Immunoregulation within the granulomas of murine schistosomiasis mansoni.
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Animals↗
Biomedical subjects
D Elliott
Publications and source records attributed to D Elliott.
St. Louis encephalitis with focal neurological signs.
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Adult↗
TRFK-5 reverses established airway eosinophilia but not established hyperresponsiveness in a murine model of chronic asthma.
We studied the effects of an anti-interleukin (IL)-5 monoclonal antibody (TRFK-5) or dexamethasone (DEX) to reverse already established airway hyperresponsiveness (AHR) and tissue eosinophilia in a Schistosoma mansoni antigen-sensitized and airway-challenged mouse model of chronic asthma. In this model at 4 d after antigen challenge there is dramatic bronchoalveolar lavage fluid (BAL) eosinophilia, AHR to intravenous methacholine (MCh), and histologic evidence of peribronchial eosinophilic infiltration and mucoid cell hyperplasia. These changes persist for up to 2 wk after antigen challenge. Treatment with DEX from Days 4 through 10 significantly reduced established airway eosinophilia compared with animals sham-treated with saline from Days 4 -10 (120 +/- 29 eosinophils/microl BAL for DEX-treated mice versus 382 +/- 60 eosinophils/microl BAL for sham-treated animals, p < 0.01). DEX-treated mice also had dramatically reduced mucoid cell hyperplasia, and airway responsiveness returned to normal. In contrast, TRFK-5 given during the same time period reduced airway eosinophilia (86 +/- 32 eosinophils/microl BAL versus 382 +/- 60 eosinophils/microl BAL, p < 0.01) but did not reduce goblet cell hyperplasia or reverse already established AHR. Treatment with DEX but not TRFK-5 also inhibited interferon gamma (IFN-gamma) content of BAL fluid (0.49 +/- 0.09 ng/ml BAL fluid for DEX versus 1.50 +/- 0.24 ng/ml BAL fluid and 1.36 +/- 0.13 ng/ml BAL fluid for TRFK-5 and sham-treated mice, respectively, both p < 0.001 versus DEX). Thus, treatment with DEX reduces established eosinophilic airway inflammation and AHR in S. mansoni-sensitized and airway-challenged mice but treatment with TRFK-5 reversed established eosinophilia without ameliorating established AHR. Together, these data suggest that once airway inflammation develops, neutralizing the effects of IL-5 or reducing eosinophilia alone may not result in inhibiting established AHR in atopic asthma.
Allergens↗
CD28 interactions with either CD80 or CD86 are sufficient to induce allergic airway inflammation in mice.
Previous studies have shown that the pan CD28/cytotoxic T lymphocyte antigen (CTL)A-4 antagonist CTLA4 immunoglobulin (Ig) inhibits eosinophilic airway inflammation in Schistosoma mansoni-sensitized and airway-challenged mice. In the present study, the importance of CD28 as well as the individual roles of CD80 and CD86 were examined in this system using wild-type and CD28 knockout (KO) mice. Unlike wild-type controls, CD28KO mice did not produce systemic IgE or eosinophilic airway inflammation after antigen challenge. However, a lymphocytic infiltrate and continued production of interferon-gamma was observed in these animals. Thus, CD28 is not essential for the initial recruitment of lymphocytes into antigen-challenged airways but critically regulates the allergic T-helper 2 phenotype. We next determined by polymerase chain reaction and flow cytometry that CD80 and CD86 molecules are constitutively expressed in the naive murine lung and on eosinophils in the allergic lung, suggesting a potential important role for both ligands in the development of asthma. Combined anti-CD80/anti-CD86 treatment throughout the antigen challenge period fully blocked the development of allergic airways, whereas a partial reduction was observed in mice treated with either anti-CD80 or anti-CD86 antibody alone. However, only anti-CD86 blocked systemic IgE production. Therefore, signaling through either CD80 or CD86 is sufficient to generate a partial local allergic response, whereas CD86 costimulation is essential to induce systemic allergic (IgE) reactions. Finally, combined anti-B7 monoclonal antibody treatment after sensitization reduced airway eosinophilia and interleukin (IL)-4/IL-5 cytokine secretion consistent with an ongoing role for CD28/B7 interactions in the effector phase of the disease. These results emphasize the importance of differential B7 expression on different cells and in different organs on subsequent CD28/B7-mediated immune events, including the potential for CD28/B7 blockade in the treatment of atopic airway disease in people.
Animals↗
Consultation with the specialist: Renal stones.
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Child↗
IL-6-deficient mice form granulomas in murine schistosomiasis that exhibit an altered B cell response.
