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Showing papers by "University of Iowa published in 1998"


Journal ArticleDOI
TL;DR: In this paper, the authors summarized the practical and theoretical implications of 85 years of research in personnel selection and concluded that the most important property of a personnel assessment method is predictive validity: the ability to predict future job performance, job related learning (such as amount of learning in training and development programs), and other criteria.
Abstract: This article summarizes the practical and theoretical implications of 85 years of research in personnel selection. On the basis of meta-analytic findings, this article presents the validity of 19 selection procedures for predicting job performance and training performance and the validity of paired combinations of general mental ability (GMA) and Ihe 18 other selection procedures. Overall, the 3 combinations with the highest multivariate validity and utility for job performance were GMA plus a work sample test (mean validity of .63), GMA plus an integrity test (mean validity of .65), and GMA plus a structured interview (mean validity of .63). A further advantage of the latter 2 combinations is that they can be used for both entry level selection and selection of experienced employees. The practical utility implications of these summary findings are substantial. The implications of these research findings for the development of theories of job performance are discussed. From the point of view of practical value, the most important property of a personnel assessment method is predictive validity: the ability to predict future job performance, job-related learning (such as amount of learning in training and development programs), and other criteria. The predictive validity coefficient is directly proportional to the practical economic value (utility) of the assessment method (Brogden, 1949; Schmidt, Hunter, McKenzie, & Muldrow, 1979). Use of hiring methods with increased predictive validity leads to substantial increases in employee performance as measured in percentage increases in output, increased monetary value of output, and increased learning of job-related skills (Hunter, Schmidt, & Judiesch, 1990). Today, the validity of different personnel measures can be determined with the aid of 85 years of research. The most wellknown conclusion from this research is that for hiring employees without previous experience in the job the most valid predictor of future performance and learning is general mental ability ([GMA], i.e., intelligence or general cognitive ability; Hunter & Hunter, 1984; Ree & Earles, 1992). GMA can be measured using commercially available tests. However, many other measures can also contribute to the overall validity of the selection process. These include, for example, measures of

3,792 citations


Journal ArticleDOI
10 Apr 1998-Science
TL;DR: The involvement of an intercellular signal molecule in the development of Pseudomonas aeruginosa biofilms suggests possible targets to control biofilm growth on catheters, in cystic fibrosis, and in other environments where P. aerug inosaBiofilms are a persistent problem.
Abstract: Bacteria in nature often exist as sessile communities called biofilms. These communities develop structures that are morphologically and physiologically differentiated from free-living bacteria. A cell-to-cell signal is involved in the development of Pseudomonas aeruginosa biofilms. A specific signaling mutant, a lasI mutant, forms flat, undifferentiated biofilms that unlike wild-type biofilms are sensitive to the biocide sodium dodecyl sulfate. Mutant biofilms appeared normal when grown in the presence of a synthetic signal molecule. The involvement of an intercellular signal molecule in the development of P. aeruginosa biofilms suggests possible targets to control biofilm growth on catheters, in cystic fibrosis, and in other environments where P. aeruginosa biofilms are a persistent problem.

3,335 citations


Journal ArticleDOI
TL;DR: A broader perspective, focused on the cognitive and motivational consequences of valence-based encoding, opens the door to a deeper understanding of the causes and consequences of framing effects.

2,238 citations


Journal ArticleDOI
TL;DR: In this article, the authors focused on another concept, core self-evaluations, which were hypothesized to comprise self-esteem, generalized self-efficacy, locus of control, and nonneuroticism.
Abstract: Past research has suggested that dispositional sources of job satisfaction can be traced to measures of affective temperament. The present research focused on another concept, core self-evaluations, which were hypothesized to comprise self-esteem, generalized self-efficacy, locus of control, and nonneuroticism. A model hypothesized that core self-evaluations would have direct effects on job and life satisfaction. It also was hypothesized that core self-evaluations would have indirect effects on job satisfaction. Data were collected from 3 independent samples in 2 countries, using dual source methodology. Results indicated that core self-evaluations had direct and indirect effects on job and life satisfaction. The statistical and logical relationship among core evaluations, affective disposition, and satisfaction was explored.

