Selective enhancement of endothelial cell VCAM-1 expression by interleukin-10 in the presence of activated leucocytes.

Although initially described as an immunomodulatory cytokine, interleukin-10 (IL-10) has also been proposed to exert proinflammatory effects both in vivo and in vitro. In particular, studies in IL-10 transgenic mice have suggested that IL-10 may activate vascular endothelium to promote leucocyte adhesion and extravasation. In the present study we investigated whether IL-10 activates endothelial cells either directly or indirectly, via signals produced by leucocytes in the endothelial cell environment, using a co-culture of human umbilical vein endothelial cells and peripheral blood mononuclear cells (PBMC). No direct effects of IL-10 on endothelial cell responses were observed. However, in the presence of phytohaemagglutinin-activated PBMC, IL-10 increased the expression on endothelial cells of vascular cell adhesion molecule-1 (VCAM-1) but not of intercellular adhesion molecule-1, E-selectin or major histocompatibility complex (MHC) antigens, an effect mediated by PBMC-derived soluble factors. We also observed that interferon-gamma (IFN-gamma) antagonized VCAM-1 expression on endothelial cells mediated by IL-4 and IL-13. Since IL-10 has previously been documented to down-regulate release of IFN-gamma by PBMC, we propose that the IL-10-mediated reduction of IFN-gamma production by PBMC results in enhanced responsiveness of endothelial cells to PBMC-derived IL-4 and IL-13, and thus increased expression of VCAM-1. Our results suggest that the relative balance of cytokines produced by infiltrating cells in developing inflammatory lesions may differentially modulate endothelial responsiveness in vivo, and that IL-10 might indirectly stabilize VCAM-1 expression on endothelial cells by affecting the balance of leucocyte-derived cytokines in the endothelial environment.     

Effects of exercise training on left ventricular function and peripheral resistance in patients with chronic heart failure: A randomized trial

CONTEXT: Exercise training in patients with chronic heart failure improves work capacity by enhancing endothelial function and skeletal muscle aerobic metabolism, but effects on central hemodynamic function are not well established. OBJECTIVE: To evaluate the effects of exercise training on left ventricular (LV) function and hemodynamic response to exercise in patients with stable chronic heart failure. DESIGN: Prospective randomized trial conducted in 1994-1999. SETTING: University department of cardiology/outpatient clinic in Germany. PATIENTS: Consecutive sample of 73 men aged 70 years or younger with chronic heart failure (with LV ejection fraction of approximately 0.27). INTERVENTION: Patients were randomly assigned to 2 weeks of in-hospital ergometer exercise for 10 minutes 4 to 6 times per day, followed by 6 months of home-based ergometer exercise training for 20 minutes per day at 70% of peak oxygen uptake (n=36) or to no intervention (control group; n=37). MAIN OUTCOME MEASURES: Ergospirometry with measurement of central hemodynamics by thermodilution at rest and during exercise; echocardiographic determination of LV diameters and volumes, at baseline and 6-month follow-up, for the exercise training vs control groups. RESULTS: After 6 months, patients in the exercise training group had statistically significant improvements compared with controls in New York Heart Association functional class, maximal ventilation, exercise time, and exercise capacity as well as decreased resting heart rate and increased stroke volume at rest. In the exercise training group, an increase from baseline to 6-month follow-up was observed in mean (SD) resting LV ejection fraction (0.30 [0.08] vs 0.35 [0.09]; P=.003). Mean (SD) total peripheral resistance (TPR) during peak exercise was reduced by 157 (306) dyne/s/cm(-5) in the exercise training group vs an increase of 43 (148) dyne/s/cm(-5) in the control group (P=.003), with a concomitant increase in mean (SD) stroke volume of 14 (22) mL vs 1 (19) mL in the control group (P=.03). There was a small but significant reduction in mean (SD) LV end diastolic diameter of 4 (6) mm vs an increase of 1 (4) mm in the control group (P<.001). Changes from baseline in resting TPR for both groups were correlated with changes in stroke volume (r=-0.76; P<.001) and in LV end diastolic diameter (r=0.45; P<.001). CONCLUSIONS: In patients with stable chronic heart failure, exercise training is associated with reduction of peripheral resistance and results in small but significant improvements in stroke volume and reduction in cardiomegaly. JAMA. 2000.     

Welche Versorgungsstrukturen werden für ältere Patienten mit rheumatischen Erkrankungen benötigt?

In the coming years the number of elderly patients with rheumatic diseases in Germany will continuously increase. Therefore, it is necessary that the structures of the healthcare system for elderly patients with rheumatic diseases are prepared for this challenge. Two important fields are of particular relevance: multimorbidity and the prevention of disability. Both points do not only affect elderly patients but are particularly important in this group. In order to solve the problems structures which facilitate interdisciplinary care should be supported. Moreover, institutions which provide rehabilitation should be utilized for the care of elderly patients with rheumatic diseases. Both can be performed in either outpatient or inpatient settings. Rheumatologists working in interdisciplinary fields, in outpatient practices, and in specialized rheumatology hospitals have key functions in the care of elderly patients with rheumatic diseases. However, practices and hospitals both have to solve the special problems of reimbursement and interfaces between the sectors.     

