[Muscle injuries in professional football : Treatment and rehabilitation]. / Muskelverletzungen im Profifußball : Versorgung und Rehabilitation.

BACKGROUND: Muscle injuries are common in professional sports, especially in football. Recent epidemiological studies showed that muscle injuries account for more than 30% of professional football injuries (1.8-2.2/1000 h exposure); however, even though there are significant differences within a European comparison, a single professional football team diagnosed on average 12 muscle injuries per season, corresponding to more than 300 availability days lost. OBJECTIVE: The aim of this work is to present the diagnosis, general treatment and comprehensive management of muscle injuries in professional football. MATERIAL AND METHODS: The present work is based on current scientific findings, experiences of the authors and examples from routine practice in the management of muscle injuries in a professional sports environment. RESULTS AND CONCLUSION: The authors present a model of gradual progression for the treatment of muscular injuries and their rehabilitation. Due to the time-pressured nature of the professional sports environment, often promoted by coaches and media, this model could help lead players to recover as quickly as possible and return to competitive sports without relapse or sequel injury. This model integrates the player into the treatment plan. The progression sequences in the rehabilitation should be made clear to players and other parties involved, which are crucial for optimal healing. Even if absolute certainty cannot be achieved, i.e. the occurrence of re-injury or secondary injury, this model attempts to minimize the level of risk involved for the returning athlete. Since it is hardly possible to act strictly in line with more conservative guidelines due to the particular circumstances of the professional sport environment, the experiences of the authors are presented in the sense of best practice in order to support future decision-making processes.

Pharmacokinetics and penetration of linezolid into inflamed soft tissue in diabetic foot infections.

OBJECTIVE: Physiological changes and local and systemic inflammation may affect plasma and tissue pharmacokinetics of antimicrobial agents in diabetics. The aim of the study was to investigate the penetration of linezolid into inflamed areas of infected diabetic foot wounds and the pharmacokinetics in the risk population of diabetics. METHODS: Pharmacokinetics and tissue penetration of linezolid into inflamed diabetic foot infection (DFI) tissue were determined at steady state in 15 patients with diabetes type 2 and DFI following administration of multiple oral doses of 600 mg given every 12 h. Second debridement was performed on days 4-6, 3 h after linezolid administration. Linezolid concentrations were determined in perinecrotic wound tissue of inflamed diabetic foot by high-performance liquid chromatography (HPLC). RESULTS: A mean maximum plasma concentration (C(max)) in plasma of 14.3 mg/L was attained at a median of 2.0 h [time to reach C(max) (T(max)) range 0.5-6.0 h). Area under the concentration time curve from zero to 12 h (AUC(0-12 h)) with a mean of 114.1 mgh/L and C(min) of 5.4 mg/L were achieved in patients with diabetes mellitus type 2. Penetration of linezolid into inflamed areas of DFI with tissue/plasma ratios of mean 101.7% [95% confidence interval (CI) 56; 148%] produced a mean concentration of 9.6 microg/g (95% CI 7.4; 11.8 microg/g) greater than those predicted to be effective against methicillin-resistant staphylococci [minimum concentration that inhibits 90% of organisms (MIC(90)) of 4 mg/L]. Tissue/plasma ratios correlated positive with systemic inflammation. CONCLUSION: Plasma pharmacokinetics of linezolid in diabetics and adequate levels in inflamed areas of diabetic foot wound suggest that an oral dose of 600 mg bd of linezolid provides effective concentrations for treating methicillin-resistant Staphylococcus aureus (MRSA) in DFI.

[Perioperative hypothermia. Impact on wound healing]. / Perioperative Hypothermie. Beeinflussung der Wundheilung.

Mild perioperative hypothermia is a common complication of anesthesia and surgery associated with several adverse effects including impaired wound healing and more frequently leads to wound infections. Perioperative hypothermia affects the hemostasis and various immune functions and therefore interferes with the initial phases of the wound healing process. Furthermore, perioperative hypothermia contributes to wound complications by inhibition of deposition of collagen and prolongation of postoperative catabolism. Wound complications prolong hospitalization and substantially increase medical costs. Thus, maintaining normothermia perioperatively is essential to reduce the number of wound complications.

Neuroendocrine and blood pressure responses to rectal distensions in individuals with high and low visceral pain sensitivity.

