Indications of proton-dominated cosmic-ray composition above 1.6 EeV.

We report studies of ultrahigh-energy cosmic-ray composition via analysis of depth of air shower maximum (X(max)), for air shower events collected by the High-Resolution Fly's Eye (HiRes) observatory. The HiRes data are consistent with a constant elongation rate d/d[log(E)] of 47.9+/-6.0(stat)+/-3.2(syst) g/cm2/decade for energies between 1.6 and 63 EeV, and are consistent with a predominantly protonic composition of cosmic rays when interpreted via the QGSJET01 and QGSJET-II high-energy hadronic interaction models. These measurements constrain models in which the galactic-to-extragalactic transition is the cause of the energy spectrum ankle at 4x10(18) eV.

First observation of the Greisen-Zatsepin-Kuzmin suppression.

The High Resolution Fly's Eye (HiRes) experiment has observed the Greisen-Zatsepin-Kuzmin suppression (called the GZK cutoff) with a statistical significance of five standard deviations. HiRes' measurement of the flux of ultrahigh energy cosmic rays shows a sharp suppression at an energy of 6 x 10(19) eV, consistent with the expected cutoff energy. We observe the ankle of the cosmic-ray energy spectrum as well, at an energy of 4 x 10(18) eV. We describe the experiment, data collection, and analysis and estimate the systematic uncertainties. The results are presented and the calculation of the statistical significance of our observation is described.

Measurement of the flux of ultrahigh energy cosmic rays from monocular observations by the High Resolution Fly's Eye experiment.

We have measured the cosmic ray spectrum above 10(17.2) eV using the two air-fluorescence detectors of the High Resolution Fly's Eye observatory operating in monocular mode. We describe the detector, phototube, and atmospheric calibrations, as well as the analysis techniques for the two detectors. We fit the spectrum to a model consisting of galactic and extragalactic sources.

Experience of cardiac rehabilitation after coronary artery surgery: effects on health and risk factors.

OBJECTIVE: Cardiac rehabilitation (CR) programs are provided to support the recovery process following acute myocardial infarction and coronary artery bypass grafting (CABG). Attendance varies. We related attendance following CABG to severity of cardiac symptoms, general health status (Short Form-36) and prevalence of modifiable coronary artery disease (CAD) risk factors. METHODS: 209 patients due to undergo CABG were recruited and assessed preoperatively as well as at a mean of 16.4 months postoperatively. General health status was measured using the Short Form-36 questionnaire. Severity of cardiac symptoms was assessed on a visual analogue scale. Modifiable coronary artery disease risk factors (smoking, body mass index, hypertension and elevated cholesterol) and social deprivation index were noted. RESULTS: There were ten early and three late deaths. Thirteen patients withdrew consent for investigation, therefore 183 were fully studied. Of these 65.0% completed a CR programme and 24.6% did not attend any programme; 10.4% partially completed (less than 50% of time) and were excluded from analysis. Nonattenders were more likely to be smokers (P=0.002), diabetic (P=0.028) and were more from socially deprived geographical areas (P=0.013), but the proportion of patients with BMI>25, BP>140/90 or cholesterol >5.0 mmol l(-1) were the same. There were no differences in age, preoperative NYHA score, number of grafts, angina recurrence (46 vs. 38%, P=0.35) or breathlessness (62 vs. 69%, P=0.40) between attenders and nonattenders. The severity scores of angina (2.7 vs. 3.2, P=0.286) and breathlessness (3.5 vs. 3.6; P=0.79) were no different. However, four of the eight health domains measured showed significantly better values for attenders than nonattenders; namely: general health (60 vs. 46%, P=0.001), physical function (64 vs. 51% P=0.01), role limitation physical (48 vs. 29%; P=0.02) and social function 74 vs. 62%, P=0.04). CONCLUSIONS: This is the first report using SF 36 to evaluate benefits from attending CR. Higher general health scores (SF-36) were associated with attendance at CR although CAD risk factors and cardiac symptoms were not improved but this may be due to the long interval between assessments.

