IL-4 and IL-13 downregulate rolling adhesion of leukocytes to IL-1 or TNF-alpha-activated endothelial cells by limiting the interval of E-selectin expression.

Leukocyte extravasation is governed by the endothelium, expressing a defined pattern of adhesion molecules in response to inflammatory stimuli. Among them, E-selectin, which is expressed in response to interleukin 1 (IL-1) or tumour necrosis factor alpha (TNF-alpha), provides rolling adhesion of the circulating leukocytes, a transient and reversible interaction that initiates leukocyte extravasation. In our experiments, E-selectin expression culminated after 4 to 6 h and declined thereafter. After 24 h a considerable amount of E-selectin was presented, reflecting its continuous expression in different inflammatory skin disorders. After preincubation of the endothelial cells with TNF-alpha together with IL-4 or IL-13, E-selectin mRNA transcription and protein expression were markedly reduced at 8 h and almost abolished at 20 h. In contrast, early E-selectin expression between 2 to 6 h was not significantly impaired. In a rotating adherence assay that mimics physiological shear forces in circulation, preincubation of the endothelial cells with TNF-alpha for 4 and 20 h induced similar adherence of neutrophils, which was largely E-selectin dependent. According to the modified expression kinetics of E-selectin in the presence of IL-4 of IL-13 rolling adhesion was unimpaired at 4 h but significantly diminished after 20 h of preincubation. Similar results were obtained with clones of the cutaneous T cell lymphoma cell line HUT78 highly expressing the E-selectin ligand cutaneous lymphocyte-associated Ag. Together, these data suggest that IL-4 and IL-13 control the rolling adhesion by limiting the period of the induced E-selectin expression and may thereby confine the acute phase of leukocyte emigration.

Tumor necrosis factor alpha enhances the expression of the interleukin (IL)-4 receptor alpha-chain on endothelial cells increasing IL-4 or IL-13-induced Stat6 activation.

Functional receptors for interleukin (IL)-4 and IL-13 on endothelial cells consist of the 130-kDa IL-4 receptor alpha-chain (IL-4Ralpha) and a 65-75-kDa IL-13 binding subunit that are expressed in a ratio of about 1:3, respectively. The restricted number of IL-4Ralpha limits subunit heterodimerization and in turn receptor-mediated signaling. We report here, the effects of tumor necrosis factor alpha (TNF-alpha) on the expression of the receptor subunits for IL-4 and IL-13. By flow cytofluorometry and receptor-binding analysis of iodinated IL-4 and IL-13, stimulation with TNF-alpha-induced a 2-3-fold increase of the IL-4Ralpha expression. The up-regulation was also confirmed at the transcriptional level by reverse transcription-polymerase chain reaction. Radioligand cross-linking experiments revealed no change in the subunit composition of the TNF-alpha-induced receptor complex. Nevertheless, TNF-alpha stimulation led to increased activation of the IL-4-specific signal transducers and activators of transcription protein (Stat6) by IL-4 and IL-13. Thus, TNF-alpha corrects the subunit imbalance of the endothelial IL-4.IL-13 receptor complex thereby increasing receptor heterodimerization and in turn the signaling capability by IL-4 and IL-13.

Interleukin-4 (IL-4) and IL-13 bind to a shared heterodimeric complex on endothelial cells mediating vascular cell adhesion molecule-1 induction in the absence of the common gamma chain.

Interleukin-4 (IL-4) and IL-13 exert similar, nonadditive effects on endothelial cells, inducing vascular cell adhesion molecule-1 (VCAM-1) expression and subsequent transmigration of eosinophils. The receptor for IL-4 and IL-13 was described as a shared heteromultimeric complex in which the common gamma-chain (gamma c) subunit was essential for activity. Endothelial cell bound both cytokines with high affinity; by flow cytofluorometry and reverse transcription-polymerase chain reaction (RT-PCR), they expressed IL-4 receptor alpha (IL-4R alpha) but did not express the gamma c of the IL-2R. Radioligand cross-linking experiments followed by immunoprecipitation with the monoclonal antibody (MoAb) S697 to the IL-4R alpha showed IL-4-specific binding at 130 kD, the IL-4R alpha, and to a minor extent to a double band coimmunoprecipitated at 65 to 75 kD. [125 I]IL-13 bound predominantly to the 65- to 75- kD band and with a trace amount of binding at 130 kD. However, no ligand-cross-linked receptor was precipitated by the MoAb S697, indicating a cognate novel IL-13-binding subunit. Excess unlabeled IL-4 completely displaced IL-13 binding. Similarly, nonsignaling IL-4 (Y124D)-mutant abolished IL-4- and IL-13-mediated signal transduction. Unlabeled IL-13 competed successfully for IL-4 binding at 65 to 75 kD but was unable to completely displace Il-4 from its binding to the IL-4R alpha. The MoAb TUGh4, specific for the gamma c, failed to precipitate ligand-cross-linked IL-4R and IL-13R. Therefore, the subunit structure of the functional receptors for IL-4 and IL-13 on human endothelial cells does not use or require the common gamma c of the IL-2R.