BACKGROUND: The mechanisms of interindividual variations in visceral pain sensitivity remain poorly understood. We characterized the neuroendocrine responses to rectal distensions in healthy individuals with high vs. low rectal pain sensitivity. METHODS: Rectal sensory and pain thresholds were determined, and a series of random painful distensions was carried out. Eighteen subjects were stratified into groups with a low rectal pain threshold ("High Sensitivity" group) vs. a high rectal pain threshold ("Low Sensitivity" group) by median split, and were compared with regard to adrenocorticotropic hormone (ACTH) and cortisol, cardiovascular, and emotional responses. RESULTS: Distensions led to an anticipatory stress response, reflected by elevated baseline anxiety, and increased baseline ACTH and cortisol in both groups. In response to distensions, the "Low Sensitivity" group showed significantly greater ACTH and cortisol concentrations analysis of variance (ANOVA time x group for ACTH: p<.05; for cortisol: p<.01), and elevated diastolic blood pressures (BP) (ANOVA group: p<.01) when compared to the "High Sensitivity" group. CONCLUSIONS: Painful rectal distensions are associated with a pronounced anticipatory stress response, reflected by elevated anxiety and elevated stress hormones. Individuals with high rectal pain sensitivity differ from those with low pain sensitivity in distension-induced hormonal and blood pressure responses, suggesting that neuroendocrine responses may be relevant to the pathophysiology of visceral hyperalgesia.

Is there a benefit from intensified medical and psychological interventions in patients with functional dyspepsia not responding to conventional therapy?

AIM: In a prospective randomized, controlled trial, to compare the long-term outcome of intensive medical therapy (with or without cognitive-behavioural or muscle relaxation therapy) vs. standard medical therapy in patients with refractory functional dyspepsia (FD), referred to a tertiary referral medical center. METHODS: A total of 100 consecutive FD patients were allocated to a standardized symptom-oriented 4 month therapy (SMT, n = 24), intensive medical therapy (IMT, medical therapy with testing-for and targeting-of abnormalities of motor-and-sensory function, n = 28) or IMT plus psychological interventions (either progressive-muscle relaxation (IMT-MR, n = 20) or cognitive-behavioural therapy (IMT-CBT, n = 28). The symptom intensity (SI) and health-related quality-of-life (HRQoL) after 12 months were prespecified primary outcome parameters. RESULTS: After 12 months, significantly greater improvement of SI occurred in patients with IMT-all (with or without psychological interventions) compared with SMT (P < 0.025 vs. IMT-all). IMT, IMT-MR and IMT-CBT alone also resulted in significantly better improvement of the primary outcome parameters (P all < 0.025 vs. SMT). HRQoL significantly improved in all groups with intensive medical therapy but not standard medical therapy. Differences between intensive medical therapy-all and standard medical therapy were not significant. Concomitant anxiety and depression was improved significantly by IMT-CBT (vs. SMT) but not other treatments. CONCLUSIONS: In FD patients with refractory symptoms, intensified medical management involving function testing and psychological intervention yields superior long-term-outcomes. Additional CBT may be effective for the control of concomitant anxiety and depression.

Visceral pain and public speaking stress: neuroendocrine and immune cell responses in healthy subjects.

Whereas responses to psychological stressors are well-characterized, little is known regarding responses to painful visceral stimuli. We analyzed the emotional, cardiovascular, neuroendocrine, and cellular immune responses to painful rectal stimulation and psychological stress in healthy individuals. Eleven healthy subjects were studied in three conditions on separate days: painful rectal distension, public speaking stress, and rest. Blood was drawn for endocrinological and immunological analyses; heart rate and blood pressure were measured continuously; state anxiety was assessed with a questionnaire (STAI-S). Anxiety scores were highest in the rectal distension condition. This was evident following rectal distension (mean STAI-S scores: 44.2+/-3.5 post-distension vs. 36.6+/-3.8 post-speech, p<.05), but anxiety was also elevated at baseline (41.6+/-3.9 vs. 32+/-3.2 recovery, p<.01). This anticipatory effect was reflected by elevated baseline cortisol (p<.05) and baseline ACTH (p<.01) levels, as well as circulating lymphocytes and lymphocyte subsets, including decreased basal CD3+CD4+ cells (p<.05) and increased CD16+CD56+ cells (p=.06) compared to rest. Both public speech and rectal distension induced cardiovascular activation, but the effect was more pronounced following rectal distension (+63.8+/-9.4 mmHg in response to distension vs. +36.4+/-6.2 mmHg in response to speech for systolic BP, p<.05). Different response patterns were also observed in the distribution of circulating leukocytes and lymphocyte subsets, including CD16+CD56+ cells (p<.05). An acute visceral pain stimulus causes profound emotional, neuroendocrine, and immune cell responses, which are markedly affected by anticipatory anxiety. These findings may have implications for conditions associated with visceral hyperalgesia.

