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M W Peterson

Publications and source records attributed to M W Peterson.

At least 19 recordsLinked to original sources
PubMed2003

The effects of testing in shifts on a clinical in-course computerized exam.

PROBLEM: Testing a large medical class over two days with a single-form computer-based test has generated questions related to test security and the influence of unequal test preparation times afforded by the testing method. METHODS: An analysis of variance (anova) design was used to compare the scores for the two days for each of the three tests. In addition, a within-student match-paired t-test of standard score differences was used to examine the relative standing of students across tests administered on different days. RESULTS: Both the anova and the match-paired t-test failed to detect a difference between first and second day testing. CONCLUSION: This research suggests that using a single test form with shift-based computerised assessments, spread over as many as two days, does not seriously compromise the integrity of the results. Since creating multiple unique-item forms is often not possible, shift-based testing with a single test form appears to be a fair method of accommodating a large number of students.

Analysis of Variance↗
PubMed2001

Ceramide regulates lipopolysaccharide-induced phosphatidylinositol 3-kinase and Akt activity in human alveolar macrophages.

The phosphatidylinositol (PI) 3-kinase pathway is an important regulator of cell survival. In human alveolar macrophages, we found that LPS activates PI 3-kinase and its downstream effector, Akt. LPS exposure of alveolar macrophages also results in the generation of ceramide. Because ceramide exposure induces apoptosis in other cell types and the PI 3-kinase pathway is known to inhibit apoptosis, we determined the relationship between LPS-induced ceramide and PI 3-kinase activation in alveolar macrophages. We found that ceramide exposure activated PI 3-kinase and Akt. When we blocked LPS-induced ceramide with the inhibitor D609, we blocked LPS-induced PI 3-kinase and Akt activation. Evaluating cell survival after ceramide or LPS exposure, we found that blocking PI 3-kinase induced a significant increase in cell death. Because these effects of PI 3-kinase inhibition were more pronounced in ceramide- vs LPS-treated alveolar macrophages, we also evaluated NF-kappaB, which has also been linked to cell survival. We found that LPS, to a greater degree than ceramide, induced NF-kappaB translocation to the nucleus. As a composite, these studies suggest that the effects of ceramide exposure in alveolar macrophages may be very different from the effects described for other cell types. We believe that LPS induction of ceramide results in PI 3-kinase activation and represents a novel effector mechanism that promotes survival of human alveolar macrophages in the setting of pulmonary sepsis.

Active Transport, Cell Nucleus↗
PubMed2001

Lipopolysaccharide activates Akt in human alveolar macrophages resulting in nuclear accumulation and transcriptional activity of beta-catenin.

Exposure of human alveolar macrophages to bacterial LPS results in activation of a number of signal transduction pathways. An early event after the alveolar macrophage comes in contact with LPS is activation of the phosphatidylinositol 3 kinase (PI 3-kinase). This study evaluates the downstream effects of that activation. We observed that LPS exposure results in phosphorylation of Akt (serine 473). We found this using both phosphorylation-specific Abs and also by in vivo phosphorylation with (32)P-loaded cells. AKT activation resulted in the phosphorylation-dependent inactivation of glycogen synthase kinase (GSK-3) (serine 21/9). We found that both of these events were linked to PI 3-kinase because the PI 3-kinase inhibitors, wortmannin and LY294002, inhibited LPS-induced phosphorylation of both AKT and GSK-3. Inactivation of GSK-3 has been shown to reduce the ubiquitination of beta-catenin, resulting in nuclear accumulation and transcriptional activity of beta-catenin. Consistent with this, we found that LPS caused an increase in the amounts of PI 3-kinase-dependent nuclear beta-catenin in human alveolar macrophages and expression of genes that require nuclear beta-catenin for their activation. This is the first demonstration that LPS exposure activates AKT, inactivates GSK-3, and causes accumulation and transcriptional activity of beta-catenin in the nucleus of any cell, including alveolar macrophages.

3-Phosphoinositide-Dependent Protein Kinases↗
PubMed2001

Asthma patient education: current utilization in pulmonary training programs.

