiniensis during fermentation. It was found that the culture remains sensitive to the antibiotic as long as no aurodox is present in the medium. Resistance only develops when aurodox is present, either exogenously added or endogenously synthesized by the culture. These observations suggest that the development of resistance is an inducible process, and evidence is presented indicating that aurodox induces a specific resistance system in S. goldiniensis.

Isolation of novel antibiotics X-14667A and X-14667B from Streptomyces cinnamonensis subsp. urethanofaciens and their characterization as 2-phenethylurethanes of monensins B and A.

Antibiotics X-14667A (1) and X-14667B (2) are novel monovalent polyether antibiotics of the spiroketal type isolated from fermented cultures of Streptomyces cinnamonensis subsp. urethanofaciens together with monensin (3), its lower homolog, factor B (4) and 1,3-diphenethylurea (6). By a combination of microanalysis, mass spectrometry and 13C nmr, antibiotics X-14667A and B have been shown to be natural 2-phenethylurethanes of monensin B and A respectively. Both structures have been confirmed by reacting the appropriate monensin with 2-phenethylisocyanate to yield semi-synthetic compounds that are identical to the natural products.

X-14547A, a new ionophorous antibiotic produced by Streptomyces antibioticus NRRL 8167. Discovery, fermentation, biological properties and taxonomy of the producing culture.

X-14547A is a novel antibiotic produced by a new strain of Streptomyces antibioticus (NRRL 8167). The antibiotic is active in vitro against Gram-positive bacteria and is capable of complexing and transporting divalent as well as monovalent metal cations.

Novel polyether antibiotics X-14873A, G and H produced by a Streptomyces: taxonomy of the producing culture, fermentation, biological and ionophorous properties of the antibiotics.

Novel polyether antibiotics X-14873A, X-14873G, and X-14873H are produced by the fermentation of Streptomyces sp. X-14873 (ATCC 31679). This report presents taxonomic studies and fermentation conditions for the antibiotic producing culture. The antibiotics are mainly active against Gram-positive bacteria. The ionophore properties of X-14873A are also characterized.

Isolation and characterization of a novel polyether antibiotic of the pyrrolether class, antibiotic X-14885A.

Antibiotic X-14885A is a polyether antibiotic belonging to the class of these natural acid ionophores known as pyrrolethers. The structure of the antibiotic was elucidated by X-ray crystallographic analysis of the hydrated sodium salt, which crystallized as a tetramer containing four antibiotic and water molecules and four atoms of sodium. Antibiotic X-14885A differs from the most well-known member of the class, A-23187, in two respects: the aromatic N-methylamino group present in the latter is replaced by a phenolic hydroxyl, and one of the four aliphatic methyls is replaced by a proton. Antibiotic X-14885A is active against Gram-positive bacteria and the spirochete, Treponema hyodysenteriae.

X-14885A, a novel divalent cation ionophore produced by a Streptomyces culture: discovery, fermentation, biological as well as ionophore properties and taxonomy of the producing culture.

Antibiotic X-14885A is a novel divalent cation ionophore produced by a Streptomyces culture isolated from soil sample collected in Wyoming. Its cation binding sequence has been found to be: Mg2+ greater than Ca2+, Sr2+ greater than Ba2+ much greater than Li+, Na+, Rb+, K+, Cs+.

Evaluating physical therapists' perception of empowerment using Kanter's theory of structural power in organizations.

BACKGROUND AND PURPOSE: Little is known about physical therapists' perceptions of empowerment. In this study, Kanter's theory of structural power in organizations was used to examine physical therapists' perceptions of empowerment in a large Canadian urban teaching hospital. Kanter's theory, which has been studied extensively in the nursing profession, proposes that power in organizations is derived from access to information, support, resources, opportunity, and proportions. SUBJECTS AND METHODS: A convenience sample of physical therapists who had been working in the hospital longer than 3 months was used to determine the scores for the physical therapists' ratings of empowerment using the Conditions of Work Effectiveness Questionnaire. RESULTS: Physical therapists' scores were similar to reported staff nurses' scores for access to support, information, resources, and opportunity (mean=2.89, 2.91, 2.62, 3.25, respectively). Physical therapists' scores were higher than the majority of reported staff nurses' and nurse managers' scores for access to sources of informal and formal power structures (mean=2.81 and 3.29, respectively). There was a relationship between the empowerment score and the physical therapists' global rating of empowerment. Unlike studies of nurses, there were no relationships when demographic attributes and empowerment scores were examined. DISCUSSION AND CONCLUSION: Evidence for the validity of Kanter's theory of empowerment was found. Kanter's theory can provide physical therapists and their managers with a useful framework for examining critical organizational factors (access to information, support, opportunity, and resources) that contribute to employees' perceptions of empowerment. A baseline measure for comparing future empowerment scores of this sample is available. Further work to examine the application of Kanter's theory to other samples of physical therapists appears to be warranted.

Nurse-physician collaboration in an intensive care unit.

BACKGROUND: Collaborative interaction between nurses and physicians on critical care units is significantly related to mortality rates and length of stay in the units. For this reason, collaborative interaction should be an integral part of quality improvement programs. OBJECTIVES: To examine perspectives of nurses and physicians on collaborative interaction in an intensive care unit, to examine differences between groups in perceptions of collaborative interaction in the unit, and to compare this unit with units examined in a national study. METHODS: A modification of the ICU Nurse-Physician Questionnaire was used to collect data from 35 nurses and 45 physicians. Descriptive statistics and analysis of variance were used to determine group scores and to examine differences between groups. RESULTS: The level of collaborative interaction in the unit was high. However, nurses and physicians and all other staff groups examined except one had significant differences in perceptions of collaborative interaction. The high level of collaborative interaction was confirmed by a comparison of the results with the results from a national sample. CONCLUSIONS: Critical care units can use this example to incorporate an assessment of the level of collaborative interaction into their quality improvement program.

End-of-life care in the intensive care unit: a challenge for nurses.

Results from several research studies combined with increasing public tensions surrounding physician-assisted suicide have fueled a growing awareness of the inadequacies of end-of-life care. Investigators also suggest that intensive care unit nurses have a limited role in end-of-life decision making and care planning. This article explores cultural issues influencing end-of-life care in intensive care units, explores factors surrounding the limited involvement of critical care nurses in end-of-life decision making and care planning, and offers recommendations for changing nursing practice. Because improving end-of-life care will require cultural changes, an understanding of the cultural issues involved is needed. Recommendations for changing nursing practice include a model of end-of-life care that incorporates the goals of both cure and comfort care, as well as a shared decision-making process. Nurses are essential to improving end-of-life care in today's intensive care units.