Safety and dose-dependency of eptacog beta (activated) in a dose escalation study of non-bleeding congenital haemophilia A or B patients, with or without inhibitors.

INTRODUCTION: Varying initial doses of activated eptacog beta (recombinant human FVIIa, rhFVIIa) may provide therapeutic options when treating bleeding in patients with congenital haemophilia who have developed inhibitory antibodies to factor VIII (FVIII) or factor IX (FIX). This study evaluated escalated doses of a new rhFVIIa product as a prelude to selecting the doses for clinical efficacy evaluation in haemophilia patients. AIM: To assess the safety, pharmacokinetics, and laboratory pharmacodynamics of 3 doses of rhFVIIa in non-bleeding patients with congenital haemophilia A or B with or without inhibitors. METHODS: Adult male patients (18-75 years old) with congenital haemophilia A or B (with or without inhibitors) received infusions of rhFVIIa at doses of 25, 75 or 225 µg/kg body weight. Ten patients were treated at each dose level, and each patient received 2 different dose levels. Descriptive methods were used to analyse the data. RESULTS: Administration of rhFVIIa at all doses was well tolerated. Pharmacokinetic analyses showed that peak FVIIa plasma levels (Cmax ) were approximately proportional to dose and correlated well with peak thrombin generation. Total AUC0-inf also was approximately dose proportional. Clot formation and duration correlated with FVIIa activity. Repeat doses did not produce an immunological response. CONCLUSION: In the first dose-escalation study of rhFVIIa to support product registration, eptacog beta at doses of 25, 75, and 225 µg/kg was pharmacodynamically active and well tolerated in non-bleeding patients with congenital haemophilia A or B.

Widespread Warming Before and Elevated Barium Burial During the Paleocene-Eocene Thermal Maximum: Evidence for Methane Hydrate Release?

Current climate change may induce positive carbon cycle feedbacks that amplify anthropogenic warming on time scales of centuries to millennia. Similar feedbacks might have been active during a phase of carbon cycle perturbation and global warming, termed the Paleocene-Eocene Thermal Maximum (PETM, 56 million years ago). The PETM may help constrain these feedbacks and their sensitivity to warming. We present new high-resolution carbon isotope and sea surface temperature data from Ocean Drilling Program Site 959 in the Equatorial Atlantic. With these and existing data from the New Jersey Shelf and Maud Rise, Southern Ocean, we quantify the lead-lag relation between PETM warming and the carbon input that caused the carbon isotope excursion (CIE). We show ~2 °C of global warming preceded the CIE by millennia, strongly implicating CO2-driven warming triggered a positive carbon cycle feedback. We further compile new and published barium (Ba) records encompassing continental shelf, slope, and deep ocean settings. Based on this compilation, we calculate that average Ba burial rates approximately tripled during the PETM, which may require an additional source of Ba to the ocean. Although the precipitation pathway is not well constrained, dissolved Ba stored in sulfate-depleted pore waters below methane hydrates could represent an additional source. We speculate the most complete explanation for early warming and rise in Ba supply is that hydrate dissociation acted as a positive feedback and caused the CIE. These results imply hydrates are more temperature sensitive than previously considered, and may warrant reconsideration of the political assignment of 2 °C warming as a safe future scenario.

Matrix metalloproteinase processing of PTHrP yields a selective regulator of osteogenesis, PTHrP1-17.

Parathyroid hormone-related protein (PTHrP) is a critical regulator of bone resorption and augments osteolysis in skeletal malignancies. Here we report that the mature PTHrP1-36 hormone is processed by matrix metalloproteinases to yield a stable product, PTHrP1-17. PTHrP1-17 retains the ability to signal through PTH1R to induce calcium flux and ERK phosphorylation but not cyclic AMP production or CREB phosphorylation. Notably, PTHrP1-17 promotes osteoblast migration and mineralization in vitro, and systemic administration of PTHrP1-17 augments ectopic bone formation in vivo. Further, in contrast to PTHrP1-36, PTHrP1-17 does not affect osteoclast formation/function in vitro or in vivo. Finally, immunoprecipitation-mass spectrometry analyses using PTHrP1-17-specific antibodies establish that PTHrP1-17 is indeed generated by cancer cells. Thus, matrix metalloproteinase-directed processing of PTHrP disables the osteolytic functions of the mature hormone to promote osteogenesis, indicating important roles for this circuit in bone remodelling in normal and disease contexts.

