PubMed Health⌕ Search

Biomedical subjects

B P Giroir

Publications and source records attributed to B P Giroir.

At least 19 recordsLinked to original sources
PubMed2005

Obesity, macrophage migration inhibitory factor, and weight loss.

OBJECTIVE: Elevated macrophage migration inhibitory factor (MIF) has been implicated as a causal mechanism in a number of disease conditions including cardiovascular disease (CVD), diabetes, and cancer. Excess body fat is associated with an increased risk of numerous health conditions including CVD, diabetes, and cancer. To our knowledge, the association between MIF and obesity status and the effect of weight loss on serum MIF concentrations have not been reported. In this study, we examined the effects of participation in a behavior-based weight loss program on MIF concentrations in obese individuals. SUBJECTS: Study participants were 71 men and women enrolled in The Cooper Institute Weight Management Program. Participants were predominantly female (68%, n=48), middle-aged (46.5+/-9.8 y), and severely obese (BMI=43.0+/-8.6). METHOD: Plasma MIF concentrations and other standard risk factors were measured before and after participation in a diet and physical activity based weight management program. RESULTS: The mean follow-up was 8.5+/-3.0 months with an average weight loss of 14.4 kg (P<0.001). The majority of clinical risk factors significantly improved at follow-up. Median levels of plasma MIF concentration were significantly lower at follow-up (median [IQR]; 5.1[3.6-10.3]) compared to baseline (8.4 [4.3-48.8]; P=0.0005). The percentage of participants with plasma MIF concentration > or =19.5 mg/nl (highest tertile at baseline) decreased from 33.8 to 5.6% (P<0.001). Further, elevated baseline plasma MIF concentration was associated with markers of beta-cell dysfunction and reductions in MIF were associated with improvements in beta-cell function. CONCLUSIONS: Circulating MIF concentrations are elevated in obese but otherwise healthy individuals; however, this elevation in MIF is not uniform across individuals. In obese individuals with elevated circulating MIF concentrations, participation in physical activity and a dietary-focused weight management program resulted in substantial reduction in MIF.

Adult↗
PubMed2001

Differential regulation of myocardial NF kappa B following acute or chronic TNF-alpha exposure.

Tumor necrosis factor alpha (TNF-alpha) is a critical mediator of myocardial dysfunction during acute inflammatory states. TNF-alpha is also present in the serum of patients with chronic cardiac diseases. In monocytes, TNF-alpha stimulates cells by activating distinct signaling pathways that involve nuclear translocation of NF kappa B. Since NF kappa B may also regulate the expression of genes that could contribute to myocardial dysfunction, the cardiomyocyte NF kappa B activation following acute or chronic TNF-alpha challenges was investigated. To accomplish this, the authors either acutely administered TNF-alpha to healthy mice, or used transgenic mice which chronically overexpress TNF-alpha exclusively in cardiac myocytes. Following acute administration of TNF-alpha, cardiac NF kappa B translocation was detected from 15 min to 2 h post-challenge. The time course of I kappa B alpha degradation was consistent with the kinetics of NF kappa B translocation. I kappa B beta degradation was slower and less dramatic. In transgenic mice chronically overexpressing TNF-alpha, myocardial NF kappa B activation was detected at all ages tested (21, 40, and 75 days). In contrast to acutely challenged animals, two distinct NF kappa B proteins were activated in chronically challenged animals, p50--65 heterodimers as well as p50 homodimers. Activation of both could be transiently blocked by administration of a recombinant chimeric TNF-alpha receptor antagonist (rhTNFR:Fc). I kappa B alpha, but not I kappa B beta, levels were elevated in transgenics when compared to wild-type animals. These data indicate that following acute TNF-alpha administration, which simulates bacterial sepsis, myocardial p50-p65 translocates within minutes. Chronic TNF-alpha exposure, which is thought to occur in long-standing congestive heart failure, results in translocation of transcriptionally inactive p50 homodimers in addition to transcriptionally active p50--65 heterodimers. It is speculated that activation of p50 homodimers constitutes an adaptive response to minimize the inflammatory consequences of chronic cardiac TNF-alpha exposure.

