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Biomedical subjects

R M Smith

Publications and source records attributed to R M Smith.

At least 145 records · Page 8Linked to original sources
PubMed1997

Enhancement of the specific mucosal IgA response in vivo by interleukin-5 expressed by an attenuated strain of Salmonella serotype Dublin.

It has been shown that cytokines have potential as therapeutic adjuvants in vaccination. Interleukin-5 (IL-5) is a cytokine that regulates antibody production, in particular enhancing IgA production by activated mucosal B cells. This study examined the expression of a cloned cytokine gene encoding murine IL-5 (mIL-5) by an attenuated aroA strain (SL5631) of Salmonella serotype Dublin. The resulting strain, SL5631(pTRXFUS-mIL-5), expressed mIL-5 as a fusion with thioredoxin as demonstrated by immunological and biological assays. When strain SL5631(pTRXFUS-mIL-5) was used as a live vaccine in BALB/c mice, it colonised and multiplied at higher levels in spleens and livers than the strain carrying the empty plasmid. A reduction in invasiveness of SL5631(pTRXFUS-mIL-5) was observed in in-vitro invasion assays. Enhanced IgA response against salmonella LPS in mucosal secretions and enhanced IgA and IgG responses were detected by ELISA and ELISPOT methods in sera of mice immunised with the strain expressing mIL-5. Results with IL-5-deficient mice showed that the enhanced IgA response was due to Salmonella-expressed mIL-5 rather than endogenous mIL-5.

Animals↗
PubMed1997

Enhanced ventilatory and exercise performance in athletes with slight expiratory resistive loading.

We determined the cardiorespiratory and performance effects of slight (1.5-3.0 cmH2O) expiratory resistive loading (ERL). Twenty-eight highly fit [peak O2 uptake (VO2 peak) = 63.6 +/- 1.3 ml . kg-1 . min-1] athletes (age = 33.5 +/- 1.3 yr) performed paired VO2 peak cycle ergometer tests (control vs. ERL). End-expiratory lung volume was separately determined in a subset of subjects (n = 12) at steady-state 75% maximum power output (POmax) and was found to increase (0.67 +/- 0.29 liter) with ERL. In the VO2 peak tests, peak expiratory pressure at the mouth, mean inspiratory flow, minute ventilation, and O2 pulse were greater with ERL at every intensity level (i.e., 75, 80, 85, and 90% POmax). Increased minute ventilation was largely due to a trend toward increased tidal volume (P < 0.05 at 80% POmax). O2 uptake was greater at 90% POmax with ERL. Increased O2 pulse with ERL at comparative workloads suggests that stroke volume was augmented with ERL. Also, with ERL, athletes attained higher VO2 peak (63.0 +/- 1.4 vs. 60.1 +/- 1.3 ml . kg-1 . min-1) and greater POmax (352.0 +/- 9.9 vs. 345.7 +/- 9.5 W). We conclude that elevated end-expiratory lung volume in response to slight ERL during strenuous exercise served to attenuate both airflow and blood flow limitations, which enhanced exercise capacity.

Adult↗
PubMed1997

Bovine surfactant therapy for patients with acute respiratory distress syndrome.

Lung surfactant is deficient in patients with acute respiratory distress syndrome (ARDS). We performed a randomized, prospective, controlled, open-label clinical study of administration of a bovine surfactant to patients with ARDS to obtain preliminary information about its safety and efficacy. Patients received either surfactant by endotracheal instillation in addition to standard therapy or standard therapy only. Three different groups of patients receiving surfactant were studied: patients receiving up to eight doses of 50 mg phospholipids/kg, those receiving up to eight doses of 100 mg phospholipids/kg, and those receiving up to four doses of 100 mg phospholipids/kg. Outcome measures included ventilatory support parameters, arterial blood gases, organ system failures, bronchoalveolar lavage (BAL) analyses, immunologic analyses, survival, and adverse events during the 28-d study period. Fifty-nine study patients were evaluable; 43 in the surfactant group and 16 in the control group. The FI(O2) at 120 h after treatment began was significantly decreased only for patients who received up to four doses of 100 mg phospholipids/kg surfactant as compared with control patients (p = 0.011). Mortality in the same group of patients was 18.8%, as compared with 43.8% in the control group (p = 0.075). The surfactant instillation was generally well tolerated, and no safety concerns were identified. This pilot study presents preliminary evidence that surfactant might have therapeutic benefit for patients with ARDS, and provides rationale for further clinical study of this agent.

Adult↗
PubMed1997

Evidence for endothelin involvement in the pulmonary vasoconstrictor response to systemic hypoxia in the isolated rat lung.

