Showing papers by "University of Louisville published in 1997"

Prospective study of blunt aortic injury: Multicenter trial of the American Association for the Surgery of Trauma

Abstract: Background: Blunt aortic injury is a major cause of death from blunt trauma. Evolution of diagnostic techniques and methods of operative repair have altered the management and posed new questions in recent years. Methods: This study was a prospectively conducted multicenter trial involving 50 trauma centers in North America under the direction of the Multi-institutional Trial Committee of the American Association for the Surgery of Trauma. Results: There were 274 blunt aortic injury cases studied over 2.5 years, of which 81% were caused by automobile crashes. Chest computed tomography and transesophageal echocardiography were applied in 88 and 30 cases, respectively, and were 75 and 80% diagnostic, respectively. Two hundred seven stable patients underwent planned thoracotomy and repair. Clamp and sew technique was used in 73 (35%) and bypass techniques in 134 (65%). Overall mortality was 31%, with 63% of deaths being attributable to aortic rupture; mortality was not affected by method of repair. Paraplegia occurred postoperatively in 8.7%. Logistic regression analysis demonstrated clamp and sew (p = 0.002) and aortic cross clamp time of 30 minutes (p = 0.01) to be associated with development of postoperative paraplegia. Conclusions: Rupture after hospital admission remains a major problem. Although newer diagnostic techniques are being applied, at this time aortography remains the diagnostic standard. Aortic cross clamp time beyond 30 minutes was associated with paraplegia; bypass techniques, which provide distal aortic perfusion, produced significantly lower paraplegia rates than the clamp and sew approach.

Fundamentals of Argumentation Theory : A Handbook of Historical Backgrounds and Contemporary Developments

Abstract: Contents: Preface. Introduction. Part I: Historical Backgrounds. Analytic, Dialectic and Rhetoric. Analysis of Fallacies, Controversy, and Discussion. Perelman and Olbrechts-Tyteca's New Rhetoric. Toulmin's Model of Argumentation. Part II: Contemporary Developments. Informal Logic and Critical Thinking. Communication and Rhetoric. Fallacies and Formal Logic. Dialogue Logic and Formal Dialectics. Pragma-Dialectics and Critical Discussion. Language-Oriented Approaches to Argumentation. Other Significant Developments.

Ischemic Preconditioning Induces Selective Translocation of Protein Kinase C Isoforms ε and η in the Heart of Conscious Rabbits Without Subcellular Redistribution of Total Protein Kinase C Activity

Abstract: Considerable controversy surrounds the role of protein kinase C (PKC) in ischemic preconditioning (PC). Previous studies have used pharmacological agents and/or measured total myocardial P...

Influences on consumer use of word-of-mouth recommendation sources

Abstract: This article reports the development and testing of a theoretical model of the initial stages of recommendation-based decision making by consumers. Although consumers use a variety of recommendation sources, they have different motivations for the use of different sources. The model focuses on the factors that influence the likelihood of consumers using strong-tie sources (e.g., friends and family) and weak-tie sources (e.g., acquaintances or strangers) or recommendations. The factors used in the model are the prior knowledge level of the consumer about the product being considered, the perceived decision task difficulty level, and the type of evaluative cues sought by the consumer. Hypotheses are tested using data collected in an extensive field study with consumers. Two paths or routes of influence on the use of recommendation sources are proposed and confirmed in the study.

Targeted disruption of the mouse gene encoding steroidogenic acute regulatory protein provides insights into congenital lipoid adrenal hyperplasia

Abstract: An essential component of regulated steroidogenesis is the translocation of cholesterol from the cytoplasm to the inner mitochondrial membrane where the cholesterol side-chain cleavage enzyme carries out the first committed step in steroidogenesis. Recent studies showed that a 30-kDa mitochondrial phosphoprotein, designated steroidogenic acute regulatory protein (StAR), is essential for this translocation. To allow us to explore the roles of StAR in a system amenable to experimental manipulation and to develop an animal model for the human disorder lipoid congenital adrenal hyperplasia (lipoid CAH), we used targeted gene disruption to produce StAR knockout mice. These StAR knockout mice were indistinguishable initially from wild-type littermates, except that males and females had female external genitalia. After birth, they failed to grow normally and died from adrenocortical insufficiency. Hormone assays confirmed severe defects in adrenal steroids—with loss of negative feedback regulation at hypothalamic–pituitary levels—whereas hormones constituting the gonadal axis did not differ significantly from levels in wild-type littermates. Histologically, the adrenal cortex of StAR knockout mice contained florid lipid deposits, with lesser deposits in the steroidogenic compartment of the testis and none in the ovary. The sex-specific differences in gonadal involvement support a two-stage model of the pathogenesis of StAR deficiency, with trophic hormone stimulation inducing progressive accumulation of lipids within the steroidogenic cells and ultimately causing their death. These StAR knockout mice provide a useful model system in which to determine the mechanisms of StAR’s essential roles in adrenocortical and gonadal steroidogenesis.