1,705 citations


Journal ArticleDOI
TL;DR: Research on relationships between anxiety and depression has proceeded at a rapid pace since the 1980s, with data converging on an integrative hierarchical model of mood and anxiety disorders in which each individual syndrome contains both a common and a unique component.
Abstract: Research on relationships between anxiety and depression has proceeded at a rapid pace since the 1980s. The similarities and differences between these two conditions, as well as many of the important features of the comorbidity of these disorders, are well understood. The genotypic structure of anxiety and depression is also fairly well documented. Generalized anxiety and major depression share a common genetic diathesis, but the anxiety disorders themselves are genetically hetergeneous. Sophisticated phenotypic models have also emerged, with data converging on an integrative hierarchical model of mood and anxiety disorders in which each individual syndrome contains both a common and a unique component. Finally, considerable progress has been made in understanding cognitive aspects of these disorders. This work has focused on both the cognitive content of anxiety and depression and on the effects that anxiety and depression have on information processing for mood-congruent material.

1,536 citations


Journal ArticleDOI
TL;DR: Two 48-week, randomized, placebo-controlled studies of two doses of alendronate in 477 men and women who were receiving glucocorticoid therapy found changes in bone density of the hip, biochemical markers of bone turnover, and the incidence of new vertebral fractures.
Abstract: Background Osteoporosis is a common complication of long-term glucocorticoid therapy for which there is no well-proved preventive or restorative treatment. Methods We carried out two 48-week, randomized, placebo-controlled studies of two doses of alendronate in 477 men and women, 17 to 83 years of age, who were receiving glucocorticoid therapy. The primary end point was the difference in the mean percent change in lumbar-spine bone density from base line to week 48 between the groups. Secondary outcomes included changes in bone density of the hip, biochemical markers of bone turnover, and the incidence of new vertebral fractures. Results The mean (±SE) bone density of the lumbar spine increased by 2.1±0.3 percent and 2.9±0.3 percent, respectively, in the groups that received 5 and 10 mg of alendronate per day (P<0.001) and decreased by 0.4±0.3 percent in the placebo group. The femoral-neck bone density increased by 1.2±0.4 percent and 1.0±0.4 percent in the respective alendronate groups (P<0.01) and decre...

1,153 citations


Journal Article
TL;DR: The long-term follow-up of small series of patients has shown that the transplantation of osteochondral autologous grafts and allografts can be effective for the treatment of focal defects of articular cartilage in selected patients.
Abstract: The degeneration of articular cartilage as part of the clinical syndrome of osteoarthritis is one of the most common causes of pain and disability in middle-aged and older people. The strong correlation between increasing age and the prevalence of osteoarthritis, and recent evidence of important age-related changes in the function of chondrocytes, suggest that age-related changes in articular cartilage can contribute to the development and progression of osteoarthritis. Although the mechanisms responsible for osteoarthritis remain poorly understood lifelong moderate use of normal joints does not increase the risk. Thus, the degeneration of normal articular cartilage is not simply the result of aging and mechanical wear. However, high-impact and torsional loads may increase the risk of degeneration of normal joints, and individuals who have an abnormal joint anatomy, joint instability, disturbances of joint or muscle innervation, or inadequate muscle strength or endurance probably have a greater risk of degenerative joint disease. Recent work has shown the potential for the restoration of an articular surface. Currently, surgeons frequently debride joints and penetrate subchondral bone as well as perform osteotomies, with the intent of decreasing symptoms and restoring or maintaining a functional articular surface. The results of these procedures vary considerably among patients. Clinical and experimental work has shown the important influence of loading and motion on the healing of articular cartilage and joints. Experimental studies have revealed that transplantation of chondrocytes and mesenchymal stem cells; use of periosteal and perichondrial grafts, synthetic matrices, and growth factors: and other methods have the potential to stimulate the formation of a new articular surface. The long-term follow-up of small series of patients has shown that the transplantation of osteochondral autologous grafts and allografts can be effective for the treatment of focal defects of articular cartilage in selected patients. Thus far, none of these methods has been shown to predictably restore a durable articular surface to an osteoarthritic joint, and it is unlikely that any one of them will be uniformly successful. Rather, the available clinical and experimental evidence indicates that future optimum methods for the restoration of articular surfaces will begin with a detailed analysis of the structural and functional abnormalities of the involved joint and the patient's expectations for future use of the joint. On the basis of this analysis, the surgeon will develop a treatment plan that potentially combines correction of mechanical abnormalities (including malalignment, instability, and intra-articular causes of mechanical dysfunction), debridement that may or may not include hunted penetration of subchondral bone, and applications of growth factors of implants that may consist of a synthetic matrix that incorporates cells or growth factors or use of transplants followed by a postoperative course of controlled loading and motion.