Serum-induced monocyte differentiation and monocyte chemotaxis are regulated by the p38 MAP kinase signal transduction pathway.

Regulation by the p38 mitogen-activated protein (MAP) kinase signaling pathway of monocytic inflammatory functions was evaluated using L-790,070, a potent and selective inhibitor of p38 MAP kinase. Three major functions of monocytes were investigated: differentiation, chemotaxis, and phagocytosis. L-790,070 inhibited serum-induced monocyte differentiation with an IC50 of 0.5 nM. Monocyte chemotaxis induced by RANTES, macrophage inflammatory protein-1alpha (MIP-1alpha), monocyte chemotactic protein- (MCP-1), and fMLP were all sensitive to L-790,070. When titrated, L-790,070 inhibited MCP-1-induced chemotaxis in a concentration-dependent manner with an IC50 of 0.3 nM. However, the ability of serum-derived macrophages to phagocytose apoptotic neutrophils was unaffected by L-790,070. The concentration with which L-790,070 inhibited both differentiation and chemotaxis was similar to that necessary to inhibit p38 MAP kinase activation of MAPKAP kinase (0.3 nM) in response to stimulation by lipopolysaccharide. Therefore, the data in this report suggest that the mechanism by which L-790,070 blocked monocyte differentiation and prevented chemotaxis was by inhibiting p38 MAP kinase activity.

Modality interfacing: the impact of a relay station.

We evaluated the effect of a deploying a relay station on demographic discrepancies, image segmentation for routing, quality control (QC), and technologist workflow in a distributed architecture type picture archiving and communication system (PACS) environment. A currently existing PACS environment for computed tomography (CT) was evaluated before and after the implementation of a relay station for demographic error-rate and correct study routing to the workstations. Assessment of the technologists' perceptions with respect to numerous workflow factors was performed with a questionnaire. Statistical analysis was performed using a chi-square test. The demographic error rate for CT examinations was nearly abolished with relay station deployment (14.0% pre-Relay v 0.55% post-Relay, P < .001, chi2). The technologists' perception was favorable, with a substantial majority indicating that a positive impact is made on correcting demographic errors (90%), facilitating QC (67%), and ensuring proper routing (77%). A majority also felt the user interface was intuitive (93.3%) and preferred relay (90%) over film handling but that training should be provided both by didactic sessions and "hands on" time with a trainer. The times to perform tasks were favorable for the relay station (1 to 5 minutes) versus film production and handling (2 to 15 minutes). In conclusion, the relay station prospectively eliminates demographic errors, effectively segments images from the same study routing them to different workstations, and can be seamlessly integrated into the technologists' current workflow. This can be scalable and a lower cost solution as opposed to deploying dedicated PACS QC workstations.

L-selectin signaling of neutrophil adhesion and degranulation involves p38 mitogen-activated protein kinase.

The adhesion molecules known as selectins mediate the capture of neutrophils from the bloodstream. We have previously reported that ligation and cross-linking of L-selectin on the neutrophil surface enhances the adhesive function of beta(2)-integrins in a synergistic manner with chemotactic agonists. In this work, we examined degranulation and adhesion of neutrophils in response to cross-linking of L-selectin and addition of interleukin-8. Cross-linking of L-selectin induced priming of degranulation that was similar to that observed with the alkaloid cytochalasin B. Activation mediated by L-selectin of neutrophil shape change and adhesion through CD11b/CD18 were strongly blocked by Merck C, an imidazole-based inhibitor of p38 mitogen-activated protein kinase (MAPK), but not by a structurally similar non-binding regioisomer. Priming by L-selectin of the release of secondary, tertiary, and secretory, but not primary, granules was blocked by inhibition of p38 MAPK. Peak phosphorylation of p38 MAPK was observed within 1 min of cross-linking L-selectin, whereas phosphorylation of ERK1/2 was highest at 10 min. Phosphorylation of p38 MAPK, but not ERK1/2, was inhibited by Merck C. These data suggest that signal transduction as a result of clustering L-selectin utilizes p38 MAPK to effect neutrophil shape change, integrin activation, and the release of secondary, tertiary, and secretory granules.