Animals↗
PubMed2001

Bactericidal/permeability-increasing protein--lessons learned from the phase III, randomized, clinical trial of rBPI21 for adjunctive treatment of children with severe meningococcemia.

OBJECTIVES: To review the scientific rationale for the clinical use of recombinant bactericidal permeability-increasing protein (rBPI21) and to discuss the results, implications, and lessons learned during the clinical development of rBPI21 for adjunctive treatment of children with severe meningococcemia. DATA SOURCES: The published medical literature. STUDY SELECTION: Of the phase I/II and phase III trials in humans, preclinical experimental studies were selected. Data from these sources are presented in the context of the authors' experiences as principal investigators in the phase I/II and/or phase III clinical trials. DATA EXTRACTION AND DATA SYNTHESIS: Bactericidal permeability-increasing protein and N-terminal fragments of bactericidal permeability-increasing protein, such as rBPI21, bind and neutralize endotoxin and are potently bactericidal against both smooth and rough forms of Gram-negative bacteria, including Neisseria meningitidis. Based on these properties and compelling preclinical data indicating that administration of rBPI21 reduced mortality in several models of sepsis, we initiated clinical trials by using rBPI21 as adjunctive therapy for children with severe meningococcemia. Data from the phase III, randomized, placebo-controlled trial indicate that rBPI21 reduces clinically significant morbidities and improves the functional outcome of children with severe meningococcemia. No statistically significant benefit in mortality was demonstrated; however, because of the rare incidence of disease and the rapidity of death in this study, the trial was substantially underpowered to detect a statistically significant mortality advantage. Before the completion of the trial, the probability that the study might have been underpowered to detect a significant reduction in mortality was recognized. An attempt at selecting a previously unvalidated composite end point to increase the meaningful event rate for the primary end point proved unsuccessful. Significant improvements were seen in other prospectively defined outcome variables that suggest an overall substantial benefit of therapy with rBPI21 in children with severe meningococcemia. CONCLUSIONS: As the largest therapeutic trial conducted in pediatric critical care, the phase III trial of rBPI21 demonstrates important principles that can influence the design of future trials targeting rare, life-threatening diseases.

Activities of Daily Living↗
PubMed2001

Human coronary endothelial cell activation by endotoxin is characterized by NF-kappa B activation and TNF-alpha synthesis.

Tumor necrosis factor-alpha (TNF-alpha), an early inflammatory mediator typically regulated by nuclear factor kappa B (NF-kappa B), plays a critical role in the development of cardiovascular dysfunction in sepsis. While several myocardial cell types synthesize TNF-alpha, the importance of the myocardial endothelium in sepsis-related cardiac cytokine production is unclear. To determine the role of the human coronary artery endothelial cell (HCA-EC) in the cytokine response to endotoxin we measured in vitro TNF-alpha synthesis, TNF-alpha mRNA, and the associated NF-kappa B response to LPS. To determine the magnitude of the HCA-EC response we assessed the TNF-alpha and NF-kappa B response to LPS in a human monocytic cell line (THP-1) as well. We observed an increase in supernatant TNF-alpha from LPS-stimulated HCA-EC (12 h) that was ablated by the proteosome inhibitor, ALLN (N-acetyl-Leu-Leu-norleucinal). Similarly, ALLN-sensitive TNF-alpha was produced by monocytes following LPS, although at concentrations 100-fold higher than HCA-EC. TNF-alpha mRNA from HCA-EC was detected at 60 min in LPS-stimulated cells, but not in unstimulated cells or cells pretreated with ALLN. NF-kappa B p50/p65 subunits were detectable in endothelial nuclear protein 60 min following LPS. In contrast, NF-kappa B subunits from monocytes were detected at 15 min. Also, while ALLN only attenuated endothelial NF-kappa B translocation, monocyte NF-kappa B translocation was completely inhibited. These data suggest endotoxin-stimulated human coronary endothelial cells express TNF-alpha, which is regulated in part by NF-kappa B activation, in a manner and degree distinct from human monocytes.

Cell Nucleus↗
PubMed2001

Overexpression of cardiac I-kappaBalpha prevents endotoxin-induced myocardial dysfunction.