Comparison of the Safety of Early Enteral vs Parenteral Nutrition in Mild Acute Pancreatitis

Abstract: Background: This prospective study was designed to compare the safety, efficacy, cost, and impact on patient outcome of early total enteral nutrition (TEN) vs total parenteral nutrition (TPN) in acute pancreatitis. Methods: Patients admitted with acute pancreatitis or an acute flare of chronic pancreatitis, characterized by abdominal pain and elevated serum amylase and lipase, were randomized to receive either isocaloric and isonitrogenous TEN (via a nasojejunal feeding tube placed endoscopically) or TPN (via a central or peripheral line) started within 48 hours of admission. Results: Thirty patients were studied over 32 admissions (TEN given on 16 and TPN on 16) for acute pancreatitis. There were no differences on admission in mean age, Ranson criteria, multiple organ failure score (MOF), or APACHE III score between TEN and TPN groups. Although slower to approach goal feeding over the first 72 hours of admission, TEN patients received 71.3% goal calories by day 4 vs 85.2% for TPN patients (not significan...

Expression of chemokine receptors by subsets of neurons in the central nervous system.

Abstract: IL-8 is expressed by activated and neoplastic astrocytes and enhances the survival of hippocampal neurons in vitro. Since mRNA encoding chemokine receptors have been demonstrated in brain, the expression of chemokine receptors by specific cell types in anatomic regions of the central nervous system (CNS) was investigated. Archival tissues from various regions of the CNS were stained with specific mAbs to the Duffy Ag/receptor for chemokines, a promiscuous receptor that binds selected chemokines; the specific receptor for IL-8 (CXCR1); and the receptor (CXCR2) shared by IL-8 and melanoma growth stimulatory activity. The Duffy Ag/receptor for chemokines was expressed exclusively by Purkinje cells in the cerebellum. Chemokine binding and radioligand cross-linking confirmed the presence of a high affinity, promiscuous chemokine receptor in the cerebellum. Although CXCR1 was not expressed in the CNS, CXCR2 was expressed at high levels by subsets of projection neurons in diverse regions of the brain and spinal cord, including the hippocampus, dentate nucleus, pontine nuclei, locus coeruleus, and paraventricular nucleus, and in the anterior horn, interomediolateral cell column, and Clarke's column of the spinal cord. Fibers that express CXCR2 included those in the superior cerebellar peduncle and the substantia gelatinosa. Immunohistochemical analysis of the involved brain tissues from patients with Alzheimer's disease revealed expression of CXCR2 in the neuritic portion of plaques surrounding deposits of amyloid. These data suggest that chemokines may play a role in reactive processes in normal neuronal function and neurodegenerative disorders.

Melatonin Prevents Death of Neuroblastoma Cells Exposed to the Alzheimer Amyloid Peptide

Abstract: Studies from several laboratories have generated evidence suggesting that oxidative stress is involved in the pathogenesis of Alzheimer’s disease (AD). The finding that the amyloid β protein (Aβ) has neurotoxic properties and that such effects are, in part, mediated by free radicals has provided insights into mechanisms of cell death in AD and an avenue to explore new therapeutic approaches. In this study we demonstrate that melatonin, a pineal hormone with recently established antioxidant properties, is remarkably effective in preventing death of cultured neuroblastoma cells as well as oxidative damage and intracellular Ca2+ increases induced by a cytotoxic fragment of Aβ. The effects of melatonin were extremely reproducible and corroborated by multiple quantitative methods, including cell viability studies by confocal laser microscopy, electron microscopy, and measurements of intracellular calcium levels. The importance of this finding is that, in contrast to conventional antioxidants, melatonin has a proposed physiological role in the aging process. Secretion levels of this hormone are decreased in aging and more severely reduced in AD. The reported phenomenon may be of therapeutic relevance in AD.