Neutrophil activation in response to immune complex-bearing endothelial cells depends on the functional cooperation of Fc gamma RII (CD32) and Fc gamma RIII (CD16).

Leukoclastic vasculitis is thought to be initiated by deposition of immune complexes (ICs) in the vascular wall. To study the neutrophil response in a related in vitro model, we primed human umbilical vein endothelial cell (HUVEC) monolayers with antibodies against human fibronectin. The resulting respiratory burst to the immobilized ICs depended on the antibody concentration used to prime the monolayers and included a marked release of primary and secondary granule constituents. On IC-bearing HUVEC monolayers, but not on ICs directly bound to tissue culture dishes, blocking monoclonal antibodies (mAbs) to crystallizable fragment-gamma receptor II (Fc gamma RII) and Fc gamma RIII markedly inhibited the respiratory burst and the release of elastase. However, on both surfaces the neutrophil response was strongly inhibited by mAbs against CD18. Regardless of whether we used neutrophils from a patient with severe paroxysmal nocturnal hemoglobinuria (PNH) lacking the Fc gamma RIII, or whether the Fc gamma RII-mediated signal transduction was blocked by pertussis toxin, the respiratory burst to the IC-bearing HUVECs was essentially unchanged. With PNH neutrophils, the respiratory burst was predominantly blocked by an anti-Fc gamma RII mAb. In contrast, the response of pertussis toxin treated neutrophils was strongly inhibited by a mAb against Fc gamma RIII. Together these data indicate that the answer of neutrophils to ICs immobilized at the endothelial barrier depends on the cooperative function of both low-affinity Fc gamma Rs.

[Probability of dying in an avalanche]. / Sterbewahrscheinlichkeit in einer Lawine.

Of 1,036 people caught in an avalanche and completely buried the burial time and whether they were recovered dead or alive is recorded. The data are used to calculate the likelihood to die in the avalanche as a function of the burial time, using Turnbull's non-parametric method. The result is compared with Brugger's et al for 332 cases. Furthermore the influence on the likelihood of mortality is investigated using further indications to reduce the time interval during which the victim has died.

Rotation and interaction with epoxide hydrase of cytochrome P-450 in proteoliposomes.

Purified rat liver cytochrome P-450MC or P-450PB was co-reconstituted with epoxide hydrase in liposomal vesicles made of phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine at a lipid to protein weight ratio of 5 by the cholate dialysis procedure. Rotational diffusion of the cytochromes was measured by observing the decay of absorption anisotropy, r(t), after photolysis of the heme.CO complex by a vertically polarized laser flash. Analysis of r(t) was based on a "rotation-about-membrane-normal" model. The measurements were used to investigate interactions of cytochrome P-450MC or P-450PB with epoxide hydrase. Different rotational mobilities of the two cytochromes were observed. The amount of mobile molecules was 78% for cytochrome P-450MC and 91% for P-450PB, and the rest was immobile within the experimental time range of 1 ms. In the presence of epoxide hydrase 85% of cytochrome P-450MC and 96% of P-450PB were mobile. Cross-linking of epoxide hydrase by anti-epoxide hydrase antibodies resulted in a drastic immobilization of the cytochromes, reducing the mobile population to 49% for P-450MC and to 60% for P-450PB. The rotational relaxation times phi of the mobile populations ranged from 210 to 283 microseconds. These results imply that both cytochromes P-450MC and P-450PB transiently associate with epoxide hydrase in liposomal membranes. Further analysis of the data showed that the angle between the heme plane of P-450MC and the membrane is 48 degrees or 62 degrees, different from the value of 55 degrees reported previously for P-450PB (Gut, J., Richter, C., Cherry, R. J., Winterhalter, K. H., and Kawato, S. (1983) J. Biol. Chem. 258, 8588-8594).

[Malaria study]. / Malariastudie.

Compliance with malaria prophylaxis or reserve drugs was investigated in 477 individuals travelling to regions with endemic malaria. Correct intake of prophylactic medication was confirmed in 225 out of 285 (= 78%). Compliance was independent of type of drug (Mefloquine, Sulfadoxine-Pyrimethamine, Chloroquine). Two tourists missed to start prophylaxis one week before the onset of their travel. 14 travellers stopped prophylactic medication too early after their return, 31 tourists took too high doses of mefloquine. None of the tourists travelling to countries with a therapeutic reserve only became sick, whereas two travelling to Africa contracted malaria.