A new modified technique of ureteroureterostomy in rat kidney transplantation.

Different strain combinations of rat are available to study immunological and transplant-related problems in kidney transplant models. Although numerous modifications of surgical techniques for ureteric reconstruction have been evaluated in order to reduce complications and to extend long-term survival, ureteric complications still occur frequently, especially when there is a disproportion in the diameter of donor and host ureters. Instead of using the current nonsplinted ureteroureterostomy, a versatile and rapid technical modification was developed to perform reconstruct the ureters of disproportionate diameter. The overall incidence of ureteric complications was 80% (8/10) using the former method, whereas this rate was significantly reduced to 15% (3/20) using the new method (P < .001). Our modification shows the feasibility of a nonsplinted ureteroureterostomy for the technical, highly demanding rat model of kidney transplantation with an acceptable rate of ureteric complications considering disproportionate differences in diameter between the host and the donor ureter.

Decision making and memory: a critique of Juslin and Olsson's (1997) sampling model of sensory discrimination.

P. Juslin and H. Olsson's (1997) distinction between Thurstonian and Brunswikian uncertainty is examined and their sampling model of sensory discrimination analyzed as a representative of the class of memoryless decision processes. The separate characteristics and combined behavior of 4 main components of the model are explored: (a) the basic decision process, (b) the assumption of deadline responding, (c) the moving window model of memory, and (d) the hypothesized basis for confidence. It is argued that grafting a moving window memory onto a memoryless decision process has several undesirable consequences. Moreover, the suggested basis for confidence leads to predictions that are counterintuitive and unsupported by empirical evidence. It is concluded that the window-sampling model is a maladapted combination of inappropriate elements, which is implausible as a model of decision making, memory, or confidence, in sensory discrimination.

[Endoscopic pretherapeutic clipping for gastrointestinal tumors. A method for exact definition of the target volume]. / Endoskopische prätherapeutische Clipmarkierung von Tumoren im Gastrointestinaltrakt. Eine Methode zur exakteren Definition von Zielvolumina.

BACKGROUND: In many cases it is not possible to exactly define the extension of carcinoma of the gastrointestinal tract with the help of computertomography scans made for 3-D-radiation treatment planning. Consequently, the planning of external beam radiotherapy is made more difficult for the gross tumor volume as well as, in some cases, also for the clinical target volume. PATIENTS AND METHODS: Eleven patients with macroscopic tumors (rectal cancer n = 5, cardiac cancer n = 6) were included. Just before 3-D planning, the oral and aboral border of the tumor was marked endoscopically with hemoclips. Subsequently, CT scans for radiotherapy planning were made and the clinical target volume was defined. Five to 6 weeks thereafter, new CT scans were done to define the gross tumor volume for boost planning. Two investigators independently assessed the influence of the hemoclips on the different planning volumes, and whether the number of clips was sufficient to define the gross tumor volume. RESULTS: In all patients, the implantation of the clips was done without complications. Start of radiotherapy was not delayed. With the help of the clips it was possible to exactly define the position and the extension of the primary tumor. The clinical target volume was modified according to the position of the clips in 5/11 patients; the gross tumor volume was modified in 7/11 patients. The use of the clips made the documentation and verification of the treatment portals by the simulator easier. Moreover, the clips helped the surgeon to define the primary tumor region following marked regression after neoadjuvant therapy in 3 patients. CONCLUSIONS: Endoscopic clipping of gastrointestinal tumors helps to define the tumor volumes more precisely in radiation therapy. The clips are easily recognized on the portal films and, thus, contribute to quality control.