The national guidelines for the diagnosis and management of asthma published in April of 1997 emphasized patient education in asthma management. It is unclear how often patient education is included in asthma management clinics. We sought to determine how often education programs are available by surveying teaching hospitals with training programs in pulmonary and critical care medicine. Using this survey, we also determined the reason programs are not offered and whether computer resources are routinely available to utilize computer-delivered patient educational materials. We sent mail questionnaires to 163 training programs in the United States. We had a response rate of 72% (117 of 163). Of the 117 programs responding, 75 (64%) reported having a formal asthma patient education program. Most (72%) were in university teaching hospitals. A majority of respondents (84%) believed that compensation for their efforts was inadequate, and those hospitals with no formal asthma education program reported that financial cost and time requirements were the primary reasons for not having such a program. Despite the fact that many programs did not have a patient education component, 96% (72 of 75) of respondents with an educational program viewed patient education as an effective patient self-management tool. Of all programs surveyed, 85% reported they would use a high-quality computer-based asthma education program if one was available. Implementation of such a program is feasible, with 69% of programs surveyed having a personal computer in their clinic and 60% having Internet access. We conclude that most training directors believe that patient asthma education is important and effective; however, cost and time issues remain barriers to its implementation. Computer-based educational programs delivered over the Internet are feasible, could address some of these limitations, and are acceptable to most programs.

Asthma↗
PubMed2001

GM-CSF increases AP-1 DNA binding and Ref-1 amounts in human alveolar macrophages.

Alveolar macrophages have been implicated in the pathogenesis of a number of acute and chronic lung disorders. A characteristic feature of many of the chronic lung diseases is that the types of macrophages in the lung change, and in most instances, the cells resemble monocyte-like cells. We have previously shown that normal human alveolar macrophages have a decreased capacity to express protein kinase C (PKC)-induced DNA binding activity of the transcription factor activator protein (AP)-1 compared with monocytes. This decrease in AP-1 DNA binding appears to be due to a defect in redox regulation of AP-1 proteins via a decrease in the redox active protein Ref-1. The hypothesis for this study is that there are factors generated during the development of chronic lung disease that increase AP-1 DNA binding activity and Ref-1 production in human alveolar macrophages. We have focused specifically on granulocyte-macrophage colony-stimulating factor (GM-CSF) as a prototype mediator that can be released by alveolar macrophages and is related to the fibrotic process in the lung. We found that after a 24-h incubation with GM-CSF, AP-1 DNA binding was significantly increased in both unstimulated, interleukin (IL)-13, and phorbol myristate acetate (PMA)-stimulated alveolar macrophages and that there was a corresponding increase in Ref-1 protein by Western blot analysis in the PMA-stimulated group. This suggests that disease-related cytokines such as GM-CSF and IL-13 may modulate AP-1 DNA binding activity in alveolar macrophages.

Base Sequence↗
PubMed2000

Protein kinase C zeta plays a central role in activation of the p42/44 mitogen-activated protein kinase by endotoxin in alveolar macrophages.

Human alveolar macrophages respond to endotoxin (LPS) by activation of a number of mitogen-activated protein kinase pathways, including the p42/44 (extracellular signal-related kinase (ERK)) kinase pathway. In this study, we evaluated the role of the atypical protein kinase C (PKC) isoform, PKC zeta, in LPS-induced activation of the ERK kinase pathway. Kinase activity assays showed that LPS activates PKC zeta, mitogen-activated protein/ERK kinase (MEK, the upstream activator of ERK), and ERK. LPS did not activate Raf-1, the classic activator of MEK. Pseudosubstrate-specific peptides with attached myristic acid are cell permeable and can be used to block the activity of specific PKC isoforms in vivo. We found that a peptide specific for PKC zeta partially blocked activation of both MEK and ERK by LPS. We also found that this peptide blocked in vivo phosphorylation of MEK after LPS treatment. In addition, we found that LPS caused PKC zeta to bind to MEK in vivo. These observations suggest that MEK is an LPS-directed target of PKC zeta. PKC zeta has been shown in other systems to be phosphorylated by phosphatidylinositol (PI) 3-kinase-dependent kinase. We found that LPS activates PI 3-kinase and causes the formation of a PKC zeta/PI 3-kinase-dependent kinase complex. These data implicate the PI 3-kinase pathway as an integral part of the LPS-induced PKC zeta activation. Taken as a whole, these studies suggest that LPS activates ERK kinase, in part, through activation of an atypical PKC isoform, PKC zeta.

