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Biomedical subjects

Helen F Galley

Publications and source records attributed to Helen F Galley.

10 recordsLinked to original sources
PubMed2006

Production of soluble triggering receptor expressed on myeloid cells by lipopolysaccharide-stimulated human neutrophils involves de novo protein synthesis.

The triggering receptor expressed on myeloid cells (TREM-1) is a recently identified receptor expressed on neutrophils and monocytes. Activation of the receptor induces neutrophils to release the enzyme myeloperoxidase and inflammatory cytokines such as interleukin-8. TREM-1 has an alternatively spliced variant that lacks the transmembrane region, resulting in the receptor being secreted in a soluble form (sTREM-1). Soluble TREM-1 has been detected in plasma during experimental and clinical sepsis and has been advocated as a diagnostic marker of infection for pneumonia and as a prognostic marker for patients with septic shock. We studied TREM-1 surface expression, using flow cytometry, and simultaneously measured sTREM-1 concentrations in culture supernatants of lipopolysaccharide (LPS)-stimulated neutrophils. TREM-1 surface expression was constitutive and was not upregulated upon LPS stimulation. However, sTREM-1 release from neutrophils was significantly upregulated by LPS stimulation (P < 0.0001), an effect that was abrogated by cycloheximide. Soluble TREM-1 is therefore secreted by human neutrophils in response to LPS challenge in a process involving de novo protein synthesis that is not accompanied by an upregulation of the TREM-1 receptor on the surfaces of the cells.

Adult↗
PubMed2005

Differential effects of three antibiotics on T helper cell cytokine expression.

OBJECTIVES: To test whether ciprofloxacin, moxifloxacin and clarithromycin affect the expression of the T helper (Th) cell cytokines, interferon-gamma and interleukin-4. Quinolone and macrolide antibiotics are routinely used for the treatment of critically ill patients with sepsis. These antibiotics modulate some aspects of immune cell function. Alteration in the profile of Th cell cytokine expression will affect the T helper cell ratio and subsequent immune responses. METHODS: Following ethics committee approval and informed consent, mononuclear cells were isolated from 20 healthy volunteers using single density gradient centrifugation. Cells were incubated with ciprofloxacin (0--100 mg/L), moxifloxacin (0--50 mg/L) or clarithromycin (0--125 mg/L) and stimulated with phorbol myristate acetate and ionomycin. For flow cytometric analysis, cells were stained with antibodies to CD3 and CD4, prior to permeabilization with saponin and intracellular staining with anti-interleukin-4 and anti-interferon-gamma. RESULTS: Both moxifloxacin and ciprofloxacin dose-dependently decreased interferon-gamma and interleukin-4 expression by Th cells (both P<0.0001). Only interleukin-4 expression however, was affected by clarithromycin (P=0.04). There was no change in the Th1/Th2 ratio for moxifloxacin or ciprofloxacin, but the Th1/Th2 ratio increased with increasing concentrations of clarithromycin, from a median [range] of 5.3 [1.3--16.0] without antibiotic to 9.1 [1.8--18.8] at 125 mg/L (P=0.017). CONCLUSIONS: Moxifloxacin and ciprofloxacin had pronounced effects on both Th1 and Th2 cytokine expression, without altering Th1/Th2 ratios. However, clarithromycin decreased only interleukin-4 expression such that the Th1/Th2 ratio increased. Since a Th1 profile is considered favourable for resolution of infection, elucidation of immunomodulatory profiles of antibiotics may permit more rational antibiotic choice in future.

Adult↗
PubMed2005

A microarray analysis of potential genes underlying the neurosensitivity of mice to propofol.

