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Biomedical subjects

F Buttgereit

Publications and source records attributed to F Buttgereit.

At least 55 records · Page 3Linked to original sources
PubMed2001

Molecular mechanisms of glucocorticoid-induced osteoporosis.

Bone loss resulting from long-term glucocorticoid therapy is common and clinically relevant. A number of different glucocorticoid-mediated effects are responsible for the reduction in bone density: (i) glucocorticoid-induced direct impairment of osteoblast, osteocyte, and osteoclast function leads to reduced bone remodeling and diminished repair of microdamage in bone; (ii) the effects of parathyroid hormone (PTH) might be more pronounced in the presence of glucocorticoids, whereas vitamin D plays a lesser role in the pathogenesis of steroid-induced osteoporosis; (iii) glucocorticoids antagonize gonadal function and inhibit the osteoanabolic action of sex steroids; and (iv) increased renal elimination and reduced intestinal absorption of calcium lead to a negative calcium balance that has been suggested to promote secondary hyperparathyroidism. From a mechanistic point of view, all of the aforementioned effects have long been considered to be mediated at the molecular level exclusively by genomic actions. However, there is now increasing evidence for the existence of rapid glucocorticoid effects that are incompatible with this classical mode of action. These rapid effects, termed nongenomic effects, are mediated by glucocorticoid interactions with biological membranes, either through binding to membrane receptors or by physicochemical interactions. It is possible, but has yet to be shown, that these effects play a role in the pathogenesis of glucocorticoid-induced osteoporosis.

Calcium↗
PubMed2001

Short-term effects of the 21-aminosteroid lazaroid tirilazad mesylate (PNU-74006F) and the pyrrolopyrimidine lazaroid PNU-101033E on energy metabolism of human peripheral blood mononuclear cells.

Two groups of antioxidant compounds, the 21-aminosteroids and the pyrrolopyrimidines, have been found to act as neuroprotective drugs against lipid peroxidation in the injured CNS. Like glucocorticoids at high doses they are assumed to produce their effects at least in part by direct membrane stabilizing effects. In order to prove this hypothesis, we have investigated in this study the effects of these drugs on the energy metabolism of activated human peripheral blood mononuclear cells (PBMC) since these cells have been shown to serve as a suitable test system for substances affecting processes of ATP turnover. We compared the in vitro effects of (i) the 21-aminosteroid lazaroid tirilazad, (ii) the pyrrolopyrimidine lazaroid PNU-101033E and (iii) the glucocorticoid methylprednisolone on mitogen-induced respiration rate and ATP-consumption. We show that tirilazad inhibits concanavalin A-stimulated respiration rate and sodium cycling across the plasma membrane. The effect of methylprednisolone is similar indicating corresponding cellular mechanisms. However, unlike methylprednisolone, tirilazad produced no significant effect on calcium cycling across the plasma membrane. PNU-101033E in our test system caused cytotoxic effects on PBMC that did not allow us to quantify cellular actions on energy metabolism. Our results underline the view that tirilazad, first, is mimicking the high-dose immunosuppressive pharmacology of glucocorticoids such as methylprednisolone and, second, is likely to produce its therapeutic effects by direct physicochemical interactions with cellular membranes.

Adenosine Triphosphate↗
PubMed2001

Norepinephrine inhibits energy metabolism of human peripheral blood mononuclear cells via adrenergic receptors.

Previous studies demonstrated that the adaptive response to stressors and inflammatory signals involves the activation of the autonomous [corrected] nervous system. Catecholamines have been shown to modulate the activity of various immune effector cells directly via membrane adrenergic receptors. Here, we investigated immediate effects of norepinephrine on energy metabolism of immune cells. Norepinephrine inhibits oxygen consumption of human peripheral blood mononuclear cells at concentrations that are relevant to its physiological range. The beta-adrenoreceptor antagonist propranolol, but not the alpha-adrenoreceptor antagonist phentolamine reversed the norepinephrine induced inhibition in quiescent cells. Conversely, phentolamine but not propranolol is capable of blocking norepinephrine mediated effects in mitogen activated human peripheral blood mononuclear cells. Our data indicate that the sensitization of alpha- and beta-adrenoreceptors on immune cells is differentially regulated, and that these processes depend on the activation state of these cells. These findings have important implications for the understanding of stress-induced suppression of immune function and may contribute to the elucidation of the pathogenesis of immunologically mediated diseases.

Adrenergic alpha-Antagonists↗
PubMed2001

Fatal atypical T-cell proliferation associated with Epstein-Barr virus infection.

We report the case of a young Caucasian man who presented with polyneuropathy and severe, ultimately fatal, congestive heart failure in the context of a chronic active Epstein-Barr virus (EBV) infection. Post-mortem examination revealed both monoclonal and polyclonal proliferation of EBV-positive atypical T lymphocytes within different organs. Predominant infiltration of the nervous system and heart with extensive myocardial scarring accounted for the clinical symptoms. The remarkable features of this case are (i) the occurrence in a Caucasian patient, (ii) the absence of detectable immunodeficiency, and (iii) the myocardial destruction by EBV-infected monoclonal T cells.