Amino Acid Sequence↗
PubMed1999

Asthma guidelines: an assessment of physician understanding and practice.

In 1997 the NHLBI updated guidelines for the diagnosis and management of asthma. We hypothesized that not all components of the updated guidelines are well understood by the physicians who care for asthmatics. To develop appropriate educational interventions that address areas of physician misunderstanding, it is important to identify these components. Based upon NHLBI guidelines, we developed a multiple-choice test of asthma knowledge that was distributed to physicians at the University of Iowa; 108 physicians completed the test, including 20 asthma specialists, 11 asthma specialty fellows, 11 General Medicine faculty, five Family Medicine faculty, 51 Internal Medicine residents, and five Family Medicine residents. The mean correct total score for all physicians was 60 +/- 2% (mean +/- SEM). Asthma specialists scored higher in total score and in pharmacology and prevention. However, no group performed well on estimating disease severity. We further identified deficits in the use of spirometry and anti-inflammatory agents in caring for asthmatic patients. Thus, deficits exist in physician understanding and implementation of the NHLBI guidelines for the diagnosis and management of asthma. By identifying specific areas of misunderstanding, we can design better educational interventions. Clearly, educational programs should emphasize new models for estimating chronic disease severity.

Adult↗
PubMed1999

Realizing the promise: delivering pulmonary continuing medical education over the Internet.

STUDY OBJECTIVES: Continuing medical education (CME) is meant to bridge the gap between new scientific observations and clinical practice. However, traditional CME has not been effective at altering the behaviors of physicians. One reason for this failure of traditional CME programs may be their inflexibility. In traditional CME, the clinician does not choose the topic, the pace of the program, or the place of learning, and the CME material cannot be easily delivered to the point of care where the clinician needs the information. Computers and computer networks have the potential to accomplish these goals. CME has begun to appear on the Internet; however, there have been few evaluations of its usefulness, acceptance, and effectiveness. Over the last 18 months, we have developed three on-line pulmonary CME programs, and we have delivered them on the Virtual Hospital, the University of Iowa's digital health sciences library on the Internet. We report our initial experience with this CME material. DESIGN: We measured the frequency with which the Internet-delivered CME is accessed by monitoring page accessions and by using a log file analysis program (Analog 1.2.3; University of Cambridge Statistical Laboratory; Cambridge, UK). In addition, we collected all completed CME examinations and evaluation forms submitted by registered users. MEASUREMENTS AND RESULTS: We have found that the frequency with which the Internet-delivered CME is accessed has continued to increase with time (2.3-fold increase over 18 months), that evaluations of technical and content issues are strongly favorable, and that some clinicians have been willing to pay to receive CME through the medium of the Internet. CONCLUSIONS: We feel that with adequate peer review and quality control, physicians will use the Internet-delivered CME. However, several obstacles to wide use remain. These obstacles include issues regarding training in using the Internet for physicians, reluctance of physicians to participate in on-line commerce, and the current unavailability of CME to be delivered in small-grained quantities to the point of care. As these issues are addressed, we feel that on-line CME will represent an increasingly important CME medium for clinicians.

Education, Medical, Continuing↗
PubMed1998

Asbestos-induced lung epithelial permeability: potential role of nonoxidant pathways.