1,111 citations


Journal ArticleDOI
04 Jun 1998-Nature
TL;DR: This investigation into the hypothesis that the human amygdala is required for accurate social judgments of other individuals on the basis of their facial appearance finds three subjects with complete bilateral amygdala damage to judge faces of unfamiliar people with respect to two attributes important in real-life social encounters: approachability and trustworthiness.
Abstract: Studies in animals have implicated the amygdala in emotional1,2,3, and social4,5,6, behaviours, especially those related to fear and aggression Although lesion7,8,9,10, and functional imaging11,12,13,14, studies in humans have demonstrated the amygdala's participation in recognizing emotional facial expressions, its role in human social behaviour has remained unclear We report here our investigation into the hypothesis that the human amygdala is required for accurate social judgments of other individuals on the basis of their facial appearance We asked three subjects with complete bilateral amygdala damage to judge faces of unfamiliar people with respect to two attributes important in real-life social encounters: approachability and trustworthiness All three subjects judged unfamiliar individuals to be more approachable and more trustworthy than did control subjects The impairment was most striking for faces to which normal subjects assign the most negative ratings: unapproachable and untrustworthy looking individuals Additional investigations revealed that the impairment does not extend to judging verbal descriptions of people The amygdala appears to be an important component of the neural systems that help retrieve socially relevant knowledge on the basis of facial appearance

1,110 citations


Journal ArticleDOI
TL;DR: A model that implicates connectivity among nodes located in prefrontal regions, the thalamic nuclei, and the cerebellum is developed that produces "cognitive dysmetria", difficulty in prioritizing, processing, coordinating, and responding to information in schizophrenia.
Abstract: Earlier efforts to localize the symptoms of schizophrenia in a single brain region have been replaced by models that postulate a disruption in parallel distributed or dynamic circuits. Based on empirical data derived from both magnetic resonance and positron emission tomography, we have developed a model that implicates connectivity among nodes located in prefrontal regions, the thalamic nuclei, and the cerebellum. A disruption in this circuitry produces "cognitive dysmetria," difficulty in prioritizing, processing, coordinating, and responding to information. This "poor mental coordination" is a fundamental cognitive deficit in schizophrenia and can account for its broad diversity of symptoms.

1,108 citations


Journal ArticleDOI
TL;DR: Comprehensive human genetic maps were constructed on the basis of nearly 1 million genotypes from eight CEPH families and incorporated >8,000 short tandem-repeat polymorphisms (STRPs), primarily from Généthon, the Cooperative Human Linkage Center, the Utah Marker Development Group, and the Marshfield Medical Research Foundation.
Abstract: Comprehensive human genetic maps were constructed on the basis of nearly 1 million genotypes from eight CEPH families; they incorporated >8,000 short tandem-repeat polymorphisms (STRPs), primarily from Genethon, the Cooperative Human Linkage Center, the Utah Marker Development Group, and the Marshfield Medical Research Foundation. As part of the map building process, 0.08% of the genotypes that resulted in tight double recombinants and that largely, if not entirely, represent genotyping errors, mutations, or gene-conversion events were removed. The total female, male, and sex-averaged lengths of the final maps were 44, 27, and 35 morgans, respectively. Numerous (267) sets of STRPs were identified that represented the exact same loci yet were developed independently and had different primer pairs. The distributions of the total number of recombination events per gamete, among the eight mothers of the CEPH families, were significantly different, and this variation was not due to maternal age. The female:male ratio of genetic distance varied across individual chromosomes in a remarkably consistent fashion, with peaks at the centromeres of all metacentric chromosomes. The new linkage maps plus much additional information, including a query system for use in the construction of reliably ordered maps for selected subsets of markers, are available from the Marshfield Website.

1,104 citations


Journal ArticleDOI
TL;DR: For instance, this paper found that sensory gain control or amplification processes play an important role in visual-spatial attention and that attentional gain control operates at an early stage of visual processing in extrastriate cortical areas.
Abstract: Both physiological and behavioral studies have suggested that stimulus-driven neural activity in the sensory pathways can be modulated in amplitude during selective attention. Recordings of event-related brain potentials indicate that such sensory gain control or amplification processes play an important role in visual-spatial attention. Combined event-related brain potential and neuroimaging experiments provide strong evidence that attentional gain control operates at an early stage of visual processing in extrastriate cortical areas. These data support early selection theories of attention and provide a basis for distinguishing between separate mechanisms of attentional suppression (of unattended inputs) and attentional facilitation (of attended inputs).