Enzymatically inactive macrophage migration inhibitory factor inhibits monocyte chemotaxis and random migration.

Macrophage migration inhibitory factor (MIF) is a cytokine that was first described as an inhibitor of the random migration of monocytes and macrophages and has since been proposed to have a number of immune and catalytic functions. One of the functions assigned to MIF is that of a tautomerase that interconverts the enol and keto forms of phenylpyruvate and (p-hydroxyphenyl)pyruvate and converts D-dopachrome, a stereoisomer of naturally occurring L-dopachrome, to 5,6-dihydroxyindole-2-carboxylic acid. The physiological significance of the MIF enzymatic activity is unclear. The three-dimensional structure of MIF is strikingly similar to that of two microbial enzymes (4-oxalocrotonate tautomerase and 5-carboxymethyl-2-hydroxymuconate isomerase) that otherwise share little sequence identity with MIF. MIF and these two enzymes have an invariant N-terminal proline that serves as a catalytic base. Here we report a new biological function for MIF, as an inhibitor of monocyte chemoattractant protein 1- (MCP-1-) induced chemotaxis of human peripheral blood monocytes. We find that MIF inhibition of chemotaxis does not occur at the level of the CC chemokine receptor for MCP-1, CCR2, since MIF does not alter the binding of (125)I-MCP-1 to monocytes. The role of MIF enzymatic activity in inhibition of monocyte chemotaxis and random migration was studied with two MIF mutants in which the N-terminal proline was replaced with either a serine or a phenylalanine. Both mutants remain capable of inhibiting monocyte chemotaxis and random migration despite significantly reduced or no phenylpyruvate tautomerase activity. These data suggest that this enzymatic activity of MIF does not play a role in its migration inhibiting properties.

Design and synthesis of potent, selective, and orally bioavailable tetrasubstituted imidazole inhibitors of p38 mitogen-activated protein kinase.

Novel potent and selective diarylimidazole inhibitors of p38 MAP (mitogen-activated protein) kinase are described which have activity in both cell-based assays of tumor necrosis factor-alpha (TNF-alpha) release and an animal model of rheumatoid arthritis. The SAR leading to the development of selectivity against c-Raf and JNK2alpha1 kinases is presented, with key features being substitution of the 4-aryl ring with m-trifluoromethyl and substitution of the 5-heteroaryl ring with a 2-amino substituent. Cell-based activity was significantly enhanced by incorporation of a 4-piperidinyl moiety at the 2-position of the imidazole which also enhanced aqueous solubility. In general, oral bioavailability of this class of compounds was found to be poor unless the imidazole was methylated on nitrogen. This work led to identification of 48, a potent (p38 MAP kinase inhibition IC50 0.24 nM) and selective p38 MAP kinase inhibitor which inhibits lipopolysaccharide-stimulated release of TNF-alpha from human blood with an IC50 2.2 nM, shows good oral bioavailability in rat and rhesus monkey, and demonstrates significant improvement in measures of disease progression in a rat adjuvant-induced arthritis model.

Role of stress-activated mitogen-activated protein kinase (p38) in beta 2-integrin-dependent neutrophil adhesion and the adhesion-dependent oxidative burst.