Nuclear factor-kappa B (NF-kappaB) is an inducible transcription factor that regulates expression of many genes, such as tumor necrosis factor-alpha (TNF-alpha), which may contribute to myocardial dysfunction. We investigated whether cardiac NF-kappaB activation is involved in the development of myocardial dysfunction after lipopolysaccharide (LPS) challenge. Mice were intraperitoneally injected with LPS, and the hearts were harvested and assayed for NF-kappaB translocation. After LPS challenge, NF-kappaB activation was detected within 30 min and remained for 8 h. In transgenic mice constitutively overexpressing a nondegradable form of I-kappaBalpha (I-kappaBalphaDeltaN) in cardiomyocytes, myocardial NF-kappaB translocation was prevented after LPS challenge. Myocytes isolated from these transgenics secreted significantly less TNF-alpha than did wild-type cardiomyocytes after LPS stimulation. When whole hearts were excised, perfused in a Langendorff preparation, and challenged with endotoxin, I-kappaBalphaDeltaN transgenic hearts displayed normal cardiac function, whereas profound contractile dysfunction was observed in wild-type hearts. These data indicate that myocardial NF-kappaB translocates within minutes after LPS administration. Inhibition of myocyte NF-kappaB activation by overexpression of myocyte I-kappaBalpha is sufficient to block cardiac TNF-alpha production and prevent cardiac dysfunction after LPS challenge.

Animals↗
PubMed2001

Targeted disruption of ICAM-1, P-selectin genes improves cardiac function and survival in TNF-alpha transgenic mice.

We have developed a transgenic mouse model in which tumor necrosis factor (TNF)-alpha is overexpressed exclusively in the heart under the regulation of the alpha-myosin heavy chain promoter. These animals develop chronic heart failure associated with severe leukocyte infiltration in both the atria and the ventricles. The purpose of this study was to investigate the role of adhesion molecules in mediating cardiac dysfunction in the TNF-alpha transgenic model. TNF-alpha transgenic mice were bred with mice null for intercellular adhesion molecule (ICAM)-1 and P-selectin genes to obtain a lineage of ICAM-1 and P-selectin null mice with selective overexpression of TNF-alpha in the heart. TNF-alpha transgenic animals showed marked upregulation of ICAM-1 mRNA and protein; however, P-selectin mRNA and protein remained undetectable despite chronic TNF overexpression. Cardiac function was markedly improved in the ICAM-1(-/-), P-selectin(-/-), TNF-alpha transgenic group versus the ICAM(+/+), P-selectin(+/+), TNF-alpha transgenic group. Kaplan-Meier survival curves showed statistically significant prolonged survival in the ICAM-1(-/-), P-selectin(-/-), TNF-alpha transgenic animals. These data suggest that ICAM-1 mediates at least in part the cardiac dysfunction induced by TNF-alpha expression by cardiac myocytes.

Animals↗
PubMed2000

Recombinant bactericidal/permeability-increasing protein (rBPI21) as adjunctive treatment for children with severe meningococcal sepsis: a randomised trial. rBPI21 Meningococcal Sepsis Study Group.