Journal ArticleDOI
TL;DR: A cognitive and anatomic double dissociation between deficits in decision making (anterior VM) and working memory (right DL/M) is revealed, the first direct evidence of such effects in humans using the lesion method and underscores the special importance of the VM prefrontal region in decisionMaking, independent of a direct role in working memory.
Abstract: We tested the hypothesis that cognitive functions related to working memory (assessed with delay tasks) are distinct from those related to decision making (assessed with a gambling task), and that working memory and decision making depend in part on separate anatomical substrates. Normal controls (n = 21), subjects with lesions in the ventromedial (VM) (n = 9) or dorsolateral/high mesial (DL/M) prefrontal cortices (n = 10), performed on (1) modified delay tasks that assess working memory and (2) a gambling task designed to measure decision making. VM subjects with more anterior lesions (n = 4) performed defectively on the gambling but not the delay task. VM subjects with more posterior lesions (n = 5) were impaired on both tasks.Right DL/M subjects were impaired on the delay task but not the gambling task. Left DL/M subjects were not impaired on either task. The findings reveal a cognitive and anatomic double dissociation between deficits in decision making (anterior VM) and working memory (right DL/M). This presents the first direct evidence of such effects in humans using the lesion method and underscores the special importance of the VM prefrontal region in decision making, independent of a direct role in working memory.

Journal Article
TL;DR: The available evidence indicates that normal matrix turnover depends on the ability of chondrocytes to detect alterations in the macromolecular composition and organization of the matrix, including the presence of degraded molecules, and to respond by synthesizing appropriate types and amounts of new molecules.
Abstract: The unique biologic and mechanical properties of articular cartilage depend on the design of the tissue and the interactions between the chondrocytes and the matrix that maintain the tissue. Chondrocytes form the macromolecular framework of the tissue matrix from three classes of molecules: collagens, proteoglycans, and noncollagenous proteins. Type II, IX, and XI collagens form a fibrillar meshwork that gives the tissue as form and tensile stiffness and strength. Type VI collagen forms part of the matrix immediately surrounding the chondrocytes and may help the chondrocytes to attach to the macromolecular framework of the matrix. Large aggregating proteoglycans (aggrecans) give the tissue its stiffness to compression and its resilience and contribute to its durability. Small proteoglycans, including decorin, biglycan, and fibromodulin, bind to other matrix macromolecules and thereby help to stabilize the matrix. They may also influence the function of the chondrocytes and bind growth factors. Anchorin CII, a noncollagenous protein, appears to help to anchor chondrocytes to the matrix. Cartilage oligomeric protein may have value as a marker of turnover and degeneration of cartilage, and other noncollagenous proteins, including tenascin and fibronectin, can influence interactions between the chondrocytes and the matrix. The matrix protects the cells from injury due to normal use of the joint, determines the types and concentrations of molecules that reach the tells and helps to maintain the chondrocyte phenotype. Throughout life, the tissue undergoes continual internal remodeling as the cells replace matrix macromolecules lost through degradation. The available evidence indicates that normal matrix turnover depends on the ability of chondrocytes to detect alterations in the macromolecular composition and organization of the matrix, including the presence of degraded molecules, and to respond by synthesizing appropriate types and amounts of new molecules. In addition, the matrix acts as a signal transducer for the cells. Loading of the tissue due to use of the joint creates mechanical, electrical, and physicochemical signals that help to direct the synthetic and degradative activity of chondrocytes. A prolonged severe decrease in the use of the joint leads to alterations in the composition of the matrix and eventually to loss of tissue structure and mechanical properties, whereas use of the joint stimulates the synthetic activity of chondrocytes and possibly the internal tissue remodeling Aging leads to alterations in the composition of the matrix and the activity of the chondrocytes, including the ability of the cells to respond to a variety of stimuli such as growth factors. These alterations may increase the probability of degeneration of the cartilage.

Journal ArticleDOI
TL;DR: In this paper, the authors conducted a meta-analysis that investigated the degree to which dimensions of the Five-Factor Model (FFM) of personality are related to performance in jobs involving interpersonal interactions and whether the nature of the interactions with others moderates the personality-performance relations.
Abstract: In this article, the results of a meta-analysis that investigates the degree to which dimensions of the Five-Factor Model (FFM) of personality are related to performance in jobs involving interpersonal interactions are reported. The article also investigates whether the nature of the interactions with others moderates the personality-performance relations. The meta-analysis was based on 11 studies (total N = 1,586). each of which assessed the FFM at the construct level using the Personal Characteristics Inventory. Results support the hypothesis that Conscientiousness, Agreeableness, and Emotional Stability are positively related to performance in jobs involving interpersonal interactions. Results also support the hypothesis that Emotional Stability and Agreeableness are more strongly related to performance in jobs that involve team- work (where employees interact interdependently with coworkers), than in those that involve dyadic interactions with others (where employees provide a direct service to custom...