Asbestos fibers are an important cause of lung fibrosis; however, the biological mechanisms are incompletely understood. The lung epithelium serves an important barrier function in the lung, and disrupting the epithelial barrier can contribute to lung fibrosis. Lung epithelial permeability is increased in patients with asbestosis, and asbestos fibers increase permeability across cultured human lung epithelium. However, the mechanism of this increased permeability is not known. Many of the biological effects of asbestos are postulated to be due to its ability to generate oxidants, and oxidants are known to increase epithelial permeability. However, we previously reported that altering the iron content of asbestos (important in oxidant generation) had no effect on its ability to increase permeability. For that reason, we undertook these studies to determine whether asbestos increases epithelial permeability through nonoxidant pathways. Both extracellular (H2O2) and intracellular (menadione) oxidants increase paracellular permeability across human lung epithelial monolayers. Extracellular catalase but not superoxide dismutase prevented increased permeability after both oxidant exposures. However, catalase offered no protection from asbestos-induced permeability. We next depleted the cells of glutathione or catalase to determine whether depleting normal cellular antioxidants would increase the sensitivity to asbestos. Permeability was the same in control cells and in cells depleted of these antioxidants. In addition to generating oxidants, asbestos also activates signal transduction pathways. Blocking protein kinase C activation did not prevent asbestos-induced permeability; however, blocking tyrosine kinase with tyrophostin A25 did prevent asbestos-induced permeability, and blocking tyrosine phosphatase with sodium vanadate enhanced the effect of asbestos. These data demonstrate that asbestos may increase epithelial permeability through nonoxidant pathways that involve tyrosine kinase activation. This model offers an important system for studying pathways involved in regulating lung epithelial permeability.

Amitrole↗
PubMed1997

Human neutrophil elastase abolishes interleukin-8 chemotactic activity.

A large body of literature supports the role of interleukin-8 (IL-8) in inflammatory lung disease. Numerous factors induce the local synthesis and secretion of this potent chemokine leading to the recruitment and activation of polymorphonuclear leukocytes. However, little is currently known about the fate of IL-8 secreted at sites of inflammatory injury. We have found that incubation of recombinant human IL-8 with purified human neutrophil elastase (HNE) results in the loss of IL-8 chemotactic activity in a dose- and time-dependent fashion. This loss in bioactivity is accompanied by a similar loss of IL-8 immunoreactivity. Western blot analysis revealed that IL-8 chemotactic activity is lost by proteolysis of the parent molecule into undetectable small fragments. The terminal digestion of IL-8 was specific to HNE as no loss of bioactivity was observed with equimolar concentrations of the serine proteases urokinase, plasmin, thrombin, or cathepsin G. This effect on chemotactic activity is not limited to recombinant IL-8 because HNE also digested IL-8 secreted by human monocytes. HNE-mediated proteolysis offers a novel mechanism for down-regulating the inflammatory cascade initiated by IL-8.

Chemotaxis, Leukocyte↗
PubMed1997

CD11b/CD18 mediates the neutrophil chemotactic activity of fibrin degradation product D domain.

Coagulation and fibrinolysis universally accompany tissue injury and repair. The accumulation of regionally generated fibrin degradation products (FDP) may modify the local inflammatory response. We have found FDP to be potent neutrophil chemotaxins. We separated plasmin FDP by chromatofocusing and found chemotactic activity limited to fractions containing the fibrinogen D domain (D-D dimer and D monomer). The bioactivity of the D-D dimer did not require an intact cross link site as removal of this sequence with puff adder venom or hypocalcemic plasmic digestion did not decrease chemotaxis. Peptide inhibition studies confirmed that the chemotactic region did not involve terminal gamma chain sequences or alpha chain RGD motifs. The internal gamma chain peptide KYGWTVFQKRLDGSV (P1), known to bind CD11b/CD18, exhibited concentration dependent chemotactic activity. Similarly, monoclonal antibodies directed against CD11b/CD18 blocked PMN migration to FDP without similar inhibition of chemotaxis to IL-8 or LTB4. Thus, neutrophil chemotaxis to FDP is mediated by interactions between the fibrinogen D domain and CD11b/CD18.

Amino Acid Sequence↗
PubMed1996

The role of fibrin degradation products in neutrophil recruitment to the lung.