Establishing the mechanism of action of general anesthetics at the molecular level is difficult because of the multiple targets with which these drugs are associated. Inbred short sleep (ISS) and long sleep (ILS) mice are differentially sensitive in response to ethanol and other sedative hypnotics and contain a single quantitative trait locus (Lorp1) that accounts for the genetic variance of loss-of-righting reflex in response to propofol (LORP). In this study, we used high-density oligonucleotide microarrays to identify global gene expression and candidate genes differentially expressed within the Lorp1 region that may give insight into the molecular mechanism underlying LORP. Microarray analysis was performed using Affymetrix MG-U74Av2 Genechips and a selection of differentially expressed genes was confirmed by semiquantitative reverse transcription-polymerase chain reaction. Global expression in the brains of ILS and ISS mice revealed 3423 genes that were significantly expressed, of which 139 (4%) were differentially expressed. Analysis of genes located within the Lorp1 region showed that 26 genes were significantly expressed and that just 2 genes (7%) were differentially expressed. These genes encoded for the proteins AWP1 (associated with protein kinase 1) and "BTB (POZ) domain containing 1," whose functions are largely uncharacterized. Genes differentially expressed outside Lorp1 included seven genes with previously characterized neuronal functions and thus stand out as additional candidate genes that may be involved in mediating the neurosensitivity differences between ISS and ILS.

Anesthetics, Intravenous↗
PubMed2005

Selective phosphodiesterase 5 inhibition does not reduce propofol sedation requirements but affects speed of recovery and plasma cyclic guanosine 3',5'-monophosphate concentrations in healthy volunteers.

UNLABELLED: Cyclic guanosine 3',5'-monophosphate (cyclic GMP) has been implicated in modulating the effects of anesthesia. We hypothesized that limiting the breakdown of cyclic GMP through selective phosphodiesterase inhibition would influence propofol sedation requirements and plasma cyclic GMP concentrations. Ten volunteers received 100 mg of sildenafil or placebo orally in this placebo-controlled, double-blind, randomized crossover pilot study. Propofol sedation was achieved using a target-controlled infusion system until loss of verbal contact (LVC). Plasma cyclic GMP concentrations were determined at baseline, LVC, and 30 min after LVC. There was no difference in the amount of propofol used, predicted plasma concentration, or duration of sedation in volunteers after sildenafil compared with placebo treatment. Return of spontaneous verbal contact was faster after sildenafil (4 [3-8] min versus 6 [3-5] min, median [range], P = 0.019). Cyclic GMP concentrations were reduced during propofol sedation in the placebo group compared with baseline (P < 0.004). The plasma cyclic GMP concentrations were larger (P = 0.004) at LVC in the sildenafil group compared with placebo. We have shown that selective phosphodiesterase 5 inhibition decreases recovery time from propofol sedation without affecting propofol requirements. The decrease of plasma cyclic GMP concentrations during propofol sedation in the placebo group indicates a potential role of cyclic GMP in propofol anesthesia in humans. IMPLICATIONS: Plasma cyclic guanosine 3',5'-monophosphate (cyclic GMP) concentrations are reduced during propofol sedation. Selective phosphodiesterase 5 inhibition, however, does not reduce propofol sedation requirements or plasma cyclic GMP concentrations but affects speed of recovery in healthy volunteers.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2005

Pharmacogenetics and anesthesiologists.

Genetic variation contributes to an individual's sensitivity and response to a variety of drugs important to anesthetic practice. Early insights into the clinical impact of pharmacogenetics were provided by anesthesiology--investigations into prolonged apnea after succinylcholine administration, thiopental-induced porphyria and malignant hyperthermia contributed to the novel science of pharmacogenetics in the early 1960s. Genetic polymorphisms involved in pharmacokinetics (absorption, distribution, metabolism, and excretion of drugs) and pharmacodynamics (receptors, ion channels and enzymes) can affect an individual's response to the drugs used in anesthetic practice. In addition, genetic variation in proteins directly unrelated to drug action or metabolism can influence responses to environmental changes that occur during anesthesia. This review will summarize the current knowledge of genetic variation in response to drugs relevant to anesthesia, and how this impacts upon clinical practice.

Anesthesiology↗
PubMed2003

Influence of interleukin-10 polymorphisms on interleukin-10 expression and survival in critically ill patients.

