Protective effect of a novel,potent inhibitor of poly(adenosine 5'-diphosphate-ribose) synthetase in a porcine model of severe bacterial sepsis

OBJECTIVE: To determine whether activation of the nuclear enzyme poly(adenosine 5'-diphosphate [ADP]-ribose) synthetase (PARS) contributes to mortality rate, myocardial dysfunction, and cardiovascular collapse in a porcine model of sepsis induced by implantation of an infected clot. DESIGN: Prospective, random animal study. SETTING: Research laboratory at Rush Presbyterian St. Luke's Medical Center. SUBJECTS: Twenty pigs were chronically instrumented with intracardiac transducers to measure left ventricular pressure, sonomicrometer crystals in the left ventricle to measure short axis diameter, an ultrasonic flow meter to measure cardiac output, and catheters in the pulmonary artery and aorta to measure blood pressures and collect samples. INTERVENTIONS: By using a randomized study design, we administered either the novel potent PARS inhibitor PJ34 (10 mg/kg for 1 hr, 2 mg x kg(-1) x hr(-1) for 96 hrs) or vehicle to pigs immediately before intraperitoneal implantation of Escherichia coli 0111.B4 (2.3 +/- 0.1 x 10(10) colony-forming units/kg)-laden fibrin clots to produce peritonitis and bacteremia. MEASUREMENTS AND MAIN RESULTS: In vehicle-treated pigs, 12% survival was recorded at 24 hrs, whereas 83% and 66% survival was recorded in the PJ34-treated animals at 24 and 96 hrs, respectively (p <.05). PJ34 treatment attenuated bacteremia-induced increases in systemic and pulmonary vascular resistances. In controls, peritonitis induced rapid increase in plasma tumor necrosis factor-alpha. PJ34 treatment significantly attenuated this cytokine response. The formation of peroxynitrite and the activation of PARS were confirmed in hearts and lungs of the septic pigs by the immunohistochemical detection of nitrotyrosine and poly(ADP-ribose), respectively. Inhibition of PARS with PJ34 abolished poly(ADP-ribose) formation in septic animals. CONCLUSIONS: Treatment with a potent PARS inhibitor improved survival and cardiovascular status and attenuated an important mediator component of the inflammatory response in a lethal porcine model of sepsis.     

Influence of genetic variations in TLR4 and TIRAP/Mal on the course of sepsis and pneumonia and cytokine release: an observational study in three cohorts

Introduction

Severe sepsis is a disease of the microcirculation, with endothelial dysfunction playing a key role in its pathogenesis and subsequent associated mortality. Angiogenesis in damaged small vessels may ameliorate this dysfunction. The aim of the study was to determine whether the angiogenic factors (vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), and angiopoietin-1 (Ang-1) and -2 (Ang-2)) are mortality indicators in Malawian children with severe bacterial infection.

Methods

In 293 children with severe bacterial infection, plasma VEGF, PDGF, FGF, and Ang-1 and Ang-2 were measured on admission; in 50 of the children with meningitis, VEGF, PDGF, and FGF were also measured in the CSF. Healthy controls comprised children from some of the villages of the index cases. Univariable and multivariable logistic regression analyses were performed to develop a prognostic model.

Results

The median age was 2.4 years, and the IQR, 0.7 to 6.0 years. There were 211 children with bacterial meningitis (72%) and 82 (28%) with pneumonia, and 154 (53%) children were HIV infected. Mean VEGF, PDGF, and FGF concentrations were higher in survivors than in nonsurvivors, but only PDGF remained significantly increased in multivariate analysis (P = 0.007). Mean Ang-1 was significantly increased, and Ang-2 was significantly decreased in survivors compared with nonsurvivors (6,000 versus 3,900 pg/ml, P = 0.03; and 7,700 versus 11,900 pg/ml, P = 0.02, respectively). With a logistic regression model and controlling for confounding factors, only female sex (OR, 3.95; 95% CI, 1.33 to 11.76) and low Ang-1 (OR, 0.23; 95% CI, 0.08 to 0.69) were significantly associated with mortality. In children with bacterial meningitis, mean CSF VEGF, PDGF, and FGF concentrations were higher than paired plasma concentrations, and mean CSF, VEGF, and FGF concentrations were higher in nonsurvivors than in survivors (P = 0.02 and 0.001, respectively).

