Nitric Oxide Administration Restores the Hepatic Artery Buffer Response During Porcine Endotoxemia

The hepatic artery buffer response, which is lost during endotoxemia, plays a central role in the autoregulation of liver perfusion. A temporarily decreased synthesis of nitric oxide during early endotoxemia might be responsible for this dysfunction; hence exogenous administration of nitric oxide could reestablish the autoregulation of hepatic blood flow and help prevent hepatic damage later in septic shock. Fifteen pigs were treated with lipopolysaccharide +/? the nitric oxide donor nitroprusside-sodium via the portal vein. Hemodynamics were measured, and serum chemistry and liver biopsies for nitric oxide synthase expression were obtained. Lipopolysaccharide decreased arterial liver perfusion after 5 hours by 38% (p =. 012), which was reversed by addition of nitroprusside (8%). Administration of nitroprusside preserved an increase of 28% in hepatic arterial upon portal vein flow reduction (p <. 001). Nitroprusside maintained mRNA levels of constitutive nitric oxide synthase in liver tissue which were decreased by lipopolysaccharide (p =. 026 vs. p =. 114) and tempered the burst in inducible nitric oxide synthase expression at t = 3 hours. The early administration of the nitric oxide donor sodium nitroprusside during endotoxemia is able to reestablish the autoregulatory response of the hepatic artery following reduction of hepatic blood flow. This beneficial effect might help to prevent subsequent hepatic damage in the course of abdominal sepsis.     

A study of coach‐team perceptual distance concerning the coach‐created motivational climate in youth sport

The purpose of this study was to examine whether coach‐team perceptual distance regarding the coach‐created motivational climate related to achievement goal orientations and affective responses. To this end, we used polynomial regression analysis with response surface methodology. The sample consisted of 1359 youth soccer players (57.8% male; M_age = 11.81 years, SD = 1.18), belonging to 87 different teams (M_size = 16.47), and 87 coaches (94.6% male, M_age = 42 years, SD = 5.67). Results showed that team perceptions of a coach‐created mastery climate were positively related to team‐rated task goal orientation and enjoyment, whereas team perceptions of a coach‐created performance climate were positively related to team‐rated ego goal orientation and anxiety, and negatively related to team‐rated enjoyment. When the coach and the team were in perceptual agreement, the outcomes increased as both coach and team perceptions of the climate increased. In situations of perceptual disagreement, the most negative effects were seen when the coach held a more favorable perception of the motivational climate compared to the team. The findings highlight the importance of perceptual agreement between the coach and his/her team, contributing to the literature focusing on the effects of the coach‐created motivational climate.     

A fusidic acid-resistant clone of Staphylococcus aureus associated with impetigo bullosa is spreading in Norway

OBJECTIVE: To investigate the possibility that the increased prevalence of fusidic acid-resistant Staphylococcus aureus in Norway is caused by clonal spread. METHODS: Fusidic acid-resistant and -susceptible clinical isolates of S. aureus from patients with skin infections in the Norwegian county of Telemark and fusidic acid-resistant isolates from other parts of Scandinavia were compared. MICs of fusidic acid for bacterial isolates and pulsed-field gel electrophoresis (PFGE) patterns were investigated. Prevalence data for fusidic acid-resistant S. aureus for the period 1992-2001 were obtained. RESULTS: The prevalence of fusidic acid resistance in S. aureus increased from 1992 to 2001. Eighty per cent of the resistant isolates investigated shared an identical PFGE pattern. The same pattern was found in fusidic acid-resistant isolates from other parts of Scandinavia. Fusidic acid-resistant S. aureus was typically found in impetigo bullosa-like skin disease in children mostly in the summer months. CONCLUSIONS: Fusidic acid resistance among S. aureus is increasing in Norway and is predominantly caused by one clone of S. aureus. The clone may spread further to other countries, and dissemination may be facilitated by extensive use of topical fusidic acid.     

Hydrocortisone and the mitogen-activated protein kinase inhibitor U0126 acutely suppress reactive oxygen species generation from circulating granulocytes after gunshot injuries in the pig

