Characterization of annexin A1 glycan binding reveals binding to highly sulfated glycans with preference for highly sulfated heparan sulfate and heparin.

Annexin A1 is a multifunctional, calcium-dependent phospholipid binding protein involved in a host of processes including inflammation, regulation of neuroendocrine signaling, apoptosis, and membrane trafficking. Binding of annexin A1 to glycans has been implicated in cell attachment and modulation of annexin A1 function. A detailed characterization of the glycan binding preferences of annexin A1 using carbohydrate microarrays and surface plasmon resonance served as a starting point to understand the role of glycan binding in annexin A1 function. Glycan array analysis identified annexin A1 binding to a series of sulfated oligosaccharides and revealed for the first time that annexin A1 binds to sulfated non-glycosaminoglycan carbohydrates. Using heparin/heparan sulfate microarrays, highly sulfated heparan sulfate/heparin were identified as preferred ligands of annexin A1. Binding of annexin A1 to heparin/heparan sulfate is calcium- but not magnesium-dependent. An in-depth structure-activity relationship of annexin A1-heparan sulfate interactions was established using chemically defined sugars. For the first time, a calcium-dependent heparin binding protein was characterized with such an approach. N-Sulfation and 2-O-sulfation were identified as particularly important for binding.

[Endocarditis or bacteremia caused by Streptococcus bovis and colorectal neoplasms]. / Endokarditis oder Bakteriämie durch Streptococcus bovis und kolorektale Neoplasien.

Streptococcus bovis is a relatively frequent causative agent of endocarditis or bacteriaemia, particularly in the elderly. In the past S. bovis has often been incompletely or even falsely classified. For therapeutic and prognostic reasons it is important to classify this agent exactly with biochemical methods even in the routine laboratory. Endocarditis or bacteriaemia due to S. bovis are often seen in conjunction with malignant, potentially malignant or benign colorectal neoplasias. After endocarditis or bacteriaemia due to S. bovis thorough investigation of colon and rectum is indicated. On the other hand, in presence of fever in patients with colorectal tumors, S. bovis bacteriaemia or endocarditis must be considered. The available literature is inconclusive on the question whether, after S. bovis endocarditis or bacteriaemia with initially normal colorectal findings, examination of the upper gastrointestinal tract and periodic inspection of the colon is needed. Up to now there has been no satisfactory explanation for the concomitant occurrence of endocarditis or bacteriaemia due to S. bovis and colorectal neoplasia.

Prevention of high-altitude pulmonary edema by nifedipine.

BACKGROUND: Exaggerated pulmonary-artery pressure due to hypoxic vasoconstriction is considered an important pathogenetic factor in high-altitude pulmonary edema. We previously found that nifedipine lowered pulmonary-artery pressure and improved exercise performance, gas exchange, and the radiographic manifestations of disease in patients with high-altitude pulmonary edema. We therefore hypothesized that the prophylactic administration of nifedipine would prevent its recurrence. METHODS: Twenty-one mountaineers (1 woman and 20 men) with a history of radiographically documented high-altitude pulmonary edema were randomly assigned to receive either 20 mg of a slow-release preparation of nifedipine (n = 10) or placebo (n = 11) every 8 hours while ascending rapidly (within 22 hours) from a low altitude to 4559 m and during the following three days at this altitude. Both the subjects and the investigators were blinded to the assigned treatment. The diagnosis of pulmonary edema was based on chest radiography. Pulmonary-artery pressure was measured by Doppler echocardiography and the difference between alveolar and arterial oxygen pressure was measured in simultaneously sampled arterial blood and end-expiratory air. RESULTS: Seven of the 11 subjects who received placebo but only 1 of the 10 subjects who received nifedipine had pulmonary edema at 4559 m (P = 0.01). As compared with the subjects who received placebo, those who received nifedipine had a significantly lower mean (+/- SD) systolic pulmonary-artery pressure (41 +/- 8 vs. 53 +/- 16 mm Hg, P = 0.01), alveolar-arterial pressure gradient (6.6 +/- 3.8 vs. 11.8 +/- 4.4 mm Hg, P less than 0.001), and symptom score of acute mountain sickness (2.0 +/- 0.7 vs. 3.9 +/- 1.9, P less than 0.01) at 4559 m. CONCLUSIONS: The prophylactic administration of nifedipine is effective in lowering pulmonary-artery pressure and preventing high-altitude pulmonary edema in susceptible subjects. These findings support the concept that high pulmonary-artery pressure has an important role in the development of high-altitude pulmonary edema.

Prevention and treatment of high altitude pulmonary edema by a calcium channel blocker.