Bacterial LPS elicits both rapid activation of the stress-activated MAP kinase p38 in polymorphonuclear leukocytes (PMN) and rapid adhesion of the PMN to ligands for the leukocyte integrin CD11b/CD18. The functional correlation between these two events was examined. The time course for tyrosine phosphorylation of p38 in PMN in response to 10 ng/ml LPS in 1% normal human serum was consistent with participation in signaling for leukocyte integrin-dependent adhesion, with transient phosphorylation peaking at 10 to 20 min. The concentration dependence of p38 phosphorylation also resembled that for PMN adhesion, with <1 ng/ml LPS eliciting a response. Phosphorylation was inhibited by mAb 60b against CD14, but not by mAb 26ic, a nonblocking anti-CD14. The function of p38 in integrin-dependent adhesion and the adhesion-dependent oxidative burst was tested using a specific inhibitor of p38, SB203580. SB203580 inhibited adhesion by diminishing the initial rate of adherence in response to both LPS and TNF, with a half-maximal concentration in the range of 0.1 to 0.6 microM. It did not, however, block adhesion in response to formyl peptide or PMA. The p38 inhibitor also blocked the adhesion-dependent oxidative burst with a half-maximal concentration similar to that for adhesion. Timed delivery of the compound during the lag phase preceding H2O2 production suggested that p38 kinase activity was required throughout the lag but not after the oxidase was assembled. These results suggest that p38 functions in PMN to signal leukocyte integrin-dependent adhesion and the subsequent massive production of reactive oxygen intermediates.

Web-based digital radiology teaching file: facilitating case input at time of interpretation.

OBJECTIVE: Our goal was to develop a software system that allows easy and rapid input of digital radiology images and text reports, at the time of interpretation, into an easily searchable electronic teaching file database using the Internet and the World-Wide Web protocols, servers, and browsers. CONCLUSION: Using the Internet, the World-Wide Web, and our software system, we can rapidly input digital radiology images and associated text reports into an easily searchable database accessed by privileged users. This inexpensive and simple method for building a digital teaching file database allows cross-platform access for users who have a Web browser.

Pyrroles and other heterocycles as inhibitors of p38 kinase.

Investigation of furans, pyrroles and pyrazolones identified 3-pyridyl-2,5-diaryl-pyrroles as potent, orally bioavailable inhibitors of p38 kinase. 3-(4-pyridyl-2-(4-fluoro-phenyl)-5-(4-methylsulfinylphenyl)-pyrrol e (L-167307) reduces secondary paw swelling in the rat adjuvant arthritis model: ID50 = 7.4 mg/kg/b.i.d.

Pkn9, a Ser/Thr protein kinase involved in the development of Myxococcus xanthus.

The Myxococcus xanthus gene, pkn9, encodes a protein that contains significant homology with eukaryotic Ser/Thr protein kinases. The pkn9 gene was singled out of a previously identified family of kinase genes by amplification techniques that displayed differences in kinase gene expression during selected periods of the M. xanthus life cycle. Pkn9 was constitutively expressed during vegetative growth and upregulated during the aggregation stage of early development. It consists of 589 amino acids, and its N-terminal 394 residues show 38% identity with both Pkn1 and Pkn2 of M. xanthus. This region also shows 29, 25 and 29% identify with myosin light-chain kinase, protein kinase C, and cAMP-dependent protein kinase, respectively. A 22-residue hydrophobic transmembrane domain separates the kinase domain from the 173-residue C-terminal domain that resides on the outside of the inner membrane. The C-terminal domain contains two sets of tandem repeats of 13 and 10 residues which have no known function. When expressed in Escherichia coli under the T7 promoter, Pkn9 was found to be phosphorylated on serine and threonine residues. Disruption of the pkn9 kinase catalytic subdomains I-III by the insertion of a kanamycin-resistance gene resulted in slightly delayed, smaller and more-crowded fruiting bodies, while spore formation was normal. Total deletion of the pkn9 gene caused severely reduced progression through development resulting in light loose mounds that become slightly more compact over time. Development progressed further at the centre than at the edge of the spot, and spore formation was significantly reduced. Two-dimensional gel analysis revealed that both the disruption and the deletion of pkn9 prevented the expression of five membrane proteins (KREP9-1-4). These results suggest that the loss of Pkn9 kinase activity caused altered fruiting-body formation, the absence of the KREP9 proteins in the membrane, and reduced spore production.

Soldier performance and strenuous road marching: influence of load mass and load distribution.

