Possible role of TNF on procalcitonin release in a baboon model of sepsis.

Procalcitonin (PCT) has been described as an early and discriminating marker of bacteria-associated sepsis in patients. However, little is known of its source and actions, especially with regard to its relation to tumor necrosis factor (TNF). TNF is responsible for the release of several other mediators of sepsis e.g., chemokines. We tested the hypothesis that plasma PCT levels during sepsis differ with regard to the degree of TNF availability. Severe hyperdynamic sepsis was induced in baboons (n = 14) by i.v. infusion of live E. coli (approximately 2 x 10(9) colony-forming units/kg) over 2 h. Animals were pretreated 2 h before E. coli either with 1 mg/kg humanized anti-TNF antibody (CDP571) or placebo (Ringer solution). Plasma PCT levels at baseline was barely detectable, but increased to about 4000 pg/mL at 4 h after E. coli infusion. Levels were maximal between 8 and 24 h and had returned nearly to baseline at 72 h. Although no TNF could be measured in the treated group, PCT levels were not different between the placebo and the TNF antibody treatment group. We conclude that PCT levels are not dependent on the systemic presence of TNF in an E. coli sepsis model in baboons. Such sepsis induced PCT release is clearly different from the previously reported PCT release during infusion of rhTNF in volunteers or chimpanzees.

Procalcitonin release patterns in a baboon model of trauma and sepsis: relationship to cytokines and neopterin.

OBJECTIVES: Procalcitonin (PCT) has been described as an early, discriminating marker of bacteria-associated sepsis in patients. However, little is known of its source and actions, in part because no appropriate animal models have been available. We tested the hypothesis that plasma PCT increases during various pathophysiological conditions, such as hemorrhagic shock and sepsis, which differ with regard to the degree of associated endotoxemia. We further hypothesized that in sepsis, PCT would be significantly different in survivors vs. nonsurvivors. DESIGN: Prospective, blinded analysis of previously collected plasma of experimental animals. SETTING: Independent nonprofit research laboratory in a trauma hospital and a contract research institute. SUBJECTS: A total of 22 male baboons (17.5-31 kg). INTERVENTIONS: Hemorrhagic-traumatic shock was induced by hemorrhage for up to 3 hrs, reperfusion with shed blood and infusion of cobra venom factor (n = 7). By using a similar experimental setup, severe hyperdynamic sepsis was induced (n = 15) by intravenous infusion of live Escherichia coli (2 x 10(9) colony-forming units/kg) over 2 hrs, followed by antibiotic therapy (gentamicin 4 mg/kg twice a day). MEASUREMENTS AND MAIN RESULTS: Plasma PCT at baseline was barely detectable, but levels increased significantly (p < .05) to 2+/-1.8 pg/mL 2 hrs after the start of reperfusion in the shock group, and to 987+/-230 pg/mL at 4 hrs after E. coli in the sepsis group. Levels were maximal between 6 and 32 hrs and had returned nearly to baseline levels at 72 hrs. Interleukin-6 levels paralleled the course of PCT measurements, whereas a significant increase in neopterin was seen at 24 hrs. PCT levels were approximately three times higher in the sepsis group than in the shock group, corresponding to endotoxin levels (at the end of hemorrhage, 286+/-144 pg/mL vs. 3576+/-979 pg/mL at the end of E. coli infusion; p = .003). PCT levels were significantly different at 24 hrs between survivors (2360+/-620 pg/mL) and nonsurvivors (4776+/-563 pg/mL) in the sepsis group (p = .032), as were interleukin-6 (1562+/-267 vs. 4903+/-608 pg/mL; p = .01) and neopterin/creatinine ratio (0.400+/-0.038 vs. 0.508+/-0.037; p = .032). CONCLUSIONS: PCT is detectable in the baboon as in humans, both in hemorrhagic shock and sepsis. PCT levels are significantly higher in sepsis than in hemorrhage, a finding that is probably related to the differences in endotoxin. The baboon can be used for the study of PCT kinetics in both models; PCT kinetics are clearly different from other markers of sepsis, either IL-6 or neopterin, in both models. There are significant differences between survivors and nonsurvivors in the sepsis model.

Analysis of Plasmodium falciparum infections in a village community in Northern Nigeria: determination of msp2 genotypes and parasite-specific IgG responses.

The genetic diversity of P. falciparum and multiplicity of infection has been studied in a village in Northern Nigeria at the end of the rainy season, when transmission is high. We analysed blood samples from 104 individuals aged 5-70 years by polymerase chain reaction (PCR) amplifying the gene for the merozoite surface protein MSP2 followed by genotyping based on restriction fragment length polymorphism (RFLP). 94.2% of all samples were parasite positive by PCR and over 80% of those had multiple infections. The age distribution of the average number of parasite clones present in P. falciparum infections showed an initial increase, then reached a peak multiplicity in children 8-10 years of age, and afterwards decreased significantly with age. Mean multiplicity in those 8-10-year-old children was 5.4 clones per carrier. Peak multiplicity and parasite diversity in Nigerian individuals is compared to findings from other study sites in Africa and PNG. The prevalence of IgG antibodies against the circumsporozoite protein (CSP), an indicator for malaria exposure, was over 85% in all age groups showing a high exposure of villagers to P. falciparum. OD values in ELISA were positively correlated with age. There was no correlation between the level of IgG against CSP and the multiplicity of P. falciparum infections determined by PCR of msp2. These results imply that in highly endemic areas multiplicity of infection is not directly correlated with exposure to P. falciparum.

[Angiotensin I biosynthesis and electrolytes]. / Angiotensin-I-Bildung und Elektrolyte.

An influence on the production of Angiotensin-I by different ions is demonstrated. Plasma Renin activity was thereby measured by the methods of Boyd et al. (pH 7.5) and of Fyhrquist et al. (pH 6.0) at a concentration of each ion of 50 mmol/L. Ions of different size were used, ranging from Lithium to the Ammonium-ion. A definitive dependency of this effect on the Angiotensin production by the ion size could be shown. With Sodium the concentration in serum was varied at 5 levels (130-170 mmol/L) and Renin measured at Potassium concentrations in low (3.4-3.7 mmol/L) or high (4.8-5.1 mmol/L) so-called normal ranges. A marked increase of the production of Angiotensin-I with increasing sodium concentrations at a low Potassium range was observed and the opposite was true at high Potassium concentrations. These effects have to be taken into account when assaying Plasma Renin activity. In addition, they offer also an explanation of the well-known but unsolved facts of the influence of Sodium and Potassium on the pathogenesis of hypertonia.