Memory capacity and intelligence: novel techniques for evaluating rival models of a fundamental information-processing mechanism.

Data from a fundamental cognitive task in which participants discriminate the relative frequency of visual or auditory binary stimuli were examined. Accuracy on this task correlates well with psychometric intelligence. The experimental paradigm is highly tractable, lending itself to rigorous analyses of precisely defined simulation models. Numerous models are evaluated, using multiple comparisons between response patterns of individual (and pooled) participants and predictive measures based on simulations for each trial sequence. Implications for theoretical accounts of short-term memory, discrimination, and absolute judgement as well as the measurement of individual differences in cognitive ability, are discussed. The results suggest a reinterpretation of memory capacity and support a new kind of model (with a single estimable parameter) in which discrete, valued units of information are stochastically displaced by further input.

Acetylated LDL endocytosis by the human monocytic Mono Mac 6sr cells is not mediated by the macrophage type I and II scavenger receptors.

We recently reported that the human monocytic Mono Mac 6sr cell line constitutively takes up and degrades acetylated (acLDL) and oxidized LDL through receptor-specific pathways. The present studies were undertaken to further characterize the acLDL binding site on a functional and molecular basis. The degradation of acLDL increased during differentiation of Mono Mac 6sr cells with lipopolysaccharide (10 ng/mL, 72 hours) and low concentrations of phorbol 12-myristate 13-acetate (PMA; 0.1 to 1.0 ng/mL, 72 hours). Higher doses of PMA (5 or 10 ng/mL), however, decreased acLDL degradation. Scatchard plots of acLDL binding in untreated and LPS-differentiated Mono Mac 6sr cells were nonlinear and suggested the presence of more than one binding site. Although the ligand specificity of the acLDL receptor in Mono Mac 6sr cells resembles that of the macrophage type I and type II scavenger receptors, we did not detect mRNA of either receptor type in untreated or differentiated Mono Mac 6sr cells by means of Northern blotting and reverse transcription polymerase chain reaction. Furthermore, ligand blotting with 125I-acLDL failed to detect the 220-kD types I and II scavenger receptor protein. Thus, Mono Mac 6sr cells express an acLDL receptor that is distinct from the type I and type II scavenger receptor found in human monocyte-derived macrophages but that, like the latter, is induced during monocytic differentiation.

n-3 fatty acids only delay early relapse of ulcerative colitis in remission.

Relapse prevention by dietary n-3 fatty acids (5.1 g/day) was studied in a double-blind, placebo-controlled trial of 64 patients with ulcerative colitis in remission and off steroids. 5-ASA compounds were stopped three months after randomization and clinical disease activity monitored for two years. Macroscopic and histologic activity and extension was assessed by colonoscopy at entry and at exit. Both treatment groups were well matched at start. Nine patients on placebo and eight on n-3 fatty acids stopped taking their medication prematurely. Actuarial relapse-free survival was improved by n-3 fatty acids only during months 2 and 3 (2P < 0.05-0.01), but cumulative relapse rate at two years was similar for those taking placebo (18/33 = 55%) and n-3 fatty acids (18/31 = 58%). There was also no consistent difference in clinical, macroscopic, and histologic disease activity between treatment groups. The n-3 fatty acids temporarily retard, but do not prevent, relapse of ulcerative colitis.

Lovastatin reduces expression of the combined adhesion and scavenger receptor CD36 in human monocytic cells.

The thrombospondin and collagen receptor CD36 was recently found to function, also, as a dominating scavenger receptor for oxidized low-density lipoproteins (oxLDL). Thus, CD36 might be a key factor in monocyte adhesion and foam cell formation. We, therefore, studied CD36 expression in monocytic cells under conditions of cholesterol depletion and overload. Human monocytic U937 cells were cultured under control conditions and in the presence of lovastatin, native, and oxLDL. The expression of lipoprotein receptors was measured by quantitative reverse transcriptase polymerase chain reaction (RT-PCR) and fluorescence-activated cell sorting (FACS). In sharp contrast to the feedback-controlled ApoB100 specific receptor for native low-density lipoprotein (LDL-R), CD36 expression was significantly reduced by lovastatin in a dose-dependent manner, both at the RNA and protein level, resulting in decreased cellular oxLDL binding. The addition of mevalonate completely reversed lovastatin effects, whereas excess LDL was only partially effective. Similarly to native LDL, oxLDL reduced LDL-R transcription, but did not affect CD36 transcription. CD36 protein surface expression fell, however, due to internalization of CD36 loaded with oxLDL. In summary, monocytic expression of CD36, in contrast to the native LDL-R, is reduced by cholesterol synthesis inhibition and not by feedback inhibition from substrate overexposure. CD36 suppression is a new pharmacological action of lovastatin that may contribute to its clinical benefit by attenuating monocyte adhesion and foam cell formation, key steps in atherosclerosis.