IL-6 can play an important role in various biological activities. Using IL-6-deficient, 129 x C57BL/6 mice and normal littermate controls, we studied the role of IL-6 in granulomas of mice infected with schistosomiasis mansoni. Granulomas from IL-6(+/+) mice produced large quantities of IL-6, derived from T, B, and myeloid cells. Yet, IL-6 mutant mice generated normal-appearing granulomas of appropriate size. Multiple-parameter flow cytometric analysis of dispersed granuloma cells revealed no substantial differences. Granuloma cells and splenocytes were cultured in vitro to measure cytokine and immunoglobulin production. Compared to control cells, IL-6(-/-) granuloma cells secreted more IL-4, IL-5, and IL-10. However, splenocytes secreted cytokines comparably. In the IL-6(-/-) state, the granuloma cells released less IgE and substantially more IgM, although IgG1, IgG2a, and IgA secretion remained normal. ELISPOT assay showed that dispersed granuloma cells from IL-6-deficient animals had substantially more IgM-secreting B cells. Thus, schistosome granulomas make IL-6 that is not essential for most aspects of granuloma development. However, IL-6 deficiency results in some disturbance of granuloma cytokine and immunoglobulin expression.
Animals↗
The substance P and somatostatin interferon-gamma immunoregulatory circuit.
Murine schistosomiasis mansoni is a parasitic disease in which flukes living in the portal vein of the host produce ova that deposit in the liver and intestines. In these organs, ova release antigens that induce chronic, focal granulomatous inflammation. IFN-gamma is an inflammatory cytokine important in macrophage activation and B-cell differentiation. A substance P (SP)/somatostatin (SOM) neurokine immunoregulatory circuit controls IFN-gamma production in schistosome granulomas. SP stimulates, while SOM inhibits IFN-gamma release, modulating IFN-gamma-dependent circuitry. SP and SOM function through interaction with authentic SP and SOM receptors located on granuloma T cells. Also, the granulomas produce authentic SP and SOM14, as evidenced by the presence of mRNA and product. The granulomas have no nerves. This, and other data suggest that the inflammatory cells make these neurokines. Granuloma macrophages produce SOM. Macrophages from various sources express SOM mRNA in response to LPS, IFN-gamma, IL-10 or several other inflammatory mediators. Thus, the inflammation of murine schistosomiasis has a complete SP/SOM immunoregulatory circuit, which in turn is subject to immunoregulation.
Animals↗
Manual asymmetries in goal-directed movement: examination of the motor output hypothesis.
Two experiments are reported which examined the viability of motor output hypothesis as an explanation for manual asymmetries in goal-directed movement. Experiment 1 isolated the variability due to force generation by directly assessing precision of force production during an isometric wrist flexion task. Experiment 2 examined the additional role of externally based and internally created timing patterns on the performance of a repetitive force production task. Virtually no effects involving hand were apparent in either experiment. These findings provide no support for a hypothesis based solely on motor output to adequately account for hand differences in the performance of rapid, goal-directed movement.
Adult↗
Manual asymmetries and saccadic eye movements in right-handers during single and reciprocal aiming movements.
Two experiments examined the coordination of eye and hand movements in right-handed subjects who completed single (Experiment 1) and reciprocal (Experiment 2) aiming movements with each hand. In both experiments eye movements preceded hand movement, and arrived well in advance of the hand to allow pickup of visual information about relative position of the hand and target to correct te ongoing movement. With reciprocal aiming differences emerged between the hands. A right hand advantage was found for movement execution, and a left hand advantage for movement initiation. Manual asymmetries were not due to practice differences between hands. Subjects made larger initial saccades and more corrective saccades when aiming with the left hand. The pattern of eye-hand coordination was consistent with Woodworth's (1899) two component model of limb control, and at odds with models of limb control which suggest that online visual pickup is of minor importance.
Adult↗
The effect of nonregulatory stimuli on the triple jump approach run.
The purpose of this experiment was to examine the approach run of the triple jump. Specifically, we examined the effect of nonregulatory stimuli (Gentile, 1972) on two different ability levels in performing the triple jump approach run. These nonregulatory constraints (situational factors such as those seen in actual competition) were employed in three jumping conditions: Control (to obtain baseline performance measures), Distance (where participants attempted to obtain as great a jump as possible), and Accuracy (participants attempted to be as accurate as possible on takeoff without sacrificing distance). The results showed that the footfall position variability for all conditions was similar to those previously reported for the long jump approach run. However, in compliance with the nonregulatory constraints, participants altered other performance parameters in executing the approach run. The situational factors created changes that revealed themselves in foot placement on the takeoff board at the end of the approach run (foot position constant error and number of fouls increased for the Distance condition) and decreased horizontal velocity at takeoff in the Accuracy condition. Changes in performance parameters were related to the context in which the skill was performed and may further reflect changes made by jumpers in the course, such as a visual-motor task in competition. We suggest that the characteristics of the approach run may not be fully revealed by the pattern of footfall variability only, as has been suggested in previous work (e.g., Lee, Lishman, & Thomson, 1982), but that the situation under which the jump is performed may have a significant effect on the performance parameters that emerge in executing this type of motor skill.