BACKGROUND: Endotoxin is a primary trigger of the inflammatory processes that lead to shock, multiorgan failure, and purpura fulminans in meningococcal sepsis. Bactericidal/permeability-increasing protein (BPI) is a natural protein, stored within the neutrophil granules, that binds to and neutralises the effects of endotoxin in vitro, in laboratory animals, and in humans. To establish whether a recombinant 21-kDa modified fragment of human BPI (rBPI21), containing the active antimicrobial and endotoxin-neutralising moiety, would decrease death and long-term disability from meningococcal sepsis, we did a randomised, double-blind, placebo-controlled trial of rBPI21 in children with severe meningococcal sepsis. METHODS: We enrolled children (2 weeks to 18 years of age) presenting to 22 centres in the UK and the USA with a clinical picture suggestive of meningococcal sepsis, and with evidence of severe disease. Children were randomly assigned rBPI21 (2 mg/kg over 30 min followed by 2 mg/kg over 24 h) or placebo (0.2 mg/mL human albumin solution) in addition to conventional medical therapy. Primary outcome variables were mortality, amputations, and change in paediatric overall performance category (POPC) from before illness to day 60. Analysis was by intention to treat. FINDINGS: Of 1287 patients screened, 892 were excluded, including 57 patients who died or who met criteria for imminent death before receiving the study drug. 190 patients received rBPI21, and 203 placebo. 34 (8.7%) of 393 patients died during the study: 14 (7.4%) in the rBPI21 group and 20 (9.9%) in the placebo group (odds ratio 1.31 [95% CI 0.62-2.74], p=0.48). Compared with patients randomised to placebo, fewer patients treated with rBPI21 had multiple severe amputations (six of 190 [3.2%] vs 15 of 203 [7.4%], odds ratio 2.47 [0.94-6.51], p=0.067), and more had a functional outcome similar to that before illness (as measured by the POPC scale) at day 60 (136 of 176 [77.3%] vs 126 of 190 [66.3%], p=0.019). INTERPRETATION: Because most deaths occurred in the interval between identification of patients and study drug administration, the mortality rate in the placebo group was substantially lower than predicted. The trial was therefore underpowered to detect significant differences in mortality. However, patients receiving rBPI21 had a trend towards improved outcome in all primary outcome variables. Given the excellent severity match between placebo and rBPI21 groups at study entry, the results overall indicate that rBPI21 is beneficial in decreasing complications of meningococcal disease.

Adolescent↗
PubMed2000

Meningococcemia as a model for testing the hypothesis of antisepsis therapies.

OBJECTIVE: To critically review the advantages and disadvantages of pediatric meningococcemia as a model for testing antisepsis therapies. DATA SOURCES: Research and review articles on the pathogenesis and treatment of human meningococcemia, as well as editorial commentaries discussing the failure of clinical trials for adult sepsis or Systemic Inflammatory Response Syndrome. Data from these sources are presented in the context of the author's experience as principal investigator in a large, randomized trial on children with invasive meningococcal disease. STUDY SELECTION AND DATA EXTRACTION: Studies were selected to include aspects of epidemiology, pathophysiology, outcome prediction, and therapeutic trials. DATA SYNTHESIS: Compared with an adult sepsis population, meningococcemia is a single disease, diagnosed clinically with high reliability. Patients are previously healthy, without underlying medical or surgical conditions. In contrast to sepsis trials, nearly all patients with meningococcal disease receive effective antibiotics. Finally, meningococcemia most closely resembles animal models of endotoxin infusion, in which most antisepsis therapies have been highly effective. However, the meningococcal model carries major disadvantages, among them that meningococcemia is rare and rapidly progressive and patients are widely dispersed geographically. In addition, a wide range of experimental therapies is routinely provided in an attempt to preserve life or limbs. CONCLUSIONS: Meningococcemia is an ideal model of a rapidly progressive bacterial infection associated with marked endotoxemia. Problems with the model can be overcome by extensive pretrial logistic planning, as well as close coordination and cooperation with national regulatory agencies.

Adult↗
PubMed2000

Increased cardiomyocyte intracellular calcium during endotoxin-induced cardiac dysfunction in guinea pigs.

Septic shock is a complex pathophysiologic state characterized by circulatory insufficiency, multiple system organ dysfunction, and frequent mortality. Although profound cardiac dysfunction occurs during sepsis, the pathogenesis of this dysfunction remains poorly understood. To determine whether abnormalities in intramyocyte calcium accumulation might contribute to the development of cardiac dysfunction, we measured myocyte intracellular calcium during peak cardiac dysfunction after an endotoxin challenge. Intraperitoneal administration of Escherichia coli lipopolysaccharide 4 mg/kg to adult guinea pigs resulted in significantly impaired cardiac performance (Langendorff preparation) 18 h after challenge compared with control. This included diminished left ventricular pressure development (56 +/- 7 versus 95 +/- 4 mm Hg, p < 0.05), maximal rate of left ventricular pressure rise (998 +/- 171 versus 1784 +/- 94 mm Hg/s, p < 0.05) and left ventricular pressure fall (1014 +/- 189 versus 1621 +/- 138 mm Hg/s, p < 0.05). Assay of intracellular calcium in fura-2AM-loaded cardiac myocytes demonstrated increased intracellular calcium concentration in myocytes obtained from lipopolysaccharide-challenged animals compared with controls (234 +/- 18 versus 151 +/- 6 nM, p < 0.05). Inhibition of calcium-release channel (ryanodine receptor) opening by administration of dantrolene prevented the increase in intracytoplasmic calcium (159 +/- 8 versus 234 +/- 18 nM, p < 0.05) and partially ameliorated systolic and diastolic ventricular dysfunction. These data indicate that abnormalities of intracellular calcium contribute to the development of endotoxin-induced myocardial dysfunction.