OBJECTIVE: Several external stimuli, including trauma, increase the endogenous production of reactive oxygen species that spontaneously attack vital biological molecules. In addition to their direct toxic effects, several secondary messenger systems are induced. To forestall a subsequent organ dysfunction, a short-term posttraumatic down-regulation of granulocyte function has been advocated. Corticosteroids are potent and universal anti-inflammatory agents, but they have well-known side effects. Modulation of the mitogen-activated protein kinase cascade is an alternative approach. The purpose of this study was to investigate how the posttraumatic production of reactive oxygen species can be modulated by hydrocortisone or the extracellular signal-regulated kinase inhibitor U0126. DESIGN: Prospective randomized trial. SETTING: Field hospital and research laboratory. SUBJECTS: Seventeen male pigs. INTERVENTIONS: In general anesthesia, the pigs were exposed to a standardized insult: one gunshot hitting the right femur from a distance of 25 m, and one pistol shot to the left upper abdomen from close range. Following immediate first aid treatment, the animals were transported to a nearby field hospital. According to randomization, the animals received either hydrocortisone 250 mg intravenously (group 1, n = 9) or a similar amount of saline (group 2, n = 8). The injections were given 5 mins after the last shot. Blood samples were drawn before shooting, immediately before hydrocortisone was given, and 60 mins after shooting. Circulating neutrophils were isolated, and the production of reactive oxygen species was measured fluorometrically. Neutrophils from nine randomly chosen animals (five from group 1 and four from group 2) were treated in vitro with the extracellular signal-regulated kinase inhibitor U0126. MEASUREMENTS AND MAIN RESULTS: The injuries as evaluated by the abbreviated injury scale did not differ between the animals. All survived the first 60 mins. While the in vivo production of reactive oxygen species tended to increase in the controls, a significant reduction was measured in the hydrocortisone group. Subsequent treatment with U0126 further reduced the synthesis of reactive oxygen species by about two thirds in both groups, independently of time. CONCLUSIONS: Early injection of hydrocortisone after trauma inhibits the synthesis of reactive oxygen species from circulating neutrophils. Inhibition of the extracellular signal-regulated kinase branch of the mitogen-activated protein kinase signaling cascade is an alternative approach. The powerful in vitro capacity of selective extracellular signal-regulated kinase inhibitors to reduce the posttraumatic reactive oxygen species generation deserves further investigations, and compelling evidence of their in vivo usefulness is still lacking.     

Systemic administration of enamel matrix derivative to lipopolysaccharide-challenged pigs: effects on the inflammatory response

BACKGROUND: Periodontitis is the primary clinical indication for enamel matrix derivative (EMD). Recent investigations, showing that EMD inhibits the production of tumor necrosis factor-alpha (TNF-alpha) when added to human whole blood, indicate a novel role for EMD as a modulator of systemic inflammation. In the present study, we investigated the systemic effects of EMD in lipopolysaccharide (LPS)-challenged pigs. METHODS: In a preparatory study, seven pigs received a prophylactic EMD bolus injection (5 mg/kg), followed by a continuous infusion (50 mg/kg/min). Thirty minutes later, a continuous infusion of LPS (1.7 mcg/kg/h) was started. An additional 12 pigs were randomized into two groups. Six of these animals were given the same treatment, except that EMD was administered 30 min after LPS. The remainder served as controls. The groups were compared according to organ injury and function, hemodynamics, and systemic markers of inflammation. RESULTS: Prophylactic administration of EMD triggered transient hemodynamic instability in two of seven pigs. In the randomized pigs, no or only nonspecific changes were observed in biopsies from vital organs, independent of treatment. Enamel matrix derivative did not modify systemic TNF-alpha, interleukin (IL)-1 beta, or IL-6 concentrations. CONCLUSIONS: In the formulation and dosages used, EMD did not modulate the inflammatory response. No true allergic or immunotoxic reactions were seen. To be usable for systemic application, a new formulation should be developed, or the active part of the protein(s) should be identified and produced in a soluble form designed for infusion. The potential of EMD as a systemic immune modulator is still unsettled.     

Activation of cytokine synthesis by systemic infusions of lipopolysaccharide and peptidoglycan in a porcine model in vivo and in vitro

BACKGROUND: The incidence of gram-positive and mixed bacterial infections in surgical patients has increased, and there has been an alarming rise in the number of drug-resistant bacteria. Peptidoglycan (PepG) is a cell wall component of gram-positive bacteria that stimulates inflammatory responses both ex vivo and in vivo. The systemic effects of PepG on inflammation have not been studied in a large animal model. METHODS: Anesthetized pigs were subjected to 8-h continuous intravenous infusions of lipopolysaccharide (LPS) (4 mcg/kg/h), PepG (40 mcg/kg/h), LPS plus PepG, or saline. The concentrations of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, IL-8, and IL-10 were measured in the plasma prior to infusion (time 0) and thereafter every second hour until the end of the experiments. Heparinized whole blood samples drawn at time 0 and after a 6-h infusion of LPS or PepG were incubated ex vivo with PepG (10 mcg/mL), LPS (10 ng/mL), or a combination of PepG and LPS to study the immunologic consequences of systemic inflammation. Concentrations of TNF-alpha, IL-8, and IL-1beta were measured in the supernatant liquids. RESULTS: In vivo, there was transient upregulation of TNF-alpha after infusion of LPS, PepG, or the combination. Interleukin-6 and IL-8 were upregulated by LPS but not by PepG. In vitro studies of whole blood obtained at time 0 revealed a synergistic effect of LPS and PepG on the release of TNF-alpha. Incubation of whole blood obtained after 6 h of infusion of LPS or PepG revealed tolerance and cross-tolerance between the two bacterial components in the induction of TNF-alpha, IL-8, and IL-1beta. CONCLUSIONS: Peptidoglycan is a potent inducer of TNF-alpha in this large animal model. Peptidoglycan and LPS synergized to increase the formation of the proinflammatory cytokine TNF-alpha. The study demonstrates for the first time the development of tolerance and cross-tolerance between LPS and PepG in a large animal model. These phenomena could be of importance for the signs and symptoms of sepsis.     