Linoleic acid esterified in low density lipoprotein serves as substrate for increased arachidonic acid synthesis in differentiating monocytic cells.

The cellular metabolism of albumin- and lipoprotein-bound 18:2(n - 6) during monocytic differentiation was examined in the human premonocytic U937 and Mono Mac 6 cells. Differentiation for 72 h of U937 cells with retinoic acid (RA, 1 microM) or 1,25-(OH)2-vitamin D3 (1,25-D3, 10 nM) and of Mono Mac 6 cells with RA (1 microM) or lipopolysaccharide (LPS, 10 ng/ml) increased the desaturation and elongation of [1-14C]18:2(n - 6) to [1-14C]20:4(n - 6). In undifferentiated U937 and Mono Mac 6 cells, incubations with human LDL (100 micrograms/ml, 18 h) resulted in a 2.5-fold increase in 18:2(n - 6) levels in the cellular phospholipids. Differentiation of U937 cells with RA or or of Mono Mac 6 cells with LPS prior to LDL addition. Significantly reduced 18:2(n - 6) and elevated 20:4(n - 6) levels in cellular phospholipids. This increase in 20:4(n - 6) was likely not due to an increased incorporation of preformed 20:4(n - 6) esterified in LDL, as the receptor-specific degradation of [125I]LDL was reduced in both the RA-treated U937 and LPS-treated Mono Mac 6 cells. In U937 cells incubated with [1-14C]18:2(n - 6), the synthesis of TXB2, PGE2 and HHT could be detected after differentiation with RA. suggesting the availability of [1-14C]20:4(n - 6), derived from [1-14C]18:2(n - 6), for cyclooxygenase metabolism. Our results show that the conversion of 18:2(n - 6) to 20:4(n - 6) increases during monocyte differentiation. The 18:2(n - 6) supplied to the cells via the receptor-mediated uptake of LDL was utilized as substrate for the increased 20:4(n - 6) synthesis.

N-3 but not N-6 fatty acids reduce the expression of the combined adhesion and scavenger receptor CD36 in human monocytic cells.

CD36, a multifunctional adhesion receptor e.g. for thrombospondin and collagen, as well as a scavenger receptor for oxidized low density lipoprotein, is expressed e.g. on platelets and monocytes. By this dual role it might be involved in early steps of atherosclerosis like the recruitment of monocytes and formation of foam cells. We therefore studied the effects of n-3 fatty acids on CD36 expression in human monocytic cells. Incorporation of eicosapentaenoic acid (EPA, C20:5n-3) and docosahexaenoic acid (DHA, C22:6n-3) into cellular phospholipids resulted in a significant reduction of CD36 expression at the mRNA and protein level, whereas arachidonic acid (AA, C20: 4n-6) and linoleic acid (LA, C18:2n-6) tended to increase CD36 expression compared to the control. This specific down-regulation of CD36 by n-3 fatty acids in cells involved in the initiation and progression of atherogenesis and inflammation, represents a further mechanism that may contribute to the beneficial effects of n-3 polyunsaturated fatty acids (PUFA) in these disorders.

Mildly oxidized LDL induces platelet aggregation through activation of phospholipase A2.