Animals↗
PubMed2000

Preoperative and postoperative endotoxemia in children with congenital heart disease.

STUDY OBJECTIVES: Recent data indicate that increases in inflammatory cytokines are seen in patients with diverse cardiac diseases. However, the primary stimulus for cytokine secretion during cardiac illness remains unknown. Since bacterial endotoxin is a potent inducer of cytokines, we determined the incidence, magnitude, and clinical relevance of endotoxemia in children with congenital heart disease before and after surgical repair. DESIGN: A prospective, observational study. SETTING: A large, urban, university-affiliated, tertiary-care children's hospital. PATIENTS: Thirty children with a variety of congenital heart defects (median age, 59 days; median weight, 4.0 kg) were sequentially enrolled. INTERVENTIONS: Blood was sampled prior to surgery, and at 1, 8, 24, 48, and 72 h following cardiopulmonary bypass. Assays included plasma endotoxin, lipopolysaccharide-binding protein (LBP), and interleukin-6 (IL-6). MEASUREMENTS AND RESULTS: Twenty-nine of 30 patients (96%) had evidence of endotoxemia during the study period. Twelve of the 30 patients (40%) were significantly endotoxemic prior to surgery. LBP, a plasma marker that responds to bacteria and endotoxin, rose significantly following cardiopulmonary bypass, as did the plasma levels of IL-6. Fifteen of 30 patients met prospectively defined criteria for experiencing a severe hemodynamic disturbance in their postoperative course. These patients had significantly higher preoperative plasma LBP (p < 0.02) and plasma endotoxin levels (p < 0.05), compared to patients with less-severely disturbed hemodynamics. Mortality was 25% in patients with preoperative endotoxemia, compared with no mortality in patients who were not endotoxemic before surgery (p = 0.05). CONCLUSIONS: These data demonstrate that endotoxemia in children with congenital heart disease is more common than previously suspected, and is associated with clinical outcomes. We conclude that clinical trials targeting endotoxin will be necessary to determine if endotoxin is a causal, etiologic agent in the disease process.

Acute-Phase Proteins↗
PubMed1998

Aspiration pneumonia-induced sepsis increases cardiac dysfunction after burn trauma.