Journal ArticleDOI
TL;DR: Results indicate that the attentional blink reflects an impairment in a postperceptual stage of processing.
Abstract: When an observer detects a target in a rapid stream of visual stimuli, there is a brief period of time during which the detection of subsequent targets is impaired. In this study, event-related potentials (ERPs) were recorded from normal adult observers to determine whether this "attentional blink" reflects a suppression of perceptual processes or an impairment in postperceptual processes. No suppression was observed during the attentional blink interval for ERP components corresponding to sensory processing (the P1 and N1 components) or semantic analysis (the N400 component). However, complete suppression was observed for an ERP component that has been hypothesized to reflect the updating of working memory (the P3 component). Results indicate that the attentional blink reflects an impairment in a postperceptual stage of processing.

Journal ArticleDOI
TL;DR: The results provide little support for the commonly held view that parent-child conflict rises and then falls across adolescence, although conclusions regarding pubertal change as well as conflict affect are qualified by the limited number of studies available.
Abstract: A series of meta-analyses addresses whether and how parent-child conflict changes during adolescence and factors that moderate patterns of change The meta-analyses summarize results from studies of change in parent-child conflict as a function of either adolescent age or pubertal maturation Three types of parent-adolescent conflict are examined: conflict rate, conflict affect, and total conflict (rate and affect combined) The results provide little support for the commonly held view that parent-child conflict rises and then falls across adolescence, although conclusions regarding pubertal change as well as conflict affect are qualified by the limited number of studies available Two diverging sets of linear effects emerged, one indicating a decline in conflict rate and total conflict with age and the other indicating an increase in conflict affect with both age and pubertal maturation In age meta-analyses, conflict rate and total conflict decline from early adolescence to mid-adolescence and from mid-adolescence to late adolescence; conflict affect increases from early adolescence to mid-adolescence Puberty meta-analyses revealed only a positive linear association between conflict affect and pubertal maturation Effect-size patterns varied little in follow-up analyses of potential moderating variables, implying similarities in the direction (although not the magnitude) of conflict across parent-adolescent dyads, reporters, and measurement procedures

Journal ArticleDOI
03 Jun 1998-JAMA
TL;DR: Evidence that older persons who report depressive symptoms are at higher risk of subsequent physical decline is provided, and results suggest that prevention or reduction of depressed mood could play a role in reducing functional decline in older persons.
Abstract: Context.—Significant symptoms of depression are common in the older community-dwelling population. Although depressive symptoms and disability may commonly occur in the same person, whether depressive symptoms contribute to subsequent functional decline has not been elucidated.Objective.—To determine whether depressive symptoms in older persons increase the risk of subsequent decline in physical function as measured by objective performance-based tests.Design.—A 4-year prospective cohort study.Setting.—The communities of Iowa and Washington counties, Iowa.Participants.—A total of 1286 persons aged 71 years and older who completed a short battery of physical performance tests in 1988 and again 4 years later.Main Outcome Measures.—Baseline depressive symptoms were assessed by the Center for Epidemiological Studies Depression Scale. Physical performance tests included an assessment of standing balance, a timed 2.4-m (8-ft) walk, and a timed test of 5 repetitions of rising from a chair and sitting down.Results.—After adjustment for baseline performance score, health status, and sociodemographic factors, increasing levels of depressive symptoms were predictive of greater decline in physical performance over 4 years (odds ratio for decline in those with depressed mood vs those without, 1.55; 95% confidence interval [CI], 1.02-2.34). Even among those at the high end of the functional spectrum, who reported no disability, the severity of depressive symptoms predicted subsequent decline in physical performance (odds ratio for decline, 1.03; 95% CI, 1.00-1.08).Conclusions.—This study provides evidence that older persons who report depressive symptoms are at higher risk of subsequent physical decline. These results suggest that prevention or reduction of depressed mood could play a role in reducing functional decline in older persons.

Journal ArticleDOI
TL;DR: This review focuses on some physiological mechanisms of cerebral vasodilatation and alteration of these mechanisms by disease states.
Abstract: Faraci, Frank M., and Donald D. Heistad. Regulation of the Cerebral Circulation: Role of Endothelium and Potassium Channels. Physiol. Rev. 78: 53–97, 1998. — Several new concepts have emerged in re...