High altitude pulmonary edema (HAPE) is characterized by marked pulmonary hypertension. Treatment of 6 subjects suffering from radiographically documented HAPE with the calcium channel blocker nifedipine, lowered pulmonary artery pressure and resulted in clinical improvement, better oxygenation, reduction of alveolar-arterial oxygen gradient and a progressive clearing of alveolar edema on chest x-ray. This amelioration occurred despite continued exercise at an altitude above 4000 m and without supplementary oxygen. Prophylactic application of nifedipine slow release preparation, 20 mg every 8 hours, prevented HAPE in 9 out of 10 subjects with a history of radiographically documented HAPE upon rapid ascent and subsequent stay to an altitude of 4559 m. Seven of 11 comparable subjects who received placebo developed pulmonary edema at 4559 m. As compared with the subjects who received placebo, those who received nifedipine had a significantly lower mean systolic pulmonary artery pressure, alveolar-arterial pressure gradient of oxygen and symptom score of acute mountain sickness at 4559 m. Thus nifedipine offers a potential emergency treatment of HAPE when descent or evacuation is impossible and oxygen is not available. Prophylactic administration of nifedipine prevents HAPE in susceptible subjects. High pulmonary artery pressure has an important role in the pathogenesis of HAPE.

[Pathophysiology, prevention and therapy of altitude pulmonary edema]. / Pathophysiologie, Prophylaxe und Therapie des Höhenlungenödems.

Alveolar hypoxia and resulting tissue hypoxia initiates the pathophysiological sequence of high altitude pulmonary edema (HAPE). Very rapid ascent to high altitude without prior acclimatization results in HAPE, even in subjects with excellent tolerance to high altitude. Upon acute altitude exposure, HAPE-susceptible individuals react with increased secretion of norepinephrine, epinephrine, renin, angiotensin, aldosterone and atrial natriuretic peptide. In response to exercise at high altitude, subjects developing acute mountain sickness and HAPE secrete more aldosterone and antidiuretic hormone than subjects who remain well. This results in sodium and water retention, reduction of urine output, increase in body weight and development of peripheral edemas. The hypoxic pulmonary vascular response is enhanced in HAPE-susceptible subjects, thus favouring the development of severe pulmonary hypertension on exposure to high altitude. It has been postulated that uneven pulmonary vasoconstriction enhances filtration pressure in non-vasoconstricted lung areas, leading to interstitial and alveolar edema. The high protein content of the edema fluid in HAPE characterizes this edema as a permeability edema. The prophylactic administration of nifedipine prevents the exaggerated pulmonary hypertension of HAPE-susceptible subjects upon rapid ascent to 4559 m and thus prevents HAPE in most cases. This finding illustrates the crucial role of hypoxic pulmonary hypertension in the development of HAPE. The causal treatment of HAPE is descent, evacuation and administration of oxygen. Treatment of HAPE patients with nifedipine results in a reduction of pulmonary artery pressure, clinical improvement, increased oxygenation, decrease of the alveolar arterial oxygen gradient and progressive clearing of pulmonary edema on chest x-ray. Thus nifedipine offers a pharmacological tool for the treatment of HAPE.

Limitations to VO2max in humans after blood retransfusion.

Seven young, healthy male subjects performed maximal exercise on a cycloergometer with central venous and arterial catheters, before and after autologous retransfusion of red blood cells. Maximal oxygen consumption (VO2max), blood gas composition and haemodynamic variables were measured, in order to test the hypothesis of monofactorial vs. polyfactorial VO2max limitation. Autologous blood retransfusion led to significant increases in haemoglobin concentration and consequently arterial oxygen concentration during maximal exercise, while maximal cardiac output, heart rate and stroke volume were not significantly changed. The relationship between maximal oxygen delivery (cardiac output.arterial oxygen concentration; (Q.CaO2)max and maximal oxygen consumption in this study was VO2max (L.min-1) = 0.02 + 0.64.(Q.CaO2)max (L.min-1), the slope being significantly less than unity. These results suggest that (Q.CaO2)max plays but a fractional role in limiting VO2max, in agreement with recent models concerning the resistance to oxygen flow in the respiratory system (di Prampero and Ferretti, Respir. Physiol. 80: 113-128, 1990). The relative increase in VO2max after blood retransfusion matched the relative increase in 'aerobic performance', measured as the maximal power output that could be maintained aerobically for 30 min. Furthermore, the increase in maximal power output (15 +/- 3 watts) could account for almost all of the extra oxygen consumption. This match suggests that there is an inability to fully utilize muscle oxidative capacity in the normocythaemic state.