Spatial resolution in digital mammography.

RATIONAL AND OBJECTIVES: Digital acquisition systems currently available limit spatial resolution in digital mammography to roughly 0.1 mm/pixel. The objective of this study is to determine if high-quality mammography is possible at this resolution. METHODS: The influence of spatial resolution on diagnostic quality was investigated by comparing observer performance on film to that on digitized film. A 0.1-mm sampling distance was used for digitization. Detection of mammographic details was studied by measuring threshold contrast as a function of detail size for small circular objects in the range of 0.12 to 2.5 mm. Characterization of microcalcifications was investigated in a receiver operating characteristic (ROC) study, in which 10 radiologists read 72 mammographic details with microcalcifications, both digitally and on film. RESULTS: Digitization improved the detectability of the larger, low contrast objects, whereas for small objects the detectability did not change. The authors found that even under the most optimal circumstances, isolated spherical calcifications with diameters smaller than 0.13 mm are not detectable with film-screen mammography, despite its resolution limit of 15 line patterns per mm (lp/mm). The ability to characterize microcalcification clusters did not change significantly with digitization. However, the results suggest that differentiation of benign from malignant cases decreases slightly, and that characterization of different types of malignancies somewhat improves by digitization. Mean differences between the two modalities were considerably smaller than the interobserver variability. CONCLUSION: A relatively low spatial resolution of 0.1 mm/pixel does not prohibit high-quality diagnostic performance in digital mammography.

Endogenous Aeromonas hydrophila endophthalmitis.

Aeromonas hydrophila as the etiologic agent of endophthalmitis is rare, having only been reported in association with a perforating injury of the eye. We describe a case of isolated spontaneous, endogenous endophthalmitis due to this agent, with no apparent source.

Endotoxemia after major vascular operations.

PURPOSE: Endotoxemia has been associated with syndromes such as adult respiratory distress syndrome and multiple organ failure. Translocation of endotoxins from the gut has been demonstrated to occur experimentally in animals after splanchnic ischemia. METHODS: We investigated endotoxemia in 11 patients with hemorrhagic shock caused by a ruptured abdominal aortic aneurysm and in five patients after elective abdominal aortic aneurysm repair. Endotoxin was measured quantitatively with a limulus assay with a detection limit of 12.5 pg/ml. RESULTS: In 7 of the 11 patients admitted to the hospital with an acute condition endotoxin was present on admission (range 15 to 25 pg/ml), even before resuscitation and operation were started. In patients treated electively endotoxin was noticed after cross-clamping of the aorta in four of five patients (mean +/- SEM: 18.9 +/- 4.6 pg/ml). After reperfusion endotoxemia increased and was present in all patients (22.8 +/- 2.8 pg/ml). All five patients treated electively had an uneventful recovery without specific organ failures or infectious complications. CONCLUSIONS: It is concluded that systemic endotoxemia as monitored by the limulus assay is a common finding in patients after major vascular operation. Hemorrhagic shock resulting in splanchnic ischemia may lead to endotoxemia. Ischemia and especially reperfusion after aortic cross-clamping also result in endotoxin translocation. However, the low concentrations of systemic circulating endotoxin found were not related to subsequent adverse effects of either the patients treated for acute conditions or in the electively treated patients.

Soluble interleukin 6 receptor in biological fluids from human origin.