Journal ArticleDOI
TL;DR: In this paper, the authors studied the joint distribution of the time of ruin, the surplus immediately before ruin, and the deficit at ruin, which can naturally be interpreted as discounting, and obtained explicit answers for zero initial surplus, very large initial surplus and arbitrary initial surplus if the claim amount distribution is exponential or a mixture of exponentials.
Abstract: This paper studies the joint distribution of the time of ruin, the surplus immediately before ruin, and the deficit at ruin. The time of ruin is analyzed in terms of its Laplace transforms, which can naturally be interpreted as discounting. Hence the classical risk theory model is generalized by discounting with respect to the time of ruin. We show how to calculate an expected discounted penalty, which is due at ruin and may depend on the deficit at ruin and on the surplus immediately before ruin. The expected discounted penalty, considered as a function of the initial surplus, satisfies a certain renewal equation, which has a probabilistic interpretation. Explicit answers are obtained for zero initial surplus, very large initial surplus, and arbitrary initial surplus if the claim amount distribution is exponential or a mixture of exponentials. We generalize Dickson’s formula, which expresses the joint distribution of the surplus immediately prior to and at ruin in terms of the probability of ult...

Journal ArticleDOI
TL;DR: There was suggestive evidence for a protective locus on chromosome 4 near the alcohol dehydrogenase genes, for which protective effects have been reported in Asian populations.
Abstract: Alcohol dependence is a leading cause of morbidity and premature death. Several lines of evidence suggest a substantial genetic component to the risk for alcoholism: sibs of alcoholic probands have a 3-8 fold increased risk of also developing alcoholism, and twin heritability estimates of 50-60% are reported by contemporary studies of twins. We report on the results of a six-center collaborative study to identify susceptibility loci for alcohol dependence. A genome-wide screen examined 291 markers in 987 individuals from 105 families. Two-point and multipoint nonparametric linkage analyses were performed to detect susceptibility loci for alcohol dependence. Multipoint methods provided the strongest suggestions of linkage with susceptibility loci for alcohol dependence on chromosomes 1 and 7, and more modest evidence for a locus on chromosome 2. In addition, there was suggestive evidence for a protective locus on chromosome 4 near the alcohol dehydrogenase genes, for which protective effects have been reported in Asian populations.

Journal ArticleDOI
12 Jun 1998-Cell
TL;DR: The results demonstrate that cellular mechanisms of human glutamine-repeat disease are conserved in invertebrates and will aid in identifying additional factors that modulate neurodegeneration.

Journal ArticleDOI
TL;DR: Findings indicate a genetic predisposition to the metabolism of irinotecan, suggesting that patients with low UGT1A1 activity, such as those with Gilbert's syndrome, may be at an increased risk for irinOTecan toxicity.
Abstract: Irinotecan (CPT-11) is a promising antitumor agent, recently approved for use in patients with metastatic colorectal cancer. Its active metabolite, SN-38, is glucuronidated by hepatic uridine diphosphate glucuronosyltransferases (UGTs). The major dose-limiting toxicity of irinotecan therapy is diarrhea, which is believed to be secondary to the biliary excretion of SN-38, the extent of which is determined by SN-38 glucuronidation. The purpose of this study was to identify the specific isoform of UGT involved in SN-38 glucuronidation. In vitro glucuronidation of SN-38 was screened in hepatic microsomes from normal rats (n = 4), normal humans (n = 25), Gunn rats (n = 3), and patients (n = 4) with Crigler-Najjar type I (CN-I) syndrome. A wide intersubject variability in in vitro SN-38 glucuronide formation rates was found in humans. Gunn rats and CN-I patients lacked SN-38 glucuronidating activity, indicating the role of UGT1 isoform in SN-38 glucuronidation. A significant correlation was observed between SN-38 and bilirubin glucuronidation (r = 0.89; P = 0.001), whereas there was a poor relationship between para-nitrophenol and SN-38 glucuronidation (r = 0.08; P = 0.703). Intact SN-38 glucuronidation was observed only in HK293 cells transfected with the UGT1A1 isozyme. These results demonstrate that UGT1A1 is the isoform responsible for SN-38 glucuronidation. These findings indicate a genetic predisposition to the metabolism of irinotecan, suggesting that patients with low UGT1A1 activity, such as those with Gilbert's syndrome, may be at an increased risk for irinotecan toxicity.