Fifteen male soldiers performed six maximal-effort, 20-km road marchers. They carried load masses of 34, 48, and 61 kg, using a standard military backpack with frame or an experimental doublepack. March times decreased as mass increased and were faster with the standard pack than with the double-pack. The doublepack resulted in less low back discomfort and a lower incidence of blisters at the highest load, but also resulted in more discomfort in the neck and hips. Neither load mass nor pack type affected soldiers' marksmanship ability, grenade throw accuracy, or cognitive ability. The maximal-effort march itself affected the marksmanship tasks by increasing the post-march vertical shot group dispersion. The concept of distributing the load mass more evenly around the center of mass of the body has both positive and negative aspects and warrants further investigation.

MlpA, a lipoprotein required for normal development of Myxococcus xanthus.

The mlpA gene encoding a 236-residue polypeptide has been identified immediately downstream of the oar gene of Myxococcus xanthus (M. Martinez-Canamero, J. Munoz-Dorado, E. Farez-Vidal, M. Inouye, and S. Inouye, J. Bacteriol. 175:4756-4763, 1993). The amino-terminal 21 residues of MlpA encode a typical prokaryotic signal sequence with a putative lipoprotein cleavage site. When expressed in Escherichia coli in the presence of [2-3H]glycerol, 3H-labeled MlpA had a molecular mass of 33 kDa and was found to be associated with the membrane fraction. Globomycin, an inhibitor of signal peptidase II, caused a shift in the mobility of E. coli-expressed MlpA to 35 kDa. Subsequently, a mlpA disruption strain (oar+) was constructed and found to have delayed fruiting body formation (by approximately 36 h), with significantly larger fruiting bodies being produced compared with those of the wild-type strain. Nevertheless, spore yields for the two strains were identical after 120 h of development. These data indicate that MlpA, the lipoprotein identified in M. xanthus, is required for normal fruiting body formation.

Second-trimester abortion by intramuscular 15-methyl-prostaglandin F2 alpha or intravaginal prostaglandin E2 suppositories: a randomized trial.

OBJECTIVE: To compare intramuscular (IM) prostaglandin 15 methyl-F2 alpha (15M-PGF2 alpha) with prostaglandin E2 (PGE2) vaginal suppositories for second-trimester abortion in terms of efficacy and side effects. METHODS: Fifty-one women were randomized to receive either 15M-PGF2 alpha IM injections or PGE2 intravaginal suppositories for second-trimester abortion. Efficacy and side effects of the two agents were analyzed by two-tailed t tests, chi 2 analysis with Fisher exact test, and survival analysis. RESULTS: The mean times to rupture of membranes, delivery of fetus, and delivery of placenta were significantly less for women receiving PGE2 vaginal suppositories. The cumulative abortion rate after 24 hours for the PGE2 group was 96%, compared with 69% for the 15M-PGF2 alpha group. Although there were few differences in side effects, the 15M-PGF2 alpha group had significantly fewer headaches, fevers, and chills. CONCLUSION: Intravaginal PGE2 is superior to IM 15M-PGF2 alpha for second-trimester abortion.

Formation of polymorphonuclear leukocyte elastase: alpha 1 proteinase inhibitor complex and A alpha (1-21) fibrinopeptide in human blood stimulated with the calcium ionophore A23187. A model to characterize inhibitors of polymorphonuclear leukocyte elastase.

Incubation of human blood with the secretagogue A23187 resulted in the formation of increased plasma concentrations of polymorphonuclear leukocyte (PMN) elastase: alpha 1 proteinase inhibitor (PMNE:alpha 1 PI) complex as well as A alpha(1-21) fibrinopeptide [A alpha(1-21)]. The formation of these species was both time and A23187 concentration dependent. Using a sandwich ELISA and a radioimmunoassay, we determined the comparative potencies of several compounds to inhibit the formation of PMNE: alpha 1 PI complexes and A alpha(1-21), respectively. L-658,758, a substituted cephalosporin, essentially irreversible elastase inhibitor, inhibited the formation of PMNE: alpha 1 PI and A alpha(1-21) with IC50 values of 38 and 15 microM, respectively. L-683,845, a monocyclic beta-lactam, was much more potent against isolated PMNE than L-658,758. However in this system it was approximately equivalent to L-658,758 with an IC50 of 15 microM against both species. ICI-200,880, a competitive slow-binding elastase inhibitor, was significantly less potent to inhibit A alpha(1-21), having an IC50 of 75 microM, while Declaben, a reversible noncompetitive inhibitor, was inactive at concentrations as great as 200 microM. We propose that evaluating inhibitors in the complex milieu of blood will provide a useful method to predict their therapeutic potential in vivo.