Adult↗
PubMed2001

Effect of glucocorticoid therapy on glucocorticoid receptors in children with autoimmune diseases.

Low-dose glucocorticoids (GC) achieve their action completely by classical genomic effects, mediated by the glucocorticoid receptor (GCR). In high doses of GC, nongenomic effects have also been found, but it is still unclear to what extent they contribute to a beneficial outcome. In this study, we present a determination of the number of lymphocyte GCR sites and the binding affinity in healthy children and children with autoimmune diseases. We further assess the effect of GC administration, especially of high-dose pulse therapy on the number of binding sites. The number of GCR sites per cell was analyzed with [(3)H]-dexamethasone radioligand binding assay and binding affinity (Kd given in nM) in peripheral blood mononuclear cells isolated from 48 healthy children and 35 patients. The patients were divided into three groups based on GC treatment: 0 mg/kg (group 1), 0.01-0.3 mg/kg orally (group 2), and 10-15 mg/kg i.v. pulse therapy (group 3) of prednisolone equivalent per day. Gender- and age-independent normal values of 4338 +/- 1687 sites/lymphocytes and Kd 6.7 +/- 2.2 nM were found. At 3463 +/- 1574, the number of receptor sites in patients without GC (group 1) was significantly lower than that of healthy volunteers (p < 0.05). In patients receiving GC treatment, this value was reduced to 2952 +/- 512 (group 2). Significant down-regulation to a minimum of 479 +/- 168 (group 3) was found after pulse therapy compared with untreated patients (p < 0.01). In pulse therapy, GC lead to a fast and dramatic receptor down-regulation. We suppose that the increase in therapeutic success of pulse-therapy may partly be mediated through additional nongenomic effects.

Adolescent↗
PubMed2000

Therapeutically targeting lymphocyte energy metabolism by high-dose glucocorticoids.

Lymphocytes use a considerable amount of energy, mainly in the form of ATP, especially when they become stimulated following activation by antibodies or mitogens. Cellular respiration is the major energy source, and in quiescent cells the ATP produced is used to drive protein synthesis and sodium transport. In stimulated cells there is significantly higher ATP production to balance the higher ATP demand of specific processes resulting from activation. The major ATP-consuming processes under these conditions are protein synthesis and Na(+),K(+)-ATPase (about 20% each), while Ca(2+)-ATPase and RNA/DNA syntheses contribute about 10% each. There is a wealth of available information about glucocorticoid effects on lymphocytes, but here we focus on the extent to which this lymphocyte bioenergetic machinery is targeted by glucocorticoids when they are used therapeutically at high doses. High-dose glucocorticoids have been shown recently to interfere with processes that are essential for the activation and maintenance of lymphocytes, such as sodium and potassium transport. Therefore, in this article we describe the bioenergetics of lymphocytes in resting, activated, and glucocorticoid-treated states and present a concept for discussion to describe the relationship among these states in fundamental and clinical terms.

Adenosine Triphosphate↗
PubMed2000

[High dosage steroid pulse therapy. Is there an indication in dermatology?].

In recent years, high-dose steroid pulse therapy has been considered an effective treatment regimen in a number of non-dermatological diseases. This review addresses in the first part the pharmacological basics and mechanisms of action of high-dose glucocorticosteroid therapy. In the second part, we discuss the clinical experience using this treatment for dermatological diseases including pemphigus vulgaris, pyoderma gangrenosum, alopecia areata, and dermatomyositis.

Autoimmune Diseases↗
PubMed2000

Mechanisms and clinical relevance of nongenomic glucocorticoid actions.

Glucocorticoids have profound anti-inflammatory and immunosuppressive actions when used therapeutically. The therapeutic dose is quite variable and depends on the disease, but ranges from very low to extremely high. The rationale for the use of various dosage regimens for specific clinical indications is the existence of three distinct, therapeutically relevant effects: genomic, specific nongenomic and unspecific nongenomic. Genomic effects are mediated by cytosolic receptors that alter expression of specific genes. Specific nongenomic effects occur within a few minutes and are mediated by steroid-selective membrane receptors. Unspecific nongenomic effects occur within seconds, but only at high glucocorticoid dosages, and seem to result from direct interactions with biological membranes. For unspecific nongenomic effects, methylprednisolone and other glucocorticoids have been shown to inhibit cation cycling across the plasma membrane, but to have little effect on protein synthesis. Thus, glucocorticoids could diminish or prevent the acute immune response by interfering with processes such as the rise in intracellular Ca2+ concentration. It is proposed that the additional therapeutic benefit of higher doses is obtained via these nongenomic effects.