OBJECTIVE: measurement of baseline soluble interleukin 6 receptor (sIL-6R) and interleukin 6 (IL-6) levels in biological fluids in non-pathological conditions. SUBJECTS AND MATERIALS: Blood and urine were obtained from healthy volunteers. Cerebrospinal fluid (CSF) and synovial fluid (SF) were obtained from patients during spinal puncture and athroscopy, respectively. Only CSF and SF of patients with proven non-pathological conditions were used in this study. Both sIL-6R and IL-6 were measured using ELISAs. It was shown that neither did sIL-6R interfere with the IL-6 ELISA nor did IL-6 interfere in the sIL-6R ELISA. Moreover, addition of recombinant sIL-6R to the IL-6 bio-assay (B9) did not influence IL-6 recovery. RESULTS: using our sIL-6R ELISA we found baseline levels for sIL-6R in serum of 76.6 +/- 19.3 ng/ml in serum and 3.7 +/- 1.3 ng/ml in urine. In non-pathological conditions sIL-6R concentrations in CSF are 1.6 +/- 0.4 ng/ml, and in SF 11.6 +/- 3.3 ng/ml, while IL-6 concentrations are below detectable ranges in these fluids. CONCLUSIONS: sIL-6R levels are detectable in serum, urine, CSF and SF during non-pathological conditions. sIL-6R levels in serum outrange levels in CSF, urine and SF and large interindividual differences in baseline concentrations for sIL-6R exist.

Differential induction of pro- and anti-inflammatory cytokines in whole blood by bacteria: effects of antibiotic treatment.

The in vitro production of interleukin-1beta (IL-1beta), IL-6, and the IL-1 receptor antagonist (IL-1ra) in whole blood upon stimulation with different bacterial strains was measured to study the possible relationship between disease severity and the cytokine-inducing capacities of these strains. Escherichia coli, Neisseria meningitidis, Neisseria gonorrhoeae, Bacteroides fragilis, Capnocytophaga canimorsus, Staphylococcus aureus, Enterococcus faecalis, Streptococcus pneumoniae, and Streptococcus pyogenes induced the cytokines IL-1beta, IL-6, and IL-1ra. Gram-negative bacteria induced significantly higher levels of proinflammatory cytokine production than gram-positive bacteria. These differences were less pronounced for the anti-inflammatory cytokine IL-1ra. In addition, blood was stimulated with E. coli killed by different antibiotics to study the effect of the antibiotics on the cytokine-inducing capacity of the bacterial culture. E. coli treated with cefuroxime and gentamicin induced higher levels of IL-1beta and IL-6 production but levels of IL-1ra production similar to that of heat-killed E. coli. In contrast, ciprofloxacin- and imipenem-cilastatin-mediated killing showed a decreased or similar level of induction of cytokine production as compared to that by heat-killed E. coli; polymyxin B decreased the level of production of the cytokines.

Interleukin-6 and its soluble receptor during acute meningococcal infections: effect of plasma or whole blood exchange.

OBJECTIVES: To determine the pattern of the soluble interleukin (IL)-6 receptor during acute meningococcal infections and recovery phase, and to measure the effect of plasma or whole blood exchange on the plasma concentrations of these mediators. DESIGN: Prospective, descriptive patient study. SETTING: University hospital intensive care unit. PATIENTS: Patients with bacteriologically proven meningococcal infections were entered in the study. Three group were formed: a) patients with meningitis without shock (group A); b) patients with meningitis and shock (group B); and c) patients with shock only (group C). INTERVENTIONS: Part (n = 9) of the patients with shock underwent plasma or whole blood exchange. MEASUREMENTS AND MAIN RESULTS: Serum concentrations of interleukin-6 and soluble IL-6 receptors were determined sequentially during the acute and recovery phases. Peak concentrations of IL-6 were highest in group C, followed by group B and group A. Soluble IL-6 receptor concentrations showed an opposite pattern and were all below normal. Soluble IL-6 receptor concentrations were negatively correlated with the IL-6 concentrations. During recovery, IL-6 rapidly decreased and soluble IL-6 receptors increased to supranormal concentrations, after which concentrations returned to normal. Plasma or whole blood exchange did not significantly influence IL-6 concentrations but did increase the soluble IL-6 receptor concentration directly after an exchange session followed by a rapid decrease. CONCLUSIONS: Soluble IL-6 receptor concentrations are low in acute meningococcal infections. Plasma or whole blood exchange temporarily increases these concentrations. It needs to be determined whether the effect of this therapy is beneficial to the patient.