Potency of antileukoprotease and alpha 1-antitrypsin to inhibit degradation of fibrinogen by adherent polymorphonuclear leukocytes from normal subjects and patients with chronic granulomatous disease.

We have studied the relative efficacy of antileukoprotease (ALP) and alpha 1-antitrypsin (alpha 1AT) to inhibit the degradation of substrate by polymorphonuclear leukocytes (PMN) attached onto a fibrinogen matrix. PMN elastase activity was assayed by radioimmunoassay of a specific 21-residue cleavage product from the amino terminus of the A alpha chain, A alpha (1-21), of fibrinogen. The adherence of PMN (1.0 x 10(6)) to a fibrinogen matrix was facilitated by incubation with recombinant tumor necrosis factor-alpha (1 nM). Subsequently, the cells were exposed to inhibitors before stimulation with cytochalasin B and formylmethionyl-leucylphenylalanine. Under these conditions, ALP inhibited A alpha (1-21) formation with an IC50 of 85 +/- 30 nM and alpha 1AT gave an IC50 of 220 +/- 98 nM (mean +/- SD). The effect of oxidant production on A alpha (1-21) formation was evaluated by comparing the effect of PMN from normal subjects with PMN from subjects with X-linked NADPH oxidase deficiency. Stimulation of PMN from the latter subjects in a similar fashion as described above resulted in the formation of 40 +/- 4 pmol/ml A alpha (1-21), or approximately twice the amount seen with cells from normal subjects. Preincubation with ALP or alpha 1AT in a concentration range between 10 to 900 nM resulted in an IC50 of 50 +/- 13 nM for ALP compared with 150 +/- 21 nM for alpha 1AT. Both inhibitors are more effective to prevent fibrinogen degradation caused by chronic granulomatous disease (CGD) PMN than by normal PMN despite the fact that CGD PMN generated more A alpha (1-21) than did normal PMN.(ABSTRACT TRUNCATED AT 250 WORDS)

rTNF alpha facilitates human polymorphonuclear leukocyte adherence to fibrinogen matrices with mobilization of specific and tertiary but not azurophilic granule markers.

rTNF alpha facilitates highly reproducible adherence of polymorphonuclear leukocyte (PMN) to fibrinogen-coated surfaces in a concentration- and time-dependent manner. The adhesion was maximal with 1.0 nM rTNF alpha within 40-50 min at 37 degrees C. A monoclonal antibody (1B4) directed toward the beta 2-chain of the integrin receptor for fibrinogen (CD11b, CD18) completely inhibited the rTNF alpha induced adhesion. TNF alpha caused a time-dependent secretion of the granule markers gelatinase and lactoferrin but no liberation of myeloperoxidase and minimal production of A alpha(1-21), a specific cleavage product of fibrinogen generated by elastase, as markers for the azurophilic granule. PMN adhered to fibrinogen in the presence of rTNF alpha could be further stimulated with cytochalasin B and N-formyl-methionyl-leucyl-phenylalanine (FMLP) to release azurophilic granule markers as measured by increasing MPO activity and A alpha(1-21) production over time. Thus the rTNF alpha-facilitated adherence of PMN to a fibrinogen matrix provides a system for partial activation of PMN resulting in release of markers of specific and tertiary but not azurophilic granules. Moreover, these conditions should provide an opportunity to define more clearly the signal transduction processes involved in azurophilic granule release.