Native LDL and LDL oxidized under various conditions were compared in terms of their ability to activate platelets. Native LDL did not induce platelet shape change or aggregation, even at high concentrations (2 mg protein/mL). LDL was mildly oxidized with either CuSO4 (mox-LDL) or 3-(N-morpholino)sydnonimine (SIN-1-LDL). Analysis of mox-LDL and SIN-1-LDL showed a small increase of dienes (E234nm from 0.28 +/- 0.04 to 0.55 +/- 0.09, mean +/- SD) and thiobarbituric acid-reactive substance (from 0 to 10.6 +/- 1.5 nmol/mg, mean +/- SEM), no change in apo B electrophoretic mobility, and a minor (12% to 30%) decrease in polyunsaturated fatty acid content. Interestingly, this small oxidative modification of LDL dramatically changed its effect on platelets. Irreversible aggregation and secretion were induced by a threshold concentration of 0.4 mg protein/mL. In contrast, LDL thoroughly oxidized with CuSO4 (ox-LDL) did not aggregate platelets. Although mox-LDL was depleted in antioxidants (alpha- and gamma-tocopherol, alpha- and beta-carotene, and other carotenoids), incubation of mox-LDL with exogenous alpha-tocopherol did not reverse its ability to induce platelet aggregation and secretion. Preincubation of platelets with the cyclooxygenase inhibitor aspirin or the phospholipase A2 inhibitors trifluoperazine, quinacrine, 4-bromophenacyl bromide, and propranolol completely prevented platelet aggregation and secretion caused by mox-LDL or SIN-1-LDL. These results indicate that mildly oxidized LDL activates platelets through a phospholipase A2/cyclooxygenase-dependent pathway. The complete inhibition of mox-LDL-induced platelet aggregation by aspirin could contribute to its beneficial effect in cardiovascular disease.

Inhibitors of protein tyrosine kinase suppress TNF-stimulated induction of endothelial cell adhesion molecules.

We studied the role of tyrosine phosphorylation in the induction of vascular cell adhesion molecule 1 (VCAM-1), endothelial leukocyte adhesion molecule 1 (ELAM-1), and intercellular adhesion molecule 1 (ICAM-1) in HUVEC. Induction of VCAM-1 and ELAM-1 surface expression by TNF was dose-dependently reduced by pretreatment with the protein tyrosine kinase inhibitors herbimycin A (HMA, IC50 300 nM) or genistein (IC50 30 microM). Only genistein attenuated ICAM-1 induction. Genistein or HMA did not affect adhesion molecule up-regulation by PMA. U937 monocyte adhesion to TNF-stimulated HUVEC was markedly inhibited by a combination of anti-VCAM-1 and anti-ELAM-1 mAb, as well as by HMA or genistein, probably due to suppression of VCAM-1 and ELAM-1 up-regulation. HMA appeared to prevent VCAM-1 transcription, since it reduced induction of VCAM-1 mRNA by TNF. Gelshift analysis demonstrated inhibition of TNF-induced nuclear factor-kappa B (NF-kappa B) mobilization by HMA. TNF rapidly enhanced tyrosine phosphorylation of a protein migrating with an apparent molecular mass of 35 kDa. HMA and genistein suppressed constitutive tyrosine phosphorylation of all detectable proteins and prevented TNF-induced tyrosine phosphorylation of the 35 kDa protein with an IC50 and dose range, similar to inhibition of VCAM-1 and ELAM-1 induction. Our data suggest that specific phosphorylation following protein tyrosine kinase activation may be required for NF-kappa B mobilization and induction of VCAM-1 and ELAM-1 by TNF.

Docosahexaenoic acid selectively attenuates induction of vascular cell adhesion molecule-1 and subsequent monocytic cell adhesion to human endothelial cells stimulated by tumor necrosis factor-alpha.

Incorporation of the n-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) but not eicosapentaenoic acid or n-6 arachidonic acid into human umbilical vein endothelial cell (HUVEC) phospholipids dose-dependently reduced tumor necrosis factor-alpha (TNF-alpha)-induced surface expression of vascular cell adhesion molecule-1 (VCAM-1). In parallel, DHA inhibited TNF-alpha-stimulated monocytic U937 cell adhesion to HUVECs but did not affect TNF-alpha- or interferon gamma-induced expression of intercellular adhesion molecule-1 and endothelial leukocyte adhesion molecule-1 or VCAM-1 induction by interleukin-1 beta. DHA appeared to attenuate VCAM-1 transcription, as it reduced induction of VCAM-1 mRNA by TNF-alpha. VCAM-1 induction is regulated by activation of nuclear factor-kappa B, which can be mediated by a TNF-alpha-responsive phosphatidylcholine-specific phospholipase C (PC-PLC). Gel-shift analysis showed inhibition of TNF-alpha-induced nuclear factor-kappa B mobilization by DHA. While the PC-PLC inhibitor D609 dose-dependently prevented VCAM-1 induction by TNF-alpha, 1,2-diacyl-glycerol (DAG) stimulated VCAM-1 expression, suggesting that VCAM-1 induction by TNF-alpha may be mediated by activation of PC-PLC. Treatment with DHA resulted in a fourfold enrichment in PC. In addition, DHA or D609 but not eicosapentaenoic acid or arachidonic acid suppressed activation of PC-PLC by TNF-alpha, estimated as [14C]DAG synthesis in prelabeled HUVECs. Incorporation of DHA into phospholipids selectively attenuates VCAM-1 induction by TNF-alpha and subsequent monocytic cell adhesion by inhibition of TNF-alpha-stimulated PC-PLC activation in HUVECs.