Combined Accelerated Tissue-Plasminogen Activator and Platelet Glycoprotein IIb/IIIa Integrin Receptor Blockade With Integrilin in Acute Myocardial Infarction Results of a Randomized, Placebo-Controlled, Dose-Ranging Trial

Abstract: Background Platelet activation and aggregation may be key components of thrombolytic failure to restore and maintain perfusion in acute myocardial infarction. We performed a placebo-controlled, dose-ranging trial of Integrilin, a potent inhibitor of platelet aggregation, with heparin, aspirin, and accelerated alteplase. Methods and Results We assigned 132 patients in a 2:1 ratio to receive a bolus and continuous infusion of one of six Integrilin doses or placebo. Another 48 patients were randomized in a 3:1, double-blind fashion to receive the highest Integrilin dose from the first phase or placebo. All patients received accelerated alteplase, aspirin, and intravenous heparin infusion; all but two groups also received an intravenous heparin bolus. The highest Integrilin dose group from the nonrandomized phase and the randomized patients were pooled for analysis and compared with placebo-treated patients. The primary end point was Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow at 90-minute angiography. Secondary end points were time to ST-segment recovery, an in-hospital composite (death, reinfarction, stroke, revascularization procedures, new heart failure, or pulmonary edema), and bleeding variables. The highest Integrilin dose groups had more complete reperfusion (TIMI grade 3 flow, 66% versus 39% for placebo-treated patients; P =.006) and a shorter median time to ST-segment recovery (65 versus 116 minutes for placebo; P =.05). The groups had similar rates of the composite end point (43% versus 42% for placebo-treated patients) and severe bleeding (4% versus 5%, respectively). Conclusions The incidence and speed of reperfusion can be enhanced when a potent inhibitor of the glycoprotein IIb/IIIa integrin receptor, such as Integrilin, is combined with accelerated alteplase, aspirin, and intravenous heparin.

The Protective Effect of Late Preconditioning Against Myocardial Stunning in Conscious Rabbits Is Mediated by Nitric Oxide Synthase: Evidence That Nitric Oxide Acts Both as a Trigger and as a Mediator of the Late Phase of Ischemic Preconditioning

Abstract: Seventy-four conscious rabbits undergoing a sequence of six 4-minute coronary occlusion/4-minute reperfusion cycles for 3 consecutive days (days 1, 2, and 3) were assigned to nine groups. In group I (controls, n=8), the recovery of systolic wall thickening (WTh) after the sixth reperfusion was markedly improved on days 2 and 3 compared with day 1, indicating late preconditioning (PC) against myocardial stunning; the total deficit of WTh after the sixth reperfusion was reduced by 56% on day 2 and 50% on day 3 compared with day 1 (P<.01). Administration on day 2 of the nonselective NO synthase (NOS) inhibitor Nω-nitro-l-arginine (L-NA) (group II, n=8) or of the selective inducible NOS inhibitors aminoguanidine (AG) (group IV, n=8) and S-methylisothiourea sulfate (SMT) (group VI, n=6) completely abrogated late PC against stunning on day 2. On day 3, the expected PC effect became manifest in all groups. Administration of L-NA, AG, or SMT on day 1 (groups III [n=7], V [n=6], and VII [n=5], respectivel...

Multiple pituitary and ovarian defects in Krox-24 (NGFI-A, Egr-1)-targeted mice.

Abstract: The zinc finger transcription factor Krox-24 (NGFI-A, Egr-1) is encoded by an immediate-early serum response gene expressed in various physiological situations and tissues. To investigate its function, we have created a null allele. Mice homozygous for the mutation have a reduced body size, and both males and females are sterile. These phenotypes were related to defects in the anterior pituitary of both sexes and in the ovary. In the pituitary, two cell lineages expressing Krox-24 are differentially affected by the mutation: somatotropes present abnormal cytological features and are reduced in number, consistent with the decreased GH content observed in these animals; in contrast gonadotropes are normal in number, but specifically fail to synthesize the beta-subunit of LH. In the ovary, LH receptor expression is prevented, indicating an involvement of Krox-24 at two levels at least of the pituitary-gonadal axis. Our data, together with the results of a previous report describing another Krox-24 mutant allele, suggest that Krox-24 may have two distinct molecular functions in the anterior pituitary: transcriptional activation of the LHbeta gene in gonadotropes and control of cell proliferation and/or survival in somatotropes by unknown mechanisms.