Reduced CD4+,CD25- T cell sensitivity to the suppressive function of CD4+,CD25high,CD127 -/low regulatory T cells in patients with active systemic lupus erythematosus

OBJECTIVE: CD4+,CD25high regulatory T (Treg) cells play a crucial role in the maintenance of self tolerance and prevention of organ-specific autoimmunity. The presence of many in vivo-preactivated CD4+,CD25++ T cells in patients with systemic lupus erythematosus (SLE) poses a difficulty in discriminating CD25++ activated T cells from CD25high Treg cells. To overcome this problem, we analyzed the phenotype and function of CD4+,CD25high,CD127(-/low) natural Treg (nTreg) cells isolated from the peripheral blood of patients with SLE. METHODS: CD4+,CD25high,CD127(-/low) nTreg cells and CD4+,CD25- responder T (Tresp) cells from patients with SLE and normal donors were separated by fluorescence-activated cell sorting. Cell proliferation was quantified by 3H-thymidine incorporation, and immunophenotyping of the cells was done using FACScan. RESULTS: Comparable percentages of CD4+,CD25high,FoxP3+ T cells were observed in patients with SLE and normal donors. Proliferation of SLE nTreg cells sorted into the subset CD4+,CD25high,CD127(-/low) was significantly decreased compared with that of SLE nTreg cells sorted into the subset CD4+,CD25high (mean +/- SEM 2,223 +/- 351 counts per minute versus 9,104 +/- 1,720 cpm, respectively), while in normal donors, these values were 802 +/- 177 cpm and 2,028 +/- 548 cpm, respectively, confirming that effector cell contamination was reduced. Notably, the suppressive activity of nTreg cells was intact in all groups. However, CD4+,CD25- Tresp cells isolated from patients with active SLE were significantly less sensitive than those from patients with inactive SLE to the suppressive function of autologous or normal donor CD4+,CD25high,CD127(-/low) nTreg cells. Furthermore, a significant inverse correlation was observed between the extent of T cell regulation in suppressor assays and the level of lupus disease activity. CONCLUSION: This study is the first to show that, in human SLE, impaired sensitivity of Tresp cells to the suppressive effects of a comparably functional, highly purified nTreg cell population leads to a defective suppression of T cell proliferation in active SLE. Studies aiming to define the mechanisms leading to Tresp cell resistance might help in the development of highly specific, alternative immunotherapeutic tools for the control of systemic autoimmune diseases such as SLE.     

Antibodies against serotonin have no diagnostic relevance in patients with fibromyalgia syndrome

OBJECTIVE: To determine the prevalence and potential diagnostic relevance of autoantibodies against serotonin, thromboplastin, and ganglioside Gm1 in patients with fibromyalgia syndrome (FM). METHODS: Sera from 203 patients with FM and 64 pain-free control subjects were analyzed with enzyme immunoassays. Clinical and psychometric data of the patients were analyzed for the presence or absence of autoantibodies. RESULTS: Compared with control subjects patients with FM had a significantly higher prevalence of autoantibodies against serotonin (20% vs 5%; p = 0.003) and thromboplastin (43% vs 9%; p < 0.001), but not against ganglioside Gm1 (15% vs 9%; p = 0.301). Differences in autoantibody prevalence between controls and FM patients were not related to age or sex. No association was found between autoantibody pattern and clinical or psychometric data, e.g., pain, depression, pain related anxiety, and activities of daily living. CONCLUSION: There is an elevated prevalence of antibodies against serotonin and thromboplastin in patients with FM. The pathophysiological significance of this finding is unknown. Calculation of positive predictive values of antiserotonin antibodies shows that measurement of these antibodies has no diagnostic relevance.     

Hematopoietic stem cell transplantation (HSCT) for primary systemic vasculitis and related diseases

Primary systemic vasculitis (PSV) as well as the related disorders behcet disease (BD) and relapsing polychondritis (RP) are a heterogenous group of autoimmune diseases with the potency for a severe and life threatening course. Patients with PSV seem to be ideal candidates for HSCT: First, when first line treatment has failed the patients are in high risk of severe organ damage or death due to active disease or treatment toxicity. Moreover, the chance to achieve complete remission with standard doses of cyclophosphamide–still standard treatment of severe manifestations of PSV- predicts that dose escalation to high dose chemotherapy will increase the effectiveness. The experience with HSCT in patients with severe PSV as published in case reports and from EULAR and EBMT-databases gives preliminary evidence that HSCT might be an effective treatment option in refractory cases of PSV and related diseases. Validated scores of disease activity and damage such as the Birmingham vasculitis activity score (BVAS) and the vasculitis activity damage index (VDI) could help to identify patients which might profit from HSCT.     