Journal ArticleDOI
TL;DR: Elevated O2-.
Abstract: The endothelium is a source of reactive oxygen species in short-term models of hypercholesterolemia and atherosclerosis. We examined a chronic model of atherosclerosis for increased vascular production of superoxide (O2-.) and determined whether endothelial overexpression of superoxide dismutase (SOD) would improve endothelium-dependent relaxation. Superoxide generation was 3 times higher in isolated aortas from Watanabe heritable hyperlipidemic (WHHL) rabbits (2 to 4 years old) compared with aortas from New Zealand White (NZ) rabbits (43+/-10 versus 14+/-2 relative light units x min(-1) x mm(-2), n=9, P<0.05). After in vitro transduction with adenovirus containing the gene for CuZn-SOD (AdCMVCuZn-SOD) or extracellular SOD (AdCMVEC-SOD), endothelial O2-. levels in WHHL aortas were significantly reduced. Gene transfer of SOD to WHHL aortas, however, failed to improve the impaired relaxation to acetylcholine or calcium ionophore. By use of the oxidative fluorescent dye hydroethidine, an in situ assay indicated markedly increased generation of O2-. throughout the wall of WHHL aorta, especially within layers of smooth muscle. This finding was confirmed by demonstrating increased O2-. levels in smooth muscle cells cultured from WHHL aorta. We conclude that elevated O2-. levels in atherosclerotic vessels are not confined to the endothelium but occur throughout the vascular wall, including smooth muscle cells. Reduction in endothelial O2-. levels is not sufficient to improve endothelium-dependent relaxation. Generation of reactive oxygen species within the media may contribute to vasomotor dysfunction in atherosclerosis.

Patent
10 Mar 1998
TL;DR: In this article, a combination of immunostimulatory oligonucleotides having at least one unmethylated CpG dinucleotide (CpG ODN) and a non-nucleic acid adjuvant was used to induce cellular immunity in infants.
Abstract: The present invention relates generally to adjuvants, and in particular to methods and products utilizing a synergistic combination of immunostimulatory oligonucleotides having at least one unmethylated CpG dinucleotide (CpG ODN) and a non-nucleic acid adjuvant. Such combinations of adjuvants may be used with an antigen or alone. The present invention also relates to methods and products utilizing immunostimulatory oligonucleotides having at least one unmethylated CpG dinucleotide (CpG ODN) for induction of cellular immunity in infants.

Journal ArticleDOI
TL;DR: A new consensus sequence TXXBXXTBXXXTBB is described, where turns bring basic interacting amino acid residues into proximity, indicating that protein‐GAG interactions play a prominent role in cell‐cell interaction and cell growth.
Abstract: Although interactions of proteins with glycosaminoglycans (GAGs), such as heparin and heparan sulphate, are of great biological importance, structural requirements for protein-GAG binding have not been well-characterised. Ionic interactions are important in promoting protein-GAG binding. Polyelectrolyte theory suggests that much of the free energy of binding comes from entropically favourable release of cations from GAG chains. Despite their identical charges, arginine residues bind more tightly to GAGs than lysine residues. The spacing of these residues may determine protein-GAG affinity and specificity. Consensus sequences such as XBBBXXBX, XBBXBX and a critical 20 A spacing of basic residues are found in some protein sites that bind GAG. A new consensus sequence TXXBXXTBXXXTBB is described, where turns bring basic interacting amino acid residues into proximity. Clearly, protein-GAG interactions play a prominent role in cell-cell interaction and cell growth. Pathogens including virus particles might target GAG-binding sites in envelope proteins leading to infection.

Book ChapterDOI
01 Jan 1998
TL;DR: The authors explored the dynamic arena of science by examining both its history and ways that the nature of science has informed and should guide science teaching, concluding that teachers must have experiences where they explore the social studies of science and contemplate the methods by which that content may be shared with students.
Abstract: This chapter has explored the dynamic arena of the nature of science by examining both its history and ways that the nature of science has informed and should guide science teaching. We have taken the position that a pragmatic consensus exists regarding some of the most important elements regarding the process of science, but have demonstrated that constructive debate exists. Research and discussion continues regarding the relationship between what teachers believe about the nature of science and what they then communicate to students. We assert that teachers must have experiences where they explore the social studies of science and contemplate the methods by which that content may be shared with students. This is the core purpose for developing this book, a book of rationales and strategies. It is vital that the science education community provide an accurate view of how science operates to students and by inference to their teachers. What follows in the accompanying chapters are tested strategies for doing just that. Whether these plans find a home in teacher education programs, in school classrooms, or simply in the minds of interested individuals, we are confident that science education will be a richer discipline and our students will be more adequately prepared for their lives as citizens when they are afforded a fuller understanding of the nature of this thing called science.