Circulating interleukin-6 receptor in patients with sepsis syndrome.

Concentrations of interleukin (IL)-6, soluble IL-6 receptor (sIL-6R), and soluble tumor necrosis factor receptor (sTNFR) p55 and p75 were measured in 25 patients with sepsis syndrome. Sequential blood samples were drawn from patients during a 7-h period. IL-6 concentrations were 34-763,000 pg/mL; they were higher in nonsurvivors than survivors, but the difference was not statistically significant. In septic patients, the median sIL-6R concentration was significantly lower than in 19 healthy volunteers (43 vs. 80 ng/mL). sIL-6R concentrations in survivors were not significantly different than those in nonsurvivors. There was a negative correlation between IL-6 and sIL-6R in septic patients (r = -.72). In patients with moderately impaired renal function, sIL-6R levels were not affected, but the concentrations of sTNFRs were significantly higher.

Circulating concentrations of soluble interleukin 6 receptors gp80 and gp130 in chronic renal failure and effects of renal replacement therapy.

BACKGROUND: Circulating receptors modulate the biological effects of cytokines. Renal insufficiency is known to influence the concentrations of the soluble tumor necrosis factor (TNF) receptors p55 and p75. No data are available on the concentrations of the circulating interleukin 6 (IL-6) receptors gp80 and gp130 during chronic renal insufficiency. METHODS: We compared the serum concentrations of the IL-6 receptors gp80 and gp130 to those of the TNF receptors p55 and p75 in end-stage chronic renal failure, continuous ambulatory peritoneal dialysis, and hemodialysis (HD). RESULTS: In healthy controls the concentrations of gp80, gp130, p55, and p75 in serum were 82.1 +/- 24.3, 87.9 +/- 20.2, 1.1 +/- 0.2, and 1.7 +/- 0.3 ng/ml, respectively. These concentrations were increased to, respectively, 112.2 +/- 18.0, 186.0 +/- 37.7, 10.5 +/- 4.3, and 15.0 +/- 7.5 ng/ml in chronic renal failure, to 138.8 +/- 18.0, 181. 3 +/- 46.1, 25.5 +/- 5.2, and 19.1 +/- 3.4 ng/ml in continuous ambulatory peritoneal dialysis, and to 107.9 +/- 29.4, 146.6 +/- 30. 5, 22.9 +/- 6.3, and 16.8 +/- 6.0 ng/ ml in HD (before dialysis session). The concentrations after HD were higher for p75 only. CONCLUSIONS: The data show that the concentrations of the IL-6 receptors (gp80 and gp130) are elevated in chronic renal insufficiency. The increase is relatively low as compared with the elevation of the TNF receptors in this situation. HD does not result in a consistent change in serum concentrations of the various receptors.

Plasma patterns of tumor necrosis factor-alpha (TNF) and TNF soluble receptors during acute meningococcal infections and the effect of plasma exchange.

In 39 patients with acute meningococcal infections, the plasma concentrations of tumor necrosis factor-alpha (TNF) and its soluble receptors (sRs) TNFsR-p55 and TNFsR-p75 were measured from admission till recovery. At admission, patients with shock had significantly higher TNF, TNFsR-p55, and TNFsR-p75 values than patients without shock. In addition, during the first 24 hours, patients with shock had higher TNFsR-p75 to TNFsR-p55 ratios, indicating that in shock the increase of TNFsR-p75 exceeds that of TNFsR-p55. TNF measured more than 12 hours after admission failed to differentiate between shock and nonshock because TNF concentrations normalized within 12-24 hours. However, because concentrations of TNFsRs remained elevated for 5-6 days, at that time plasma TNFsRs still differentiated between shock and nonshock. Plasma exchange or whole blood exchange (PEBE), performed in 20 patients with shock, accelerated the decrease of plasma TNFsRs. However, because of a rebound after each PEBE session, the overall half-lives of both TNFsRs were not affected by PEBE.