COMING OUT AND CROSSING OVER Identity Formation and Proclamation in a Transgender Community

Abstract: Drawing on data from interviews with 65 masculine-to-feminine transgenderists, the authors examine the coming-out experiences of transgendered individuals. Drawing on the literature that shows gender to be an inherent component of the social infrastructure that at an individual level is accomplished in interaction with others, they demonstrate that interactional challenges to gender are insufficient to challenge the system of gender. Whereas many transgenderists believe that their actions and identities are radical challenges to the binary system of gender, in fact, the majority of such individuals reinforce and reify the system they hope to change.

Evidence that late preconditioning against myocardial stunning in conscious rabbits is triggered by the generation of nitric oxide.

Abstract: Recent studies in conscious pigs and rabbits have demonstrated that a series of brief coronary occlusions renders the heart relatively resistant to myocardial “stunning” 24 hours later (late preconditioning [PC] against stunning). The mechanism of this powerful cardioprotective response is unknown. The goal of the present study was to test the hypothesis that the development of late PC against stunning is triggered by increased generation of NO during the first ischemic challenge. Conscious rabbits underwent a sequence of six 4-minute coronary occlusion/4-minute reperfusion cycles for 3 consecutive days (days 1, 2, and 3). On day 1, rabbits received either an intravenous infusion of the NO synthase inhibitor Nω-nitro-l-arginine (L-NA, 13 mg/kg before the first occlusion) (group II, n=10) or vehicle (group I [control], n=10). In the control group, on day 1 systolic wall thickening (WTh) in the ischemic/reperfused region remained significantly depressed for 4 hours after the sixth reperfusion, indi...

Preconditioning of Human Myocardium With Adenosine During Coronary Angioplasty

Abstract: Background It is unknown whether adenosine can precondition human myocardium against ischemia in vivo. Methods and Results Thirty patients were randomized to receive a 10-minute intracoronary infusion of adenosine (2 mg/min) or normal saline; 10 minutes later, they underwent percutaneous transluminal coronary angioplasty (PTCA; three 2-minute balloon inflations 5 minutes apart). In control patients, the ST-segment shift on the intracoronary ECG was significantly greater during the first inflation than during the second and third inflations, consistent with ischemic preconditioning. In contrast, in adenosine-treated patients, there were no differences in ST-segment shift during the three inflations. The ST-segment shift was significantly smaller in the adenosine-treated group compared with the control group during all three inflations. The reduction in ST-segment shift afforded by adenosine during the first inflation (−72% versus first inflation in control subjects) was greater than that afforded by ischem...

Group selection and assortative interactions

Abstract: Natural selection at all levels requires heritable phenotypic variation among units. At the group level, variation is often increased by reproduction coupled with limited dispersal, which forms the basis of kin selection and traditional group selection models. Assortative interactions are another possible mechanism for creating variation among groups that has received less attention. We present a series of models in which altruism is a continuously varying trait and individuals are free to choose their associates, based on information that is acquired through experience, observation, or cultural transmission. Assortative interactions can generate highly nonrandom variation among groups, favoring the evolution of altruism and other group-level adaptations among genealogically unrelated individuals. Altruism can evolve even when the initial phenotypic variation in altruism is not heritable, a form of genetic assimilation. The importance of assortative interactions depends in part on cognitive abilities that...

Overexpression of metallothionein in the heart of transgenic mice suppresses doxorubicin cardiotoxicity.