Pulmonary epithelial injury leads to increased permeability and plasma exudation. Plasma rapidly forms an insoluble fibrin clot in the distal airspace because of the potent procoagulant activity expressed there. Because these airspaces also express potent fibrinolytic activity, digestion of fibrin results in high local concentrations of fibrin degradation products (FDP), which are biologically important molecules with numerous proinflammatory actions. Inflammatory lung injury is associated with neutrophil accumulation, and other matrix proteins affect inflammatory cell traffic. In this study we examined the potential role of FDP in neutrophil recruitment to the lung. Using a chemotaxis assay, we found that FDP are potent chemotactic proteins when neutrophils are prestimulated with lipopolysaccharide (LPS) or formylmethionylleucylphenylalanine (fMLP). Although FDP are high molecular weight proteins, we found that these potent chemoattractants induce polymorphonuclear leukocyte (PMN) migration across epithelial monolayers. The magnitude of response is dependent upon the monolayers' ability to form and maintain tight junctions. Human neutrophil elastase (HNE), another fibrinolytic enzyme released from neutrophils, digests fibrin into chemotactic peptides which are more potent on a weight basis than plasmin-generated FDP. Furthermore, HNE secondarily digests plasmin FDP, producing molecules which are more potent chemoattractants than native plasmin FDP. These observations suggest a potential mechanism whereby FDP may contribute to the neutrophil accumulation which characterizes many inflammatory lung diseases.

Cell Line↗
PubMed1995

Effect of neutrophil mediators on epithelial permeability.

Inflammatory lung disease is associated with increased epithelial permeability, but it is unclear how inflammatory cells alter epithelial permeability. Neutrophils have azurophilic granules containing elastase, cathepsin G, and defensins which are released at sites of inflammation. Experiments using whole animals and cultured cells suggest that neutrophil elastase contributes to increased epithelial permeability. Using Madin-Darby canine kidney epithelial (MDCK) monolayers, a well-described epithelial model, we asked whether neutrophil elastase directly affects epithelial permeability independent of cell death or cell detachment from the substratum. We measured permeability using 3H-mannitol. We found that neutrophil elastase increased epithelial permeability in a time- and concentration-dependent fashion. Increased permeability required prolonged (> or = 6 h) exposure to elastase, but was not associated with cytolytic injury or cell detachment. These findings are potentially relevant to the lung because we found a similar time- and concentration-dependent effect when we added elastase to cultured human bronchial epithelial cells. In MDCK cells, permeability increased without alterations in cell actin at the light microscopic level. Interestingly, elastase-induced permeability was both prevented and reversed by serum, but not by serum albumin. Complete reversal occurred if serum was added up to 16 h after adding elastase. Proteolytic activity is important in HNE-induced epithelial permeability because soy bean trypsin inhibitor completely blocks the effect and alpha 1 proteinase inhibitor (alpha 1 PI) partially blocks the effect. Charge interactions also appear to be important because the polyanions heparin and sulfated dextran completely blocked increased permeability following elastase but only partially blocked elastolytic activity in isotonic solutions.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Predicting postoperative pulmonary function in patients undergoing lung resection.

OBJECTIVE: Our aim was to determine the effect of lung resection on spirometric lung function and to evaluate the accuracy of simple calculation in predicting postoperative pulmonary function in patients undergoing lung resection. DESIGN: We reviewed preoperative and postoperative pulmonary function test results on patients who were followed in the multidisciplinary lung cancer clinic between July 1991 and March 1994 and who underwent lung resection. The predicted postoperative FEV1 and FVC were calculated based on the number of segments resected and were compared with the actual postoperative FEV1 and FVC. SETTING: This study was conducted at a university, tertiary referral hospital. PATIENTS: All patients were evaluated at a multidisciplinary lung cancer clinic and underwent lung resection by one surgeon (L.A.L.). MEASUREMENTS AND MAIN RESULTS: Sixty patients undergoing 62 pulmonary resections were reviewed. The predicted postoperative FEV1 and FVC were calculated using the following formula: predicted postoperative FEV1 (or FVC) = preoperative FEV1 (or FVC) x (1-(S x 0.0526)); where S = number of segments resected. The actual postoperative FEV1 and FVC correlated well with the predicted postoperative FEV1 and FVC for patients undergoing lobectomy (r = 0.867 and r = 0.832, respectively); however, the predicted postoperative FEV1 consistently underestimated the actual postoperative FEV1 by approximately 250 mL. For patients undergoing pneumonectomy, the actual postoperative FEV1 and FVC did not correlate as well with the predicted postoperative FEV1 and FVC (r = 0.677 and r = 0.741, respectively). Although there was considerable variability, the predicted postoperative FEV1 consistently underestimated the actual postoperative FEV1 by nearly 500 mL. Of the patients undergoing lobectomy, eight also received postoperative radiation therapy. When analyzed separately, patients receiving combined therapy lost an average of 5.47% of FEV1 per segment resected. This contrasts with a 2.84% per segment reduction in FEV1 for patients who did not receive radiation therapy. CONCLUSIONS: This simple calculation of predicted postoperative FEV1 and FVC correlates well with the actual postoperative FEV1 and FVC in patients undergoing lobectomy. The predicted postoperative FEV1 consistently underestimated the actual postoperative FEV1 by approximately 250 mL. The postoperative FEV1 and FVC for patients undergoing pneumonectomy is not accurately predicted using this equation. The predicted postoperative FEV1 for patients undergoing pneumonectomy was underestimated by an average of 500 mL and by greater than 250 mL in 12 of our 13 patients. Thus, by adding 250 mL to the above calculation of predicted postoperative FEV1, we improve our ability to we identify a minimal postoperative FEV1 for patients undergoing pneumonectomy. Finally, combined modality treatment with surgery followed by radiation therapy may result in additive lung function loss.