We investigated the effect of systemic hypoxia (Krebs-Henseleit solution gassed with 5% CO2/95% N2) on an isolated, perfused rat lung. Hypoxia resulted in a slowly developing sustained increase in pulmonary perfusion pressure (PPP) accompanied by an increase in lung weight (LW). The endothelin (ET) receptor antagonists BQ123 (3 and 10 microM), BQ788 (3 microM) and bosentan (1.5 and 5 microM) all attenuated the hypoxia-induced increases in LW and PPP. In addition, phosphoramidon (1 microM), an ET-converting enzyme inhibitor, also significantly attenuated the hypoxia-induced increases in PPP and LW. The use of two agents that alter peptide secretion, phalloidin (10 and 50 nM) and colchicine (100 nM), and the peptide synthesis inhibitor cycloheximide (5 microM) all significantly attenuated the hypoxia-induced increases in PPP and LW. The increase in PPP and LW after the onset of hypoxia was accompanied by an increase in perfusate levels of ET-1 compared with normoxic time-matched controls. The results show that in this model, systemic hypoxia is capable of causing a sustained vasoconstriction and increased LW. The fact that these increases can be attenuated by an ET-converting enzyme inhibitor, ET receptor antagonists and agents that block peptide synthesis and secretion, together with the increase in perfusate levels of ET-1, suggests that ET production and release contribute to the changes seen.

Animals↗
PubMed1997

FIM measurement properties and Rasch model details.

To summarize, we take issue with the criticisms of Dickson & Köhler for two main reasons: 1. Rasch analysis provides a model from which to approach the analysis of the FIM, an ordinal scale, as an interval scale. The existence of examples of items or individuals which do not fit the model does not disprove the overall efficacy of the model; and 2. the principal components analysis of FIM motor items as presented by Dickson & Köhler tends to undermine rather than support their argument. Their own analyses produce a single major factor explaining between 58.5 and 67.1% of the variance, depending upon the sample, with secondary factors explaining much less variance. Finally, analysis of item response, or latent trait, is a powerful method for understanding the meaning of a measure. However, it presumes that item scores are accurate. Another concern is that Dickson & Köhler do not address the issue of reliability of scoring the FIM items on which they report, a critical point in comparing results. The Uniform Data System for Medical Rehabilitation (UDSMRSM) expends extensive effort in the training of clinicians of subscribing facilities to score items accurately. This is followed up with a credentialing process. Phase 1 involves the testing of individual clinicians who are submitting data to determine if they have achieved mastery over the use of the FIM instrument. Phase 2 involves examining the data for outlying values. When Dickson & Köhler investigate more carefully the application of the Rasch model to their FIM data, they will discover that the results presented in their paper support rather than contradict their application of the Rasch model! This paper is typical of supposed refutations of Rasch model applications. Dickson & Köhler will find that idiosyncrasies in their data and misunderstandings of the Rasch model are the only basis for a claim to have disproven the relevance of the model to FIM data. The Rasch model is a mathematical theorem (like Pythagoras') and so cannot be disproven by empirical data once it has been deduced on theoretical grounds. Sometimes empirical data are not suitable for construction of a measure. When this happens, the routine fit statistics indicate the unsuitable segments of the data. Most FIM data do conform closely enough to the Rasch model to support generalizable linear measures. Science can advance!

Activities of Daily Living↗
PubMed1997

Dimensionality of an early childhood scale using rasch analysis and confirmatory factor analysis.

This paper explores the use of Rasch analysis and linear confirmatory factor analysis as methods for investigating the dimensionality of an early childhood test (Gesell School Readiness Screening Test), taking into account the theoretical basis of test construction. The paper presents the results of empirical analyses using both approaches and discusses the theoretical and psychometric considerations that guide the selection and application of each technique.

Aptitude Tests↗
PubMed1997

Validating standard setting with a modified nedelsky procedure through common item test equating.

It is often impossible to validate cut scores set using judged item review methods due to the fact that many high stakes testing programs attempt to limit the number of common items across consecutively administered forms. However, over time, with a stable item pool, secondary links through other test administrations allow the use of common item equating to test the stability of the judged cut scores. In this study five forms of a basic science examination administered over a three year period in a national board testing program were analyzed to determine the stability of judged cut scores. The stability was determined by comparison of the judged cut scores with the equated cut scores derived by the Rasch common item equating technique. The results indicate cut scores derived from the modified Nedelsky procedure were within equating error of the Rasch equated cut scores over five administrations.

Educational Measurement↗
PubMed1996

Mechanism of first-dose cytokine-release syndrome by CAMPATH 1-H: involvement of CD16 (FcgammaRIII) and CD11a/CD18 (LFA-1) on NK cells.