Abstract: Metallothionein (MT) may provide protection against doxorubicin-induced heart damage. To test this hypothesis, a heart-specific promoter was used to drive the expression of human MT-IIa gene in transgenic mice. Four healthy transgenic mouse lines were produced. Cardiac MT was constitutively overexpressed from 10- to 130-fold higher than normal. The MT concentration was not altered in liver, kidneys, lungs, or skeletal muscles. Other antioxidant components including glutathione, glutathione peroxidase, glutathione reductase, catalase, and superoxide dismutase were not altered in the MT-overexpressing heart. Mice (7-wk-old) from transgenic lines expressing MT activity 10- or 130-fold higher than normal and from nontransgenic controls were treated intraperitoneally with doxorubicin at a single dose of 20 mg/kg, and were killed on the 4th day after treatment. As compared to normal controls, transgenic mice exhibited a significant resistance to in vivo doxorubicin-induced cardiac morphological changes, and the increase in serum creatine phosphokinase activity. Atria isolated from transgenic mice and treated with doxorubicin in tissue bath was also more resistant to functional damage induced by this drug. The results provide direct evidence for the role of MT in cardioprotection against doxorubicin toxicity.

Characterization of the Promoter Region of the Mouse Gene Encoding the Steroidogenic Acute Regulatory Protein

Abstract: Steroidogenic acute regulatory protein (StAR) delivers cholesterol to the inner mitochondrial membrane, where the cholesterol side-chain cleavage enzyme carries out the first committed step in steroid hormone biosynthesis. StAR expression is restricted to steroidogenic cells and is rapidly induced by treatment with trophic hormones or cAMP. We analyzed the 5'-flanking region of the mouse StAR gene to elucidate the mechanisms that regulate its cell-specific and hormone-induced expression. In transient transfection assays, a luciferase reporter gene driven by the StAR 5'-flanking region was preferentially expressed by steroidogenic Y1 adrenocortical and MA-10 Leydig cells in a cAMP-responsive manner. 5'-Deletion and site-directed mutagenesis studies identified a region between -254 and -113 that is essential for full levels of promoter activity. This region contains a binding site for the orphan nuclear receptor steroidogenic factor-1 (SF-1) that, although not required for hormone induction, is critical for basal promoter activity, thus implicating SF-1 in StAR expression. Analyses of knockout mice deficient in SF-1 further supported an important role for SF-1 in StAR gene expression. These studies provide novel insights into the mechanisms that regulate StAR gene expression and extend our understanding of SF-1's global roles within steroidogenic cells.

Hydroxychloroquine Reverses Thrombogenic Properties of Antiphospholipid Antibodies in Mice

Abstract: Background Previous studies have demonstrated that human monoclonal and polyclonal anticardiolipin antibodies have thrombogenic properties in vivo. Using such a model in which these antibodies have been shown to increase both the size of an induced thrombus and the duration of time in which such a clot lasts, we investigated whether hydroxychloroquine alters the dynamics of such thrombus formation. Methods and Results Three groups of nine mice were injected with purified immunoglobulin G (IgG) from a patient with the antiphospholipid syndrome (IgG-APS) and then fed with hydroxychloroquine at various doses (100, 6, and 3 mg/kg body wt). Three control groups of mice were also studied, including mice injected with IgG-APS and then fed with placebo, as well as two other groups injected with IgG from normal human serum and fed either hydroxychloroquine or placebo. A standardized thrombogenic injury was subsequently induced in the femoral vein of each mouse and the area (size) of thrombus measured as well as th...

Differential utilization of CCR5 by macrophage and T cell tropic simian immunodeficiency virus strains

Abstract: Certain chemokine receptors serve as cofactors for HIV type 1 envelope (env)-mediated cell-cell fusion and virus infection of CD4-positive cells. Macrophage tropic (M-tropic) HIV-1 isolates use CCR5, and T cell tropic (T-tropic) strains use CXCR4. To investigate the cofactors used by simian immunodeficiency viruses (SIV), we tested four T-tropic and two M-tropic SIV env proteins for their ability to mediate cell-cell fusion with cells expressing CD4 and either human or nonhuman primate chemokine receptors. Unlike HIV-1, both M- and T-tropic SIV envs used CCR5 but not CXCR4 or the other chemokine receptors tested. However, by testing a panel of CCR5/CCR2b chimeras, we found that the structural requirements for CCR5 utilization by M-tropic and T-tropic SIV strains were different. T-tropic SIV strains required the second extracellular loop of CCR5 whereas a closely related M-tropic SIV strain could, like M-tropic HIV-1 strains, use the amino-terminal domain of CCR5. As few as two amino acid changes in the SIV env V3 domain affected the regions of CCR5 that were critical for fusogenic activity. Receptor signaling was not required for either fusion or infection. Our results suggest that viral tropism may be influenced not only by the coreceptors used by a given virus strain but also by how a given coreceptor is used.