Different osteosyntheses for Colles' fracture: A mechanical study in 42 cadaver bones

Background and purpose In recent years several different plate designs for internal fixation of fractures of the distal radius have been developed. However, few biomechanical studies have been performed to compare these new implants. The purpose of this study was to compare the mechanical properties of 5 different commercially available plates (3 volar and 2 dorsal) with standard K-wire fixation using a distal radial cadaver model.Material and methods 42 human radial bones from 26 cadavers were included. The bone mineral density (BMD) was measured by DEXA in all bones, and the radial bones were assigned to 6 equiv alent groups based on bone density and total amount of mineral. A distal radial osteotomy was done and a dorsal 30-degree wedge of bone was removed. 1 K-wire fixation group and 5 plate groups were tested for rigidity, yield load, and maximum load.Results When data from dorsally and volarly applied plates were pooled, we did not find any statistically significant differences between them regarding stiffness, yield load, and maximum load. The K-wire group showed significantly lower yield load than 3 of the plate groups. There were no statistically significant differences in yield load between the 5 plate groups. The K-wire group showed lower rigidity than the plate groups. The K-wire group and 1 plate group failed at a statistically significant lower maximum load than the 4 other plate groups.Interpretation The volar plates had the same mechanical stability as the dorsally applied plates, and they are therefore a good alternative to dorsally applied plates. K-wire osteosynthesis was inferior to plate osteosyntheses regarding all mechanical properties.     

Neuropsychological deficit among elderly workers in aluminum production

A cross-sectional study was conducted at a Norwegian primary aluminum plant. All workers aged 61-66 years were offered early retirement benefits. Among the workers, 47 met the study criteria and 38 (81%), comprising 14 potroom workers, 8 foundry workers, and 16 controls, volunteered to participate. They were tested with a neuropsychological test battery. Workers in potrooms with Søderberg electrolytic cells were found to show signs of impairment of the nervous system. A test for tremor discriminated significantly between the potroom group and the controls. There was a suggestion of increased risk of impaired visuospatial organization and a tendency to a decline in psychomotor tempo in the potroom workers. We suggest that the above findings may be related to long-term occupational exposure in the potroom, and further to chronic low-dose exposure to aluminum. © 1994 Wiley-Liss, Inc.     

Variability of quantitative coronary angiography: an evaluation of on-site versus core laboratory analysis

To assess the validity of locally performed off-line quantitative coronary angiography (QCA) measurement in clinical trials, we carried out a comparative study between on-site QCA analysis and analysis performed at an independent external core laboratory. One local operator analyzed the pre, post and follow-up angiograms of 116 patients participating in the Stenting in Small Coronary Arteries Study (SISCA) prior to final QCA analysis in the core laboratory. The mean values of the reference diameter (RD), minimal lumen diameter (MLD) and diameter stenosis (DS) showed acceptable agreement between study site and core laboratory. However, on the level of individuals the interobserver differences were large, affecting the outcome of restenosis rate significantly, and in a such way that the conclusions in the SISCA trial might have come out differently if a core laboratory had not been used. This emphasizes the importance of using independent core laboratories in coronary interventional trials.     

TLR agonists induce the differentiation of human bone marrow CD34+ progenitors into CD11c+ CD80/86+ DC capable of inducing a Th1-type response

We recently reported that human bone marrow hematopoietic CD34(+) progenitors express functional Toll-like receptors (TLR) and can differentiate into myeloid cells just by stimulation with resiquimod (R848), a specific agonist for TLR7/8. However, the mechanisms by which R848 induces cell differentiation, the effects of other TLR agonists and the functionality of the differentiated cells are not known. Comparable to R848, loxoribine (a TLR7 agonist) and Pam(3)CSK(4) (a TLR2 agonist) induced cytokine production and cell differentiation along the myeloid lineage. R848 and loxoribine were more effective than Pam(3)CSK(4) at inducing the lineage-negative (CD11c(+) CD14(-)) dendritic cells (DC), whereas Pam(3)CSK(4) was more effective at inducing CD11c(+) CD14(+) monocytes. Both cell subsets expressed CD80/CD86 and HLA-DR molecules; however, they showed differential expression of CD1a, CD1b, CD1c, CD11b, CD206 and CD207 markers when compared with each other. Cell differentiation into DC was significantly inhibited by an anti-TNF-alpha nonoclonal antibody. The CD11c(+) CD14(-) subset was isolated and shown to be more potent in stimulating an alloreaction than the CD11c(+) CD14(+) subset. Collectively, these data highlight the differential effects of TLR agonists on human bone marow CD34(+) progenitor cells and provide a new opportunity for generating functional DC that would be useful in cancer vaccination.