Aspirin inhibits nuclear factor-kappa B mobilization and monocyte adhesion in stimulated human endothelial cells.

BACKGROUND: The induction of vascular cell adhesion molecule-1 (VCAM-1) and E-selectin by tumor necrosis factor-alpha (TNF) is mediated by mobilization of the transcription factor nuclear factor-kappa B (NF-kappa B). Since salicylates have been reported to inhibit NF-kappa B activation by preventing the degradation of its inhibitor I kappa B, we studied a potential inhibition of this pathway by acetylsalicylate (aspirin) in human umbilical vein endothelial cells (HUVECs). METHODS AND RESULTS: Gel-shift analyses demonstrated dose-dependent inhibition of TNF-induced NF-kappa B mobilization by aspirin at concentrations ranging from 1 to 10 mmol/L. Induction of VCAM-1 and E-selectin surface expression by TNF was dose-dependently reduced by aspirin over the same range, while induction of intercellular adhesion molecule-1 (ICAM-1) was hardly affected. Aspirin appeared to prevent VCAM-1 transcription, since it dose-dependently inhibited induction of VCAM-1 mRNA by TNF. As a functional consequence, adhesion of U937 monocytes to TNF-stimulated HUVECs was markedly reduced by aspirin due to suppression of VCAM-1 and E-selectin upregulation. These effects of aspirin were not related to the inhibition of cyclooxygenase activity, since indomethacin was ineffective. CONCLUSIONS: Our data suggest that aspirin inhibits NF-kappa B mobilization, induction of VCAM-1 and E-selectin, and subsequent monocyte adhesion in endothelial cells stimulated by TNF, thereby providing an additional mechanism for therapeutic effects of aspirin.

Retinoic acid inhibits basal and interferon-gamma-induced expression of intercellular adhesion molecule 1 in monocytic cells.

Retinoic acid (RA) and 1,25-(OH)2-vitamin D3 (1,25-D3) induced U937 cell maturation into distinct monocytic phenotypes, as demonstrated by up-regulation of CD23 by RA and CD14 by 1,25-D3. Differentiation by RA but not by 1,25-D3 was associated with reduction of basal and complete suppression of interferon-gamma (IFN-gamma)-stimulated intercellular adhesion molecule 1 (ICAM-1) expression. Induction of cyclooxygenase activity by RA and attenuation of basal ICAM-1 expression exhibited similar kinetics. Treatment with indomethacin prevented and prostaglandin E2 (PGE2), dibutyryl-cAMP, or forskolin mimicked reduction of basal ICAM-1 expression by RA, indicating that this effect of RA is mediated by PGE2 synthesis and subsequent cAMP elevation. In contrast, suppression of IFN-gamma-induced ICAM-1 expression by RA was only partly reversible by indomethacin, suggesting that inhibition of IFN-gamma stimulation was not completely due to cyclooxygenase induction. RA did not always counter-act IFN-gamma, as it cooperated with IFN-gamma in down-regulating very late activation antigen 4. Specific polymerase chain reaction and Northern blotting of ICAM-1 mRNA revealed that RA suppressed ICAM-1 induction by IFN-gamma at the transcriptional level. RA also blocked ICAM-1 induction by IFN-gamma in isolated human blood monocytes. In conclusion, inhibition of basal and stimulated ICAM-1 expression in monocytic cells may provide a mechanism for beneficial anti-inflammatory effects of retinoids.