Pneumonia occurs in approximately 50% of incubated patients in burn intensive care units and carries a mortality as high as 40%. A model was developed to study altered cardiopulmonary function in burn complicated by pneumococcal pneumonia. Sprague-Dawley rats were given a 43% total body surface area scald burn or sham burn; 24 h later they were transtracheally inoculated with either 10(7) Streptococcus pneumoniae in 0.5 ml phosphate buffer solution (PBS) or 0.5 ml PBS alone. The four groups were: Sham (N = 7), Burn alone (N = 10), Pneumonia alone (N = 11), and Burn and Pneumonia ( N = 12). A fifth group of burned rats (N = 10), given an identical fluid resuscitation regimen, was sacrificed 24 h postburn to examine the early cardiac responses to burn injury alone. Shams and burned animals had normal lung histology, negative bronchoalveolar lavage (BAL) cultures, and negative blood cultures. Pneumonia and burn plus pneumonia animals had abnormal lung histology, positive BAL cultures, and positive blood cultures. Cardiac function was assessed 24 h after S.pneumoniae challenge (48 h after burn) (Langendorff preparation). Compared to the Sham group, Pneumonia group, and Burn group, the Burn plus Pneumonia group had the lowest left ventricular pressure (LVP: 94 +/- 4, 71 +/- 3, and 87 +/- 3 mm Hg vs 63 +/- 4 mm Hg, P < 0.05), the lowest maximal rate of LVP rise (+dP/dt[max]:1932 +/- 115, 1419 +/- 71, and 1772 +/- 96 mm Hg vs 1309 +/- 59 mm Hg/s, P < 0.05), and the lowest maximal rate of LVP fall (-dP/dt[max]:1704 +/- 120, 1263 +/- 73, and 1591 +/- 83 mm Hg vs 1025 +/- 98 mm Hg/s, P < 0.05). Cardiac contraction and relaxation deficits were confirmed in animals 24 h postburn (group 5), as indicated by a significantly lower LVP and +/-dP/dt(max) (62 +/- 3 mm Hg 1210 +/- 60, and 909 +/- 50 mm Hg/s, respectively, P < 0.05 compared to Sham group). Tumor necrosis factor-alpha (TNF-alpha) concentrations in serum, but not bronchoalveolar lavage, were greater in burned animals with aspiration pneumonia-induced sepsis than in animals with either burn alone or aspiration pneumonia-induced sepsis alone. While our data suggest that elevated circulating TNF-alpha levels may contribute, in part, to depressed cardiac function, further studies are needed to fully define the mechanisms underlying cardiac contractile deficits in this model. We speculate that depressed cardiopulmonary function due to burn complicated by pneumonia and sepsis contributes to the high mortality of this patient population.

Animals↗
PubMed1998

Molecular biology of septic shock.

Septic shock is a complex pathophysiologic state which often leads to multiple organ dysfunction, multiple organ failure, and death. This review summarizes current views on the molecular biology of three aspects of septic shock: recognition of bacterial invasion and induction of the cytokine response; genetic variability among humans and their predispositions toward pathologic inflammatory responses; and the signal transduction mechanisms which account for the transfer of molecular signals from cytokine receptors on the plasma membrane to cytokine-responsive genes in the nucleus. In particular, the review summarizes the pathway involved in tumor necrosis factor signaling through nuclear factor-kappaB, and elucidates the molecular signals involved in inflammatory responses and apoptosis.

Apoptosis↗
PubMed1997

Preliminary evaluation of recombinant amino-terminal fragment of human bactericidal/permeability-increasing protein in children with severe meningococcal sepsis.

BACKGROUND: Meningococcal sepsis remains an important cause of morbidity and mortality. We hypothesised that children with severe meningococcaemia might benefit from inhibition of the inflammatory processes thought responsible for fulminant disease. rBPI21 is a recombinant, N-terminal fragment of human bactericidal/permeability-increasing protein, which kills meningococci and binds to and clears bacterial endotoxin, these being the primary inducers of the systemic inflammation. The aim of this study was to determine the safety and kinetics of rBPI21 in children with severe meningococcaemia and to make a preliminary assessment of clinical outcome. METHODS: In this open-label, dose-escalation, phase I/II trial in severe meningococcaemia (Glasgow meningococcal prognostic septicaemia score [GMSPS] > or = 8), 26 patients aged 1-18 years, who had received their first dose of antibiotics no more than 8 hours earlier were given rBPI21 by infusion at total doses of 1.0, 2.0, and 4.0 mg/kg. FINDINGS: The patients had significantly raised plasma concentrations of bacterial endotoxin and cytokines. Peak and steady state BPI concentrations were comparable with pharmacokinetic data in healthy adults. All complications were compatible with the expected pattern for severe meningococcal sepsis. Only one patient died. This outcome was found to compare favourably with a predicted mortality of > or = 30% by GMSPS, > or = 15% by plasma endotoxin values, > or = 28% by plasma interleukin-6 concentrations, 29-49% by severity of coagulopathy, and 20% (11/54) by comparison with recent historical patients consecutively treated in participating centres before this study. INTERPRETATION: This, the first clinical trial or rBPI21, shows that rBPI21 can be safely administered to children with severe meningococcaemia and that the pharmacokinetics are consistent with patterns seen in healthy adults. Predicted mortality, on the basis of GMSPS, laboratory indices of inflammation and coagulopathy, and historical controls, was for between four and eight deaths. These findings have prompted a phase III randomised trial.

Adult↗