Conclusions

Lower plasma VEGF, PDGF, FGF, and Ang-1 concentrations and higher Ang-2 concentrations are associated with an unfavorable outcome in children with severe bacterial infection. These angiogenic factors may be important in the endothelial dysregulation seen in severe bacterial infection, and they could be used as biomarkers for the early identification of patients at risk of a poor outcome.     

Cerebrospinal fluid findings in adult patients with multiple erythema migrans

This prospective study was performed at the Department of Infectious Diseases, University Medical Centre Ljubljana, Slovenia, in the period from 1991 to 2000. We included all adult patients with multiple erythema migrans who gave consent to lumbar puncture, had routine blood and CSF tests performed, and borrelial antibody titres in CSF and blood determined. In the majority of these patients skin, blood, and CSF specimens were cultured in MKP medium for the presence of Borrelia. Of 332 patients with multiple erythema migrans, 200 (115 females, 85 males, aged 15-80 years) fulfilled inclusion criteria. The median number of skin lesion was three (2-60). Sixty-three (31.5%) patients had no associated symptoms, whereas 137 (68.5%) patients (including two with arthritis, six with radicular pain, a patient with facial palsy, another patient with foot palsy and a patient with transitory diplopia) reported local and/or constitutional symptoms. Routine CSF examination revealed abnormal results in 62/200 (31%) patients: lymphocytic pleocytosis (6-1119 x 10(6)/L leukocytes) was found in 15 (7.5%) patients (six were clinically without systemic symptoms, six had mild systemic symptoms, three reported radicular pains) and elevated CSF protein concentration was present in 52 (26%) patients (nine also had elevated CSF cell counts). Intrathecal borrelial antibody production was demonstrated in eight (4%) patients (only three of them had elevated CSF cell counts) and B. burgdorferi sensu lato was isolated from skin lesions, blood, and CSF in 77/191 (40.3%), 3/154' (1.95%), and 2/200 (1%) patients, respectively. B. afzelii predominated among the isolates. In patients with multiple erythema migrans abnormal CSF findings are not rare and may be present without any clinical sign of central nervous system involvement.     

Diet quality in 116 Norwegian men and women with coronary heart disease.

BACKGROUND AND AIMS: Clinical intervention studies have provided strong evidence that a healthy diet can prevent coronary heart disease. The aims of this study were to describe the diet quality in Norwegian subjects from Sogn and Fjordane County with coronary heart disease, and to investigate if the diet quality was associated with demographic and lifestyle variables. METHODS: We used a self-administered questionnaire to assess information from 116 participants. A Healthy Diet Score (HDS) indicated the diet quality. Multiple Linear regression analyses were used to investigate associations between relevant variables and the HDS. RESULTS: We found that 26.7% of the participants had a poor HDS, 64.6% had a fair HDS and 8.7% had a good HDS. We found that the widespread suboptimal diet quality (poor or fair HDS) was partially related to low consumption of nonhydrogenated mayonnaise products, vegetables, and fruit/berries/juice. Multiple linear regression analysis showed that women had better HDS than men, and that subjects with high education had better HDS than subjects with low education (P < 0.05). CONCLUSION: We found that 91.3% of the participants had a suboptimal diet quality. The consumption of nonhydrogenated mayonnaise products, vegetables and fruit/berries/juice were poor and a principal goal should be to increase the consumption of these food items. Health professionals should keep in mind that gender and educational level may be associated with dietary habits. An important clinical implication of this study is that more attention should be paid to dietary counselling.