Adult↗
Principles of clinical medicine: Oregon Health Sciences University School of Medicine.
In 1992, the School of Medicine at Oregon Health Sciences University inaugurated a Principles of Clinical Medicine (PCM) course as part of an overall curricular revision. The PCM course, which covers the first and second years of medical school, integrates material from ten separate courses in the previous curriculum. Students learn longitudinally over the two years, rather than "cramming" discrete areas of knowledge and then moving on. Course sessions are related to concurrently taken basic science classes. Meeting two afternoons per week, the PCM course offers preceptorships, health care issues sessions, and patient examination sessions. The PCM course aims to encompass the body of knowledge, skills, and attitudes necessary to become a competent physician. First- and second-year students have more opportunities than previously to interact with patients and practicing physicians in the community. Competition between learning areas, student perceptions of "soft" and "hard" courses, teacher recruitment, and administrative burnout are ongoing difficulties, while faculty recognition and development, administrative commitment and flexibility, and student and faculty feedback all contribute to the success of the course. The PCM course is now the backbone of the first two years of medical school and creates a solid foundation for the third and fourth years.
Attitude of Health Personnel↗
The control of sequential goal-directed movement: learning to use feedback or central planning?
Fifteen participants practiced a two-target sequential aiming movement with either full vision of the movement environment, vision during flight, or vision while in contact with the first target. After 100 acquisition trials, participants performed a retention test in their own condition and then were transferred to each of the other two vision conditions. Both performance and kinematic data indicated that rather than becoming less dependent on visual information with practice, subjects learned to adjust their movement trajectories to use the visual information available in their particular vision condition. Although transfer to a degraded vision condition disrupted performance, when vision was augmented participants quickly adjusted their aiming trajectories to use the added information. The findings suggest that at least part of learning involves the development of rapid and efficient procedures for processing afferent information, including visual response-produced feedback.
Adolescent↗
CTLA4Ig inhibits airway eosinophilia and hyperresponsiveness by regulating the development of Th1/Th2 subsets in a murine model of asthma.
Complete T-cell activation requires two distinct signals, one delivered via the T-cell receptor, and the second "co-stimulatory" signal through CD28/B7 ligation. Previous studies showed that the blockade of CD28/B7 ligation alters differentiation of Th1/Th2 lymphocyte subsets in vitro and in vivo. The present study was designed to determine the effect of a CD28/B7 antagonist (CTLA4Ig) on Th1/Th2 development in Schistosoma mansoni-sensitized and airway-challenged mice. Treatment of mice with CTLA4Ig beginning 1 wk after sensitization abolished airway responsiveness to intravenous methacholine determined 96 h following antigen challenge. We also found a significant reduction in bronchoalveolar lavage (BAL) eosinophilia, and reduced peribronchial eosinophilic infiltration and mucoid-cell hyperplasia. Furthermore, CTLA4Ig treatment significantly decreased interleukin (IL)-4 and IL-5 content in BAL fluid in vivo, and the production of IL-5 by lung lymphocytes stimulated with soluble egg antigen (SEA) in vitro. In contrast, the content of interferon-gamma in BAL fluid and supernatant from SEA-stimulated lung lymphocytes from CTLA4Ig-treated mice was increased significantly compared with untreated animals. Thus, CTLA4Ig inhibits eosinophilic airway inflammation and airway hyperresponsiveness in S. mansoni-sensitized and airway-challenged mice, most likely due to attenuated secretion of Th2-type cytokines and increased secretion of Th1-type cytokines.
Abatacept↗
Influence of spatial mapping on manual aiming asymmetries.
Two experiments were conducted to examine manual asymmetries in a one-dimensional aiming task. In Exp. 1, 10 right-handed adults slid a computer mouse 13 cm on a graphics tablet with both the right and left hands to targets of 3 different diameters. Under these conditions, the movement time for the right hand was significantly faster as expected. In Exp. 2, subjects performed similar movements to move a cursor 13 cm on a computer monitor. Thus the study was identical except the stimulus-response mapping was indirect. In this situation, there were no significant difference for either movement time or movement error between hands despite these performance measures indicating the target aiming was more difficult in Exp. 2. Because increases in task difficulty generally result in a greater advantage for the right hand, as indicated by Todor & Smiley, 1985, the present studies suggest that superiority of the right hand in aiming tasks may be diminished when spatial translation is required. Perhaps the spatial translation requires greater involvement of the right hemisphere, a process associated with manual advantage for the left hand, previously suggested by Roy and MacKenzie.
