Endogenous interleukin-10 regulates hemodynamic parameters, leukocyte-endothelial cell interactions, and microvascular permeability during endotoxemia

The objective of this study was to determine whether endogenous IL-10 is capable of regulating hemodynamic parameters, leukocyte recruitment, and microvascular permeability in response to endotoxin. Intravital microscopy was used to examine hemodynamic parameters, leukocyte rolling and adhesion, and microvascular permeability in cremasteric postcapillary venules in wild-type mice and in IL-10-deficient (IL-10(-/-)) mice exposed to lipopolysaccharide (LPS). Doses of LPS (3 or 30 microg/kg, IV), which did not reduce blood pressure and minimally altered microvascular hemodynamic factors in wild-type mice, caused significant reductions in these parameters in IL-10(-/-) mice, demonstrating at least a 10-fold increased sensitivity in IL-10(-/-) mice to LPS-induced hemodynamic alterations. Furthermore, in response to LPS (30 microg/kg, IV), leukocyte rolling, adhesion, and fluorescein isothiocyanate-albumin extravasation were increased in the IL-10(-/-) mice. Antibody blockade experiments showed that in both types of mice, leukocyte rolling was mediated by E-selectin and P-selectin. Leukocyte accumulation into other tissues, such as lung, also was enhanced greatly in IL-10(-/-) mice. This was specific to endotoxin, because acute chemotactic stimuli including N-formyl-methionyl-leucyl-phenylalanine elicited similar responses in IL-10(-/-) and wild-type mice. These results suggest that endogenous IL-10 may be a homeostatic regulator of hemodynamic parameters, leukocyte-endothelial cell interactions, and microvascular dysfunction in response to endotoxin and provide potential mechanisms to explain the protective effect of IL-10 against LPS-induced mortality.     

Multinuclear magnetic resonance characterization of paramagnetic contrast agents. The manifold effects of concentration and counterions

RATIONALE AND OBJECTIVES: Proper fitting of the nuclear magnetic resonance dispersion (NMRD) profiles to the numerous factors governing nuclear relaxation in paramagnetic systems requires knowledge of some parameters usually obtained by other techniques. The rotational correlation time (tau R) for example can be measured by carbon-13, hydrogen-2, or oxygen-17 NMR. Discrepancies between values reported in the literature might be attributed to the different concentration ranges used so far in these modalities. In the present work focussing on commercial nonspecific contrast agents, the influence of the solution composition (type and concentration of the complexes and of the counterions) has been examined with regard to the water proton relaxation enhancement and molecular dynamics. METHODS: The proton relaxation rate enhancement of Magnevist, Dotarem, Omniscan, and ProHance was measured in aqueous solution up to a concentration of 0.5 M. In the same concentration window, the rotational correlation times were obtained from the study of deuterium relaxation rates of the diamagnetic deuterated analogs (lanthanum complexes) of the gadolinium chelates. RESULTS: Above 50 mM, the relaxation rate enhancement versus concentrations strongly deviates from linearity. Magnevist, a clinical formulation containing two meglumine counterions per molecule of paramagnetic complex, exhibits the largest concentration effect. A slowing down of the molecular dynamics accounts for this behavior as confirmed by the analysis of the rotational correlation times obtained by deuterium relaxometry. At low concentrations (< or = 50 mM), tau R values obtained by proton NMRD analysis and by deuterium relaxation are in very good agreement. CONCLUSIONS: This study shows that NMR analyses of small molecular weight complexes should be carried out on solutions containing no more than 50 mM to avoid the biaising effects of concentration. On the other hand, the benefitting relaxivity enhancement induced by highly concentrated solutions has to be taken into account in the context of bolus injection or vesicular entrapment.     