OBJECTIVE: To determine the functionality of identified polymorphisms in the promoter and upstream regions of the interleukin-10 gene in terms of release of interleukin-10 from lipopolysaccharide-stimulated whole blood from healthy volunteers and to evaluate the relationship of interleukin-10 polymorphisms to interleukin-10 release, development of sepsis, and mortality in critically ill patients. DESIGN: Observational study. SETTING: The academic unit of anesthesia and intensive care, university laboratories, and ten-bed general intensive care unit in a university teaching hospital. SUBJECTS: A total of 132 healthy volunteers plus 67 consecutive critically ill patients recruited within 24 hrs of admission to the intensive care unit, regardless of diagnosis. MEASUREMENTS: Plasma interleukin-10 levels were measured by enzyme-linked immunosorbent assay. Single nucleotide polymorphisms were detected by restriction fragment length polymorphism analysis. Dinucleotide repeat polymorphisms were identified after polymerase chain reaction using a DNA size analyzer. MAIN RESULTS: Stimulated interleukin-10 release in critically ill patients was significantly lower than in healthy subjects (p < .0001). In addition, in the patients who developed sepsis, interleukin-10 release at admission to the intensive care unit was significantly lower than in patients who did not subsequently develop sepsis (median [range] 1.47 [0.13-6.90] ng/mL compared with 4.93 [0.03-16.80] ng/mL, p = .001). The A allele of the single nucleotide polymorphism at -592 base pairs was associated with lower interleukin-10 release and higher mortality in critically ill patients. Other polymorphisms were not linked to interleukin-10 release, sepsis, or mortality. CONCLUSIONS: The A allele of the -592 base pair single nucleotide polymorphism in the interleukin-10 gene is associated with lower stimulated interleukin-10 release and increased mortality. Further investigations are required to determine the nature of the functionality and the potential diagnostic and therapeutic aspects of this marker.

Adolescent↗
PubMed2003

The effect of N-acetylcysteine on nuclear factor-kappa B activation, interleukin-6, interleukin-8, and intercellular adhesion molecule-1 expression in patients with sepsis.

OBJECTIVE: Expression of inflammatory mediators is controlled in part at the transcriptional level via nuclear factor-kappa B. Inhibition of nuclear factor-kappa B activation may be beneficial in critically ill patients. N-acetylcysteine is an antioxidant that inhibits nuclear factor-kappa B activation in vitro. In this pilot study we investigated the effect of N-acetylcysteine on nuclear factor-kappa B activation and circulating cytokine and adhesion molecules in patients with sepsis. DESIGN: Prospective, randomized, double blind, placebo-controlled pilot trial. SETTING: Eight-bed intensive care unit in a university teaching hospital. PATIENTS: Twenty consecutive patients within 12 hrs of fulfilling the consensus criteria for sepsis. INTERVENTIONS: A bolus of 150 mg/kg N-acetylcysteine in 100 mL of 0.9% saline over 15 mins, then 50 mg/kg in 100 mL of 0.9% saline over 4 hrs as a loading dose, and then a maintenance infusion of 50 mg/kg in 200 mL of 0.9% saline over each 24-hr period for a total of 72 hrs, or an equivalent volume of saline. MEASUREMENTS AND MAIN RESULTS: Nuclear factor-kappa B activation was measured in mononuclear leukocytes using electrophoretic mobility shift assay, at baseline and 24, 48, 72, and 96 hrs later. Activation decreased significantly in patients treated with N-acetylcysteine (p =.016) but not placebo and was significantly reduced at 72 hrs compared with both preinfusion values (p =.028) and patients receiving placebo (p =.01). Plasma interleukin-6, interleukin-8, and soluble intercellular adhesion molecule-1 concentrations were measured using enzyme immunoassay. Interleukin-6 concentrations were high initially and then decreased in all patients, regardless of whether they received N-acetylcysteine or placebo. Interleukin-8 decreased significantly only in those who received N-acetylcysteine (p =.0081). Soluble intercellular adhesion molecule-1 concentrations remained unchanged in all patients. CONCLUSIONS: Administration of N-acetylcysteine results in decreased nuclear factor-kappa B activation in patients with sepsis, associated with decreases in interleukin-8 but not interleukin-6 or soluble intercellular adhesion molecule-1. These pilot data suggest that antioxidant therapy with N-acetylcysteine may be useful in blunting the inflammatory response to sepsis. Further studies are warranted.

Acetylcysteine↗