Adult↗
Alcohol, tobacco and cannabis use among Nova Scotia adolescents: implications for prevention and harm reduction.
OBJECTIVE: To characterize adolescent drug use in terms of a risk continuum and to explore the rationale for harm reduction as a potential approach for school-based drug prevention. DESIGN: Self-reported surveys, in 1991 and 1996, of adolescent students concerning their use of drugs, especially alcohol, tobacco and cannabis, and the harmful consequences of such use. SETTING: Nova Scotia. PARTICIPANTS: A total of 3452 (in 1991) and 3790 (in 1996) junior and high school students in randomly selected classes in the public school system. OUTCOME MEASURES: Prevalence of drug use and patterns of multiple drug use and of alcohol- and drug-related problems; independent risk factors for multiple drug use. The risk continuum for the response to alcohol problems was used as a policy framework. RESULTS: The prevalence of cigarette smoking and the use of hallucinogens and stimulants was markedly higher in 1996 than in 1991. Over one-fifth (21.9%) of the students reported multiple drug use of alcohol and tobacco and cannabis in the 12 months before the 1996 survey. The 3 main subgroups--nonusers, users of alcohol only and users of multiple drugs--had distinct patterns of use, numbers of problems and risk factors. In all, 27.1% of the students had experienced at least 1 alcohol-related problem and 6% had experienced at least 1 drug-related problem in the 12 months before the 1996 survey. CONCLUSION: There is a need for integrated school- and community-based drug prevention programs, with goals, strategies and outcome measures capturing the full spectrum of patterns of use and levels of risk among subgroups of the adolescent student population.
Adolescent↗
Hand, space and attentional asymmetries in goal-directed manual aiming.
Two experiments were conducted to explore the interaction of the two cerebral hemispheres in motor control, by examining hand, space and attentional asymmetries in goal-directed aiming. In Experiment 1, right-handed subjects moved to targets more quickly with their right hand than their left hand. In addition, each hand was faster when moving in its own hemispace. Although in a control condition, movements were initiated more quickly with the left hand, visual distractors disrupted left hand performance more than right hand performance. For contralateral aiming, ipsilateral distractors caused the greatest interference. In Experiment 2, when targets and distractors were all presented at the midline, a right hand advantage was found for movement time along with a left hand advantage for reaction time, independent of target and distractor location. Our findings are discussed in terms of a right hemisphere role in movement preparation and the allocation of attention in space, and greater left hemisphere involvement in movement execution.
Adolescent↗
Costing intensive care services: a review of study methods, results and limitations.
Critical care services are an identified, resource-intensive component of health-care provision. Examining cost containment and clinical effectiveness in this specialty is therefore highly appropriate, although difficult to achieve in practice. The studies reviewed in this paper utilised various methodologies to capture different components of service and patient costs. The methods included combinations of per diem costs, hospital charges, direct consumption and unspecified cost estimates. Medical fees were commonly excluded and other costs, such as equipment and overheads, often not identified. Some more recent studies used clinical costing methods to capture individual patient-specific data, and demonstrated the feasibility and importance of these projects. Differing methods and data collection resulted in a limited comparative analysis, but issues requiring further research are highlighted. Funding of ICU services in Australia and nursing staff costs are also discussed. Future research will be aided by further sophistication in clinical information systems and the desire for clinicians to examine the link between costs and outcomes of the different activities pursued within the ICU.
Australia↗
The gift relationship between pharmaceutical companies and physicians: an exploratory survey of physicians.
The purpose of this exploratory study was to survey physicians' attitudes surrounding the 'gift relationship' between pharmaceutical companies and physicians. A survey was mailed to 1000 randomly selected West Virginia physicians, of which 283 (28.3%) responses were received. The most commonly received gifts reported by the study physicians were trinkets (77.4%), followed by books (41.7%) and meals (41%). Principal component analysis and varimax rotation identified seven physician belief constructs. The mean ratings of the constructs indicated that the physicians slightly agreed that pharmaceutical companies give gifts to physicians to influence their prescribing, moderately disagreed that they do so as a form of professional recognition of physicians, and strongly disagreed that their prescribing behaviour could be influenced by the gifts they receive. Physicians slightly disagreed that pharmaceutical companies' sponsoring of CME programmes are only promotional gimmicks. Although the study physicians slightly disagreed that it may be inappropriate for them to accept gifts from pharmaceutical companies, they seemed slightly averse to having 'gift relationships' between pharmaceutical companies and physicians made public. Correlation analysis suggested that physicians who have a large number of patients in their practice, see a larger number of patients per day, or write a large number of prescriptions per day are more likely to be offered gifts by pharmaceutical companies, and they are also more likely to condone the practice of gift giving and receiving.
Attitude of Health Personnel↗