Phospholipase A2: its role in ADP- and thrombin-induced platelet activation mechanisms

ADP and thrombin are two of the most important agonists of platelet aggregation--a cellular response that is critical for maintaining normal hemostasis. However, aberrant platelet aggregation induced by these agonists plays a central role in the pathogenesis of cardiovascular and cerebrovascular diseases. Agonist-induced primary or secondary activation of phospholipases leads to generation of the second messengers that participate in biochemical reactions essential to a number of platelet responses elicited by ADP and thrombin. Phospholipase A2 (PLA2) has been linked to cardiovascular diseases. However, the mechanism(s) of activation of PLA2 in platelets stimulated by ADP and thrombin has remained less well defined and much less appreciated. The purpose of this review is to examine and compare the molecular mechanisms of activation of PLA2 in platelets stimulated by ADP and thrombin.     

Time utilization of a population of general surgeons in a prepaid group practice

Seven general surgeons in a prepaid group practice previously shown to have a mean operative work load of 9.2 hernia equivalents (HE) per week were found to have a standardized mean daytime working week of 56.2 hours, exclusive of evening activities of which 50.7 hours were devoted to professional activities. The surgeons also devoted a mean of 6.7 evening hours per week to professional activities for a mean net professional week of 57.4 hours. Comparisons with a population of previously studied community surgeons revealed that the prepaid group surgeons were able to produce a surgical output more than double that of the community surgeons while devoting only one and a half as much time to professional activities. Economies in the utilization of surgical manpower in the prepaid group appear to stem from: 1) restriction of practice setting to a single geographic location, 2) restriction of patients to surgical patients, 3) reduced surgeon waiting time in the office, and 4) the utilization of paraprofessional personnel for selected operative assisting. These economies were achieved while the prepaid group surgeons were observed to average more time per patient visit both on rounds and in the office than the community surgeons.     

Estimation of maprotiline in serum by gas-chromatography, with use of a nitrogen-specific detector

We describe a gas-chromatographic procedure for estimating therapeutic concentrations of maprotiline, a new tetracyclic antidepressant, in serum by use of a nitrogen-specific detector. Desmethyldoxepin, a secondary amine similar in structure to maprotiline, is added as a mass internal standard to the specimen before extraction, to obviate the need for accurate measurements of volumes during extraction and analysis. Both maprotiline and the internal standard are converted to acetyl derivatives, to avoid the adsorption of secondary amines on the column. A highly selective liquid phase is used, which allows a very good separation of desmethyldoxepin, maprotiline, desmethylmaprotiline, and the interferences from serum and reagents.     

Functional evaluation of normal and pathologic knees during gait

The functional performance of the knee joints of 29 normal volunteers, 65 patients with degenerative joint disease and 30 patients with rheumatoid arthritis was studied according to clinical (historical, physical and roentgenographic) and biomechanical gait parameters. Temporal and distance gait factors (velocity, cadence and stride length) were significantly reduced in patients with diseased knees. Sagittal plane knee motion was markedly reduced, as was stance phase flexion, indicating poor tolerance of loading the flexed knee in the patient groups. There was no correlation between passive motion of the diseased knee and the amount of motion used during gait. Patients with rheumatoid arthritis generally showed more compromise of knee joint function than did patients with degenerative joint disease. Statistically, significant correlations between various clinical and biomechanical gait parameters suggest that the techniques used are an objective measurement of knee joint function and may be employed as a means of evaluating various treatment modalities for the diseased knee.     

Automated determination of protein-nitrogen in cereals and grains

This paper presents the design, performance, and operational characteristics of a new direct reading instrument for determining nitrogen in cereal and grain. Precision, accuracy, range, speed, ease of operation, sensitivity, sample size, and flexibility of the instrument are presented. Results on various cereals and grains are presented and compared with those obtained by the Kjeldahl technique. The apparatus is the result of research for a rapid method for determining nitrogen in organic material. The instrument uses a combination of a unique high temperature sample oxidation, a sampling valve for separating combustion products, and thermal conductivity detection for the liberated nitrogen in a helium carrier gas.