Journal Article
TL;DR: Examination of the effects of CpG-motif oligodeoxynucleotides in a murine model of asthma and a previously sensitized mouse suggest that exposure to C pG DNA may protect against asthma.
Abstract: Asthma has been increasing in industrialized countries Evidence suggests that asthma is caused by a Th2 immune response to inhaled environmental Ags and that childhood infections protect against this We have shown that bacterial DNA contains motifs, centered on unmethylated CpG dinucleotides, which induce Th1-type responses We hypothesized that the Th1 effect of these CpG motifs may oppose the Th2 type allergic response and suggest that this may account for the protective effect of childhood infection against asthma We examined the effects of CpG-motif oligodeoxynucleotides (CpG ODN) in a murine model of asthma Airway eosinophilia, Th2 cytokine induction, IgE production, and bronchial hyperreactivity were prevented by coadministration of CpG ODN with the Ag Significantly, in a previously sensitized mouse, CpG ODN can prevent allergen-induced airway inflammation These studies suggest that exposure to CpG DNA may protect against asthma

Journal ArticleDOI
TL;DR: Results demonstrate that, in addition to several recently identified signaling molecules, reactive oxygen intermediates play a critical role in activation of NF-κB, activated protein-1, c-Jun kinase, and apoptosis induced by TNF and other agents.

Journal ArticleDOI
TL;DR: Human β-defensins mRNAs are expressed in excised surface and submucosal gland epithelia from non-CF and CF patients and data suggest that in the lung HBD-2 expression is induced by inflammation, whereas H BD-1 may serve as a defense in the absence of inflammation.
Abstract: Human β-defensins (HBDs) are antimicrobial peptides that may play a role in mucosal defense. Diminished activity of these peptides has been implicated in the pathogenesis of cystic fibrosis (CF) lung disease. We show that HBD-1 and HBD-2 mRNAs are expressed in excised surface and submucosal gland epithelia from non-CF and CF patients. The pro-inflammatory cytokine interleukin-1β stimulated the expression of HBD-2 but not HBD-1 mRNA and peptide in primary cultures of airway epithelia. HBD-1 was found in bronchoalveolar lavage (BAL) fluid from normal volunteers, CF patients, and patients with inflammatory lung diseases, whereas HBD-2 was detected in BAL fluid from patients with CF or inflammatory lung diseases, but not in normal volunteers. Both HBD-1 and HBD-2 were found in BAL fluid in concentrations of several ng/ml, and both recombinant peptides showed salt-sensitive bactericidal activity. These data suggest that in the lung HBD-2 expression is induced by inflammation, whereas HBD-1 may serve as a defense in the absence of inflammation.

Journal ArticleDOI
TL;DR: Overall, U.S. isolates were considerably more resistant than those from Canada, and distinct differences were noted in the antimicrobial susceptibilities of several pathogens.
Abstract: The SENTRY Program was established in January 1997 to measure the predominant pathogens and antimicrobial resistance patterns of nosocomial and community-acquired infections over a broad network of sentinel hospitals in the United States (30 sites), Canada (8 sites), South America (10 sites), and Europe (24 sites). During the first 6-month study period (January to June 1997), a total of 5,058 bloodstream infections (BSI) were reported by North American SENTRY participants (4,119 from the United States and 939 from Canada). In both the United States and Canada, Staphylococcus aureus and Escherichia coli were the most common BSI isolates, followed by coagulase-negative staphylococci and enterococci. Klebsiella spp., Enterobacter spp., Pseudomonas aeruginosa, Streptococcus pneumoniae, and beta-hemolytic streptococci were also among the 10 most frequently reported species in both the United States and Canada. Although the rank orders of pathogens in the United States and Canada were similar, distinct differences were noted in the antimicrobial susceptibilities of several pathogens. Overall, U.S. isolates were considerably more resistant than those from Canada. The differences in the proportions of oxacillin-resistant S. aureus isolates (26.2 versus 2.7% for U.S. and Canadian isolates, respectively), vancomycin-resistant enterococcal isolates (17.7 versus 0% for U.S. and Canadian isolates, respectively), and ceftazidime-resistant Enterobacter sp. isolates (30.6 versus 6.2% for U.S. and Canadian isolates, respectively) dramatically emphasize the relative lack of specific antimicrobial resistance genes (mecA, vanA, and vanB) in the Canadian microbial population. Among U.S. isolates, resistance to oxacillin among staphylococci, to vancomycin among enterococci, to penicillin among pneumococci, and to ceftazidime among Enterobacter spp. was observed in both nosocomial and community-acquired pathogens, although in almost every instance the proportion of resistant strains was higher among nosocomial isolates. Antimicrobial resistance continues to increase, and ongoing surveillance of microbial pathogens and resistance profiles is essential on national and international scales.