Scale-dependent determinants and consequences of benthic algal heterogeneity

Abstract: The objectives of this paper were to introduce frameworks for predicting the determinants and consequences of the great heterogeneity in benthic algal assemblages. A hierarchical framework of environmental factors affecting benthic algal spatial heterogeneity is presented with the ultimate determinants (climate, geology, land use, and biogeography) that are important constraints on benthic algal assemblage structure at large spatial scales. These ultimate determinants constrain expression of intermediate and proximate determinants of benthic algal function and structure. A similar framework for temporal heterogeneity distinguishes how assemblages respond to short-term and long-term environmental changes, referred to as disturbances and stresses, respectively. Assemblages recover from punctuated (short-term) environmental change (disturbance) by immigration and reproduction of both persistent and recolonizing species. Assemblages adapt to permanent (longterm) environmental change (stress) by changing speci...

The relationship of socioeconomic status, race, and modifiable risk factors to outcomes in patients with systemic lupus erythematosus.

Abstract: Objective. To study the relationship of race, socioeconomic status (SES), clinical factors, and psychosocial factors to outcomes in patients with systemic lupus erythematosus (SLE). Methods. A retrospective cohort was assembled, comprising 200 patients with SLE from 5 centers. This cohort was balanced in terms of race and SES. Patients provided information on socioeconomic factors, access to health care, nutrition, self-efficacy for disease management, health locus of control, social support, compliance, knowledge about SLE, and satisfaction with medical care. Outcome measures included disease activity (measured by the Systemic Lupus Activity Measure), damage (measured by the SLICC/ACR damage index), and health status (measured by the SF-36). Results. In multivariate models that were controlled for race, SES, center, psychosocial factors, and clinical factors, lower self-efficacy for disease management (P ≤ 0.0001), less social support (P < 0.005), and younger age at diagnosis (P < 0.007) were associated with greater disease activity. Older age at diagnosis (P ≤ 0.0001), longer duration of SLE (P ≤ 0.0001), poor nutrition (P < 0.002), and higher disease activity at diagnosis (P < 0.007) were associated with more damage. Lower self-efficacy for disease management was associated with worse physical function (P ≤ 0.0001) and worse mental health status (P ≤ 0.0001). Conclusion. Disease activity and health status were most strongly associated with potentially modifiable psychosocial factors such as self-efficacy for disease management. Cumulative organ damage was most highly associated with clinical factors such as age and duration of disease. None of the outcomes measured were associated with race. These results suggest that education and counseling, coordinated with medical care, might improve outcomes in patients with SLE.

Evolution of HIV-1 coreceptor usage through interactions with distinct CCR5 and CXCR4 domains

Abstract: The chemokine receptor CXCR4 functions as a fusion coreceptor for T cell tropic and dual-tropic HIV-1 strains. To identify regions of CXCR4 that are important for coreceptor function, CXCR4–CXCR2 receptor chimeras were tested for the ability to support HIV-1 envelope (env) protein-mediated membrane fusion. Receptor chimeras containing the first and second extracellular loops of CXCR4 supported fusion by T tropic and dual-tropic HIV-1 and HIV-2 strains and binding of a monoclonal antibody to CXCR4, 12G5, that blocks CXCR4-dependent infection by some virus strains. The second extracellular loop of CXCR4 was sufficient to confer coreceptor function to CXCR2 for most virus strains tested but did not support binding of 12G5. Truncation of the CXCR4 cytoplasmic tail or mutation of a conserved DRY motif in the second intracellular loop did not affect coreceptor function, indicating that phosphorylation of the cytoplasmic tail and the DRY motif are not required for coreceptor function. The results implicate the involvement of multiple CXCR4 domains in HIV-1 coreceptor function, especially the second extracellular loop, though the structural requirements for coreceptor function were somewhat variable for different env proteins. Finally, a hybrid receptor in which the amino terminus of CXCR4 was replaced by that of CCR5 was active as a coreceptor for M tropic, T tropic, and dual-tropic env proteins. We propose that dual tropism may evolve in CCR5-restricted HIV-1 strains through acquisition of the ability to utilize the first and second extracellular loops of CXCR4 while retaining the ability to interact with the CCR5 amino-terminal domain.