Adult↗
PubMed1994

Thermal stress induces epithelial permeability.

The mechanisms by which heat injury results in multiorgan system failure are unknown, but the presence of endotoxemia and intestinal hemorrhage suggests that changes in gut epithelial permeability may be crucial to this process. To determine whether alterations in epithelial permeability occur at physiologically relevant temperatures, heat-induced changes on epithelial barrier integrity were studied using a high-resistance clone of Madin-Darby canine kidney epithelial cells. Transepithelial electrical conductance increased when monolayers were heated above 38.3 degrees C. Early changes in conductance were completely reversible with cooling. Increased conductance was due to increased paracellular permeability because heat also induced increased mannitol permeability across the monolayers. A conditioning heat stress (42 degrees C for 90 min) altered heat-induced permeability. When cell monolayers were exposed to this conditioning stress 48 h before measurement of conductance with increasing temperatures, the conductance increase did not occur until they were heated to 39.4 degrees C compared with 38.8 degrees C in naive control cells. This conditioning treatment also conferred thermotolerance as measured by cell survival after a lethal 45.0 degrees C heat stress. There was no difference in the temperature at which conductance increased between preheated and control cells 96 h after a preconditioning heat stress. The conditioning heat stress resulted in accumulation of heat-shock protein (HSP) 70 in cells at 48 h, but HSP 70 returned to control levels at 96 h. These studies demonstrate that small temperature elevations increase epithelial permeability and that prior heat stress which induces HSP 70 shifts the threshold temperature required to disrupt the epithelium.

Adaptation, Physiological↗
PubMed1994

Asbestos exposure increases paracellular transport of fibrin degradation products across human airway epithelium.

The inflammatory response to asbestos fiber inhalation suggests that the distal respiratory epithelium is an important early target of asbestos-induced injury. We have previously found that asbestos exposure increases the fibrinolytic activity and mannitol permeability of human airway epithelial cell monolayers. Because fibrin degradation products (FDP) are potent inflammatory mediators, we asked whether asbestos fiber exposure would increase the transepithelial flux of FDP into the interstitial space. To stimulate the pericellular environment following fiber deposition, asbestos-exposed epithelial monolayers grown on permeable filters were covered with human plasma containing fluorescein isothiocyanate (FITC)-labeled human fibrinogen. After 24 h, nearly twice as much FITC-FDP appeared in the abluminal chamber of asbestos-exposed monolayers compared with unexposed controls. This did not result solely from increased degradation product production because asbestos-exposed epithelium was more permeable at all apical FDP concentrations. The proteins that crossed asbestos-exposed monolayers included biologically relevant high-molecular-weight FDP, as demonstrated by streptavidin blotting of biotin-labeled FDP. We also found that FDP flux was not vectorial, was not saturable, did not involve proteolytic processing of FDP, and did not require active transport. Thus asbestos exposure increases the paracellular flux of intact FDP across human airway epithelium. This represents a novel mechanism whereby fiber-induced epithelial dysfunction may initiate and sustain inflammation in the distal airspace.

Asbestos↗