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Biomedical subjects

M Harnett

Publications and source records attributed to M Harnett.

8 recordsLinked to original sources
PubMed2006

Predictive power of an in vitro system to assess drug interactions of an antimuscarinic medication: a comparison of in vitro and in vivo drug-drug interaction studies of trospium chloride with digoxin.

The authors studied a potential drug-drug interaction via findings from in vitro and in vivo studies, to assess whether the in vitro system was predictive of in vivo clinical pharmacokinetic outcomes. An in vitro experiment and a clinical study were performed to assess the potential for interaction. The effect of trospium chloride on human P-glycoprotein-mediated transport of [3H]-digoxin was determined in vitro. A randomized, crossover clinical trial in 40 subjects was performed to evaluate the effect of trospium on the pharmacokinetics of digoxin in vivo. The findings from the studies were then compared. The in vitro findings in this study were corroborated by the clinical study via assessment of inhibition and impact on pharmacokinetic parameters. The in vitro system for assessment of a potential interaction of 2 drugs excreted primarily through the kidney was predictive of the pharmacokinetic outcomes obtained from a clinical setting.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

Chronic hypoxia induces constitutive p38 mitogen-activated protein kinase activity that correlates with enhanced cellular proliferation in fibroblasts from rat pulmonary but not systemic arteries.

Pulmonary hypertension occurs commonly in patients with chronic hypoxic lung disease and is characterized by the remodeling of the pulmonary artery walls. The molecular mechanisms underlying such remodeling are unknown but we have recently shown that the stress-activated (Jnk and p38) mitogen-activated protein (MAP) kinases are activated in pulmonary artery fibroblasts following acute hypoxia. We now show that Erk and p38 MAP kinases are constitutively activated in fibroblasts derived from the remodeled pulmonary, but not the systemic circulation from rats exposed to chronically hypoxic conditions. Moreover, we find that such fibroblasts show sustained enhanced proliferative capacities relative to pulmonary artery fibroblasts derived from normoxic rats or to aortic fibroblasts from either normoxic or hypoxic rats. Finally, abrogation of p38, but not Erk MAP kinase activity by use of specific inhibitors, prevents the enhanced proliferative capacity exhibited by pulmonary artery fibroblasts. Taken together, these data suggest that enhanced p38 MAP kinase activity provides a molecular mechanism to explain the proliferation of pulmonary artery fibroblasts required for remodeling of the pulmonary vasculature.

Animals↗
PubMed2001

Rewiring of CD40 is necessary for delivery of rescue signals to B cells in germinal centres and subsequent entry into the memory pool.

Memory B-cell development is impaired by in vivo blockade of the CD40-CD40 ligand (CD40L) interaction using human Fc immunoglobulin G1 (IgG1)-mouse CD40 fusion protein (CD40-Ig); however, germinal centre (GC) formation is not. We show here that the block in B-cell differentiation in these mice is at the stage of rescue from apoptosis and exit from the GC. Thus, GC from CD40-Ig-treated mice contain a three- to fourfold higher level of apoptotic cells than found in control mice injected with human IgG1 alone. This increase in apoptosis is not caused by a blockade of the CD40L-mediated rescue signal but is the result of an intrinsic defect of GC B cells in CD40-Ig-treated mice to receive rescue signals via CD40. While anti-CD40 stimulation maintained the viability in culture of GC B cells from control mice, it did not rescue GC B cells from CD40-Ig-treated mice. This data is consistent with the notion that a 'rewiring' of the CD40 molecule is induced by CD40 ligation early in the response and is necessary to allow B-cell rescue from apoptosis when they subsequently enter the GC.

Animals↗
PubMed2000

Airway complications in infants: comparison of laryngeal mask airway and the facemask-oral airway.

PURPOSE: To compare the incidence of airway complications in children less than one year of age whose airways were maintained during anesthesia with either a laryngeal mask airway (LMA) or a facemask and oral airway (FM-OA). METHODS: We randomized 49 - ASA class 1&2 - infants to an LMA or FM-OA group. All infants were undergoing minor general, urological or orthopedic procedures. Anesthesia was induced and maintained with halothane in nitrous oxide 50% and oxygen. The airway was removed in both groups when the infant was awake. The occurrence of airway complications (breath-holding, coughing, laryngospasm, secretions, obstruction and oxygen saturation < 95%) at induction of anesthesia, intraoperatively and during emergence from anesthesia was recorded. RESULTS: Airway complications occurred perioperaively in 15 of 27 infants in the LMA group and in 5 of 22 infants in the FM-OA group (P: 0.02). CONCLUSION: In infants, the use of the LMA is associated with an increased incidence of airway complications compared with the use of the FM-OA.

Airway Obstruction↗
PubMed1998

Fractured cervical spine and aortic transection.

A 17-year-old victim of a road traffic accident presented. Following investigation diagnoses of fractured first cervical vertebra, aortic transection, diffuse cerebral oedema, fractured right ribs 2-4 and pubic rami were made. Management of this case presented a number of anaesthetic dilemmas: management of the airway, use of cross-clamp vs. shunting or heparinization and bypass, cardiovascular and neurological monitoring, maintenance of cardiovascular stability during and post cross-clamp, minimizing the risk of post-operative renal and neurological dysfunction.

Accidents, Traffic↗
PubMed1992

The role of G-proteins versus protein tyrosine kinases in the regulation of lymphocyte activation.

The relative roles of G-proteins and protein tyrosine kinases (PTKs) in the regulation of antigen receptor-mediated signalling in B and T cells is controversial. As they, and the biochemical events they control, are potential targets for intervention in various immune dysfunctions, the resolution of the controversy is of great interest. Here, Margaret Harnett and Kevin Rigley provide a timely assessment of current understanding, and propose a model for the interaction of G-proteins and PTKs in antigen receptor-mediated signalling.

Animals↗