Legionnaires' disease with rhabdomyolysis and acute reversible myoglobinuric renal failure.

We have described a patient with rhabdomyolysis, myoglobinuria, and acute reversible renal failure. Serologic studies were diagnostic for legionnaires' disease and were negative for other viruses associated with rhabdomyolysis. Bacteriologic cultures were also negative, and other nontraumatic causes of rhabdomyolysis were ruled out. No other causes of acute reversible renal failure were found. With a clinical picture of pneumonia, rhabdomyolysis, myoglobinuria, and acute renal failure, legionnaires' disease should be considered in the differential diagnosis and appropriate antibiotic therapy instituted.

[Evolutionary significance of reciprocal biological effects of form and function using the example of the scapula in higher primates. 1]. / Zur entwicklungsgeschichtlichen Bedeutung von biologischen Form-Funktionsbeziehungen am Beispiel des Schulterblattes bei höheren Primaten. Teil I.

The shoulder-blades of 99 catarrhine primates were investigated metrically and morphologically. In order to obtain comparable data, each analysed shoulder-blade was orientated in the same way in a 3-dimensional coordinate system. With the help of a diopthograph, the 3 planes were drawn without distorsion. On these planes the dimensions and angles were measured. These method produced the advantages of taking homologues data as well as of being able to compare the morphological data and its variability. Within the catarrhine primates, the area of the scapula (Fossa infra- and supraspinata) correlates highly significant with the body weight. Regarding the proportions and dimensions of the area of the scapula, there is no difference between the gibbons and the monkeys, regarding the dimensions, proportions and angles of the processes (acromion and coracoid) as well as the vertebral border of the scapula, the gibbons are close to the great apes. The areas of the shoulder-blades of the monkeys, where the shoulder stabilizing muscles originates, are fundamentally equal to each other. Whether body weight nor locomotion have an essential influence on its shape and structure (excl. Mandrillus). On the other hand, the variability of the joint area is considered and the processes are small. The gibbons, the great apes, and men are highly variable regarding the dimensions and the proportions of the area of the shoulder-blades. Regarding the dimensions, proportions, and angles of the acromion and the coracoid, where the shoulder joint stabilizing muscles originate, as well as the vertebral border, there are no fundamental differences between them and the processes are large and robuste.

[Evolutionistic significance of biological form-function relationship based on the example of the shoulder-blade in higher primates. II. Form and function, goal and random factor: literature]. / Zur entwicklungsgeschichtlichen Bedeutung von biologischen Form-Funktionsbeziehungen am Beispiel des Schulterblattes bei höheren Primaten. II. Form und Funktion, Zweck und Zufall; Literatur.

The shoulder-blades of the monkeys are mainly constructed as a shock-absorbing platform, supporting the weight of the torso, which is hung up between the 2 forelegs in a muscle sling, composed by the M. serratus ventralis. The mobility of the arms are of less importance, although this mobility is more developed in monkeys than in other quadrupedal mammals. The shoulder-blades of the hominoids are freed from the supporting function and are mainly constructed for the mobility of the arms. Therefore all the areas are well developed, where the important arm-moving muscles originate. The constructions of the catarrhine shoulder-blades are in a very close accordance with the function. Under the modern viewpoint of scientific evolutionary theory the relation between form and function is causal and is developing in the time-space continuum. It can be shown that the thinking in categories of time, space and causality is inadequate for the understanding of the evolutionary process. The hazardness which plays an important role in the neo-darwinistic modell, where mutations occur, has to bee replaced by synchronistic phenomena. Therefore the facts of live refer empirically to the existence of the "One-beeing". According to this, evolution occurs as a psycho-physical process, which is experiencable by synchronistic phenomena in archetypical moments as a reference to a reality, which is feeling its way in a finalistic manner.

[Proceedings: 70 mm photofluorography: a valuable aid in coronary angiographic studies]. / 70-mm-Photofluorographie: eine wertvolle Hilfe bei koronarangiographischen Untersuchungen

With the development of new intensifiers using cesium iodide as the input phosphor and having a spatial frequency of up to 4 lines/mm, it has become possible to obtain high contrast serial photographs using a 70 mm camera. In 48 patients undergoing coronary arteriography, 35 mm cine and 70 mm spotfilms were obtained at exposures as follows: 3 msec, 75-95 kV at 200 mA for the 35 mm cine (50 frames/sec) and 6-10 msec, 75-95 kV at 300 mA (4 FRAMES/SEc) for the 70 mm images. Image quality and diagnostic information of the two media were compared. 70 mm films were of excellent quality. The vessel edges showed up sharp, the pictures were high in contrast, and small arteries in particular could be well defined. 70 mm photofluorography offers many advantages which are discussed.