First pass metabolism of ethanol is strikingly influenced by the speed of gastric emptying

Background—Ethanol undergoes a first passmetabolism (FPM) in the stomach and liver. Gastric FPM of ethanolprimarily depends on the activity of gastric alcohol dehydrogenase(ADH). In addition, the speed of gastric emptying (GE) may modulateboth gastric and hepatic FPM of ethanol.
Aims—To study the effect of modulation of GE onFPM of ethanol in the stomach and liver.
Methods—Sixteen volunteers (eight men andeight women) received ethanol (0.225 g/kg body weight) orally andintravenously, and the areas under the ethanol concentration timecurves were determined to calculate FPM of ethanol. In seven of thesesubjects, FPM of ethanol was measured after the intravenousadministration of 10 mg metoclopramide (MCP) and 20 mgN-butylscopolamine (NBS) in separate experiments to eitheraccelerate or delay GE. GE was monitored sonographically by integrationof the antral area of the stomach every five minutes for 90 minutesafter oral ethanol intake. In addition, gastric biopsy specimens weretaken to determine ADH activity and phenotype, as well as to evaluategastric histology. Blood was also drawn for ADH genotyping.
Results—GE time was significantly delayed by theadministration of NBS as compared with controls (p<0.0001) and ascompared with the administration of MCP (p<0.0001). This wasassociated with a significantly enhanced FPM of ethanol with NBScompared with MCP (p = 0.0004). A significant correlation was notedbetween GE time and FPM of ethanol (r = 0.43, p = 0.0407).Gastric ADH activity did not significantly correlate with FPM of ethanol.
Conclusion—FPM of ethanol is strikingly modulatedby the speed of GE. Delayed GE increases the time of exposure ofethanol to gastric ADH and may therefore increase gastric FPM ofethanol. In addition, hepatic FPM of ethanol may also be enhanced asthe result of slower absorption of ethanol from the small intestine. Thus a knowledge of GE time is a major prerequisite for studying FPM ofethanol in humans.

Keywords:first pass metabolism of ethanol; gastric emptying; alcohol dehydrogenase; ethanol metabolism; stomach

     

Plasma and intracellular levels of lactate dehydrogenase,phosphohexose isomerase and lysozyme activity in acute leukemia

Summary Plasma and intracellular levels of lactate dehydrogenase (LDH), phosphohexose isomerase (PHI) and lysozyme activities were investigated in 20 patients with acute myelocytic leukemia (AML), 18 patients with acute lymphatic leukemia (ALL) and 10 patients with chronic myelocytic leukemia in blast transformation (CML/BT). Though the plasma levels of LDH and PHI in all patients with acute leukemia were elevated as compared to control persons there was no distinctive pattern which could be of use in the classification of acute leukemia. On the other hand the intracellular levels of these enzymes could be of value in classifying acute leukemia. The leukemic lymphoblasts were characterized by low levels of PHI and lysozyme as compared to leukemic myeloblasts or to normal lymphocytes (p<0.01). The LDH/PHI ratio is also significantly higher in leukemic lymphoblasts than in leukemic myeloblasts or in normal lymphocytes (p always <0.01). These characteristics might also be made use of in identifying the blasts of CML/BT als lymphoid or myeloid in corresponding cases.     

Human gut microbiome adopts an alternative state following small bowel transplantation

Small bowel transplants provide an exceptional opportunity for long-term study of the microbial ecology of the human small bowel. The ileostomy created at time of transplant for ongoing monitoring of the allograft provides access to samples of ileal effluent and mucosal biopsies. In this study, we used qPCR to assay the bacterial population of the small bowel lumen of 17 small bowel transplant patients over time. Surprisingly, the posttransplant microbial community was found to be dominated by Lactobacilli and Enterobacteria, both typically facultative anaerobes. This represents an inversion of the normal community that is dominated instead by the strictly anaerobic Bacteroides and Clostridia. We found this inverted community also in patients with ileostomies who did not receive a transplant, suggesting that the ileostomy itself is the primary ecological determinant shaping the microbiota. After surgical closure of the ileostomy, the community reverted to the normal structure. Therefore, we hypothesized that the ileostomy allows oxygen into the otherwise anaerobic distal ileum, thus driving the transition from one microbial community structure to another. Supporting this hypothesis, metabolomic profiling of both communities demonstrated an enrichment for metabolites associated with aerobic respiration in samples from patients with open ileostomies. Viewed from an ecological perspective, the two communities constitute alternative stable states of the human ileum. That the small bowel appears to function normally despite these dramatic shifts suggests that its ecological resilience is greater than previously realized.