The administration of the immunosuppressive humanized monoclonal antibody CAMPATH 1-H, which recognizes CD52 on lymphocytes and monocytes, is associated with a first-dose cytokine-release syndrome involving TNFalpha, IFNgamma, and IL-6 clinically. In vitro models have been used to establish the cellular source and mechanism responsible for cytokine release, demonstrating that cytokine release is isotype dependent, with the rat IgG2b and human IgG1 isotype inducing the highest levels of cytokine release, which was inhibited with antibody to CD16, the low affinity Fc-receptor for IgG (FcgammaR). Cross-linking antibody opsonized CD4 T lymphocytes failed to stimulate TNFalpha release, which together with the observation that TNFalpha release by purified natural killer (NK) cells stimulated by fixed autologous CAMPATH 1-H-opsonized targets was inhibited with anti-CD16, indicates that cytokine release results from ligation of CD16 on the NK cells, rather than Fc-receptor (FcR)-dependent cross-linking of CD52 on the targeted cell. Since the hierarchy of isotypes inducing cytokine release in these cultures matches that seen clinically, we conclude that ligation of CD16 on NK cells is also responsible for cytokine release after injection of CAMPATH 1-H in vivo.

Alemtuzumab↗
PubMed1996

Insulin-induced egr-1 and c-fos expression in 32D cells requires insulin receptor, Shc, and mitogen-activated protein kinase, but not insulin receptor substrate-1 and phosphatidylinositol 3-kinase activation.

Many studies suggest that insulin utilizes multiple signal transduction pathways. Insulin's effects are initiated by insulin binding to the insulin receptor, resulting in tyrosine phosphorylation of insulin receptor and intracellular substrates, such as insulin receptor substrate-1 (IRS-1), IRS-2, or Shc. We recently demonstrated that immediate-early gene egr-1 transcription was fully induced without phosphorylation of IRS-1 in Chinese hamster ovary cells (Harada, S., Smith, R. M., Smith, J. A., Shah, N. , Hu, D.-Q. & Jarett, L. (1995) J. Biol. Chem. 270, 26632-26638). In the present study, we examined the effects of insulin on immediate-early gene egr-1 and c-fos expression in 32D cells overexpressing the insulin receptor (32D/IR), IRS-1 (32D/IRS), or both (32D/IR+IRS) and compared these effects with insulin-induced tyrosine phosphorylation. Insulin (17 nM) increased egr-1 and c-fos expression in 32D/IR and 32D/IR+IRS cells, but not in parental cells or 32D/IRS cells, as determined by Northern blot analysis. Insulin treatment (5 min at 37 degrees C) markedly increased tyrosine phosphorylation of several proteins, including the insulin receptor, IRS-1, and Shc, in 32D/IR+IRS cells as determined by immunoprecipitation and Western blot analysis with anti-phosphotyrosine antibody. In contrast, only two tyrosine-phosphorylated proteins, i.e. insulin receptor and Shc, were detected in 32D/IR cells. These data suggest that insulin receptor and Shc phosphorylation is necessary for insulin-induced egr-1 and c-fos expression, but IRS-1 phosphorylation is not necessary or sufficient for the expression of these genes. Furthermore, the effect of specific inhibitors on insulin-induced egr-1 expression was examined. Wortmannin (25 nM), a phosphatidylinositol 3-kinase inhibitor, had no effect on insulin-induced egr-1 expression. In contrast, PD 98059 (30 microM), a mitogen-activated protein kinase kinase inhibitor, totally blocked egr-1 expression induced by insulin. These data indicate that mitogen-activated protein kinase activation, but not phosphatidylinositol 3-kinase activation, is involved in insulin-induced egr-1 expression. Taken together, insulin receptor tyrosine phosphorylation, Shc tyrosine phosphorylation, and mitogen-activated protein kinase activation appear to be the signal transduction pathway responsible for insulin-induced egr-1 expression in 32D cells. These data demonstrate that insulin has multiple signal transduction pathways that vary from cell to cell.

Adaptor Proteins, Signal Transducing↗
PubMed1996

The cytosolic subunit p67phox contains an NADPH-binding site that participates in catalysis by the leukocyte NADPH oxidase.

The NADPH-dependent respiratory burst oxidase of human neutrophils catalyzes the reduction of oxygen to superoxide using NADPH as the electron donor and is essential for normal host defenses. To gain insight into the function of the various oxidase subunits that are required for the full expression of catalytic activity, we studied the interactions between the 2',3'-dialdehyde derivative of NADPH (NADPH dialdehyde) and neutrophil cytosol. NADPH dialdehyde treatment of cytosol resulted in the loss of the ability of the cytosol to participate in cell-free oxidase activation; this inactivation was blocked by NADPH but not by NAD, NADP, or GTP. Partial purification of neutrophil cytosol yielded a single peak which could restore the activity lost in cytosol treated with NADPH dialdehyde. This peak contained p67phox but not p47phox or Rac2. Purified recombinant p67phox was similarly able to restore the activity lost in NADPH dialdehyde-treated cytosol and bound [32P]NADPH dialdehyde in a specific fashion. The activity of recombinant p67phox in cell-free oxidase assays was lost on treatment with NADPH dialdehyde. Together, these data suggest p67phox contains the catalytic NADPH-binding site of the leukocyte NADPH oxidase.

Aldehydes↗