Acute-Phase Proteins↗
PubMed2000

The influence of obesity on perioperative morbidity and mortality in revision total hip arthroplasty.

The significance of obesity as a risk factor for postoperative complications was determined in a consecutive series of 229 cases of revision total hip replacement. The body mass index (BMI) was used as an objective measure to classify the patients. The group-wise analysis of data included all medical and procedure-related complications, the number of fatal cases, operative time, requirement for analgesics, the number of transfusions and perioperative haemoglobin levels. The results of our study demonstrate a clear association between obesity and operative time, whereas no statistically significant relationships were observed between obesity and the other parameters. We conclude that obesity does not have any significant influence on perioperative morbidity and mortality but is clearly related to operation time and, therefore, to higher costs per operation.

Adult↗
PubMed2000

Bioenergetics of human peripheral blood mononuclear cell metabolism in quiescent, activated, and glucocorticoid-treated states.

The first quantitative findings on the energy metabolism of human immune cells are presented. In quiescent peripheral blood mononuclear cells (PBMC) protein biosynthesis and Na+,K+-ATPase activity each accounted for 8% of cellular oxygen consumption. Stimulation with 25, 50, and 75 microg Con A/ml (1.25, 2.5 or 3.75 microg/10(6) cells) increased total oxygen consumption within seconds by 8, 36, and 53%, respectively. After addition of 75 microg Con A/ml, the proportion of cellular oxygen consumption due to protein biosynthesis, Na+,K+-ATPase activity, and Ca2+-ATPase activity was 15% each and that due to DNA/RNA synthesis was 8%. On the basis of these findings the immediate effects of five different glucocorticoids on cellular energy metabolism were investigated. The various glucocorticoids exerted basically the same inhibitory effects on Con A-stimulated cellular respiration and individual ATP-consuming processes, but differed significantly in potency. Similar to previous studies on rat thymocytes, the relative potencies of the glucocorticoids were found to be: prednylidene (1.7) > dexamethasone (1.5) > methylprednisolone (1.0) > prednisolone (0.3) > betamethasone (< 0.2). Given their rapidity of onset, these effects must be nongenomically mediated. The differences between the relative potencies of the various glucocorticoids for these effects and those for the classical genomic effects have important clinical implications, in particular for high-dose systemic and local glucocorticoid therapy.

Calcium-Transporting ATPases↗
PubMed2000

Arterial thrombosis associated with anticardiolipin and anti-beta2-glycoprotein-I antibodies in patients with non-Hodgkin's lymphoma: a report of two cases.

Autoimmune phenomena in lymphoid malignancies are often observed. However, clinical manifestations such as a secondary antiphospholipid syndrome in the presence of antiphospholipid antibodies are rarely reported. Furthermore, in the few cases of lymphomas so far reported with thrombosis associated with elevated antiphospholipid antibodies, the anti-beta2-glycoprotein-I antibodies have not been studied. We report on two cases of arterial thrombosis occuring in patients with B-cell lymphoma who presented with positive anticardiolipin and anti-beta2-glycoprotein-I antibodies. Our observation suggests that patients with non-Hodgkin's lymphoma and both anticardiolipin and anti-beta2-glycoprotein-I antibodies may be, similar to lupus patients, at considerable risk towards thrombosis, especially towards arterial thrombosis.

Aged↗
PubMed2000

Localized pigmented villonodular synovitis of the knee joint: neoplasm or reactive granuloma? A review of 18 cases.

OBJECTIVE: The localized form of pigmented villonodular synovitis of the knee joint is a rare disease with limited alteration of the synovial membrane, the pathogenesis of which is the subject of controversial discussion. METHODS: Eighteen cases have been documented in our hospital since 1976. All of the patients had additional cartilage or meniscus damage. Treatment consisted of excision of the lesion and the adjacent synovial membrane, as well as therapy of the additional damage. RESULTS: The patients who had received such therapy were followed for 3-9 yr, without any clinical, sonographic or magnetic resonance tomographic signs of recurrence. In addition to the lack of a tendency towards recurrence, none of the cases displayed any further characteristics of the diffuse form of villonodular synovitis, such as invasiveness or malignant transformation. CONCLUSIONS: We therefore suggest that pigmented villonodular synovitis of the knee joint should be classified more strictly than before into a potentially neoplastic (diffuse) form and a reactive granulomatous (local) form. From the cases observed, we conclude that degenerative joint lesions may be the cause of the reactive granulomatous form.

Adolescent↗
PubMed2000

Influencing factors on perioperative morbidity in knee arthroplasty.

In an unselected, prospective case control study, the incidence of risk factors and perioperative complications was investigated in 237 knees (203 patients) undergoing implantation of cementless total knee endoprostheses. Intraoperative complications and postoperative complications occurred in 84 patients (99 knees), with 61 specific orthopaedic complications in 50 patients (57 knees) and 74 nonsurgical complications in 55 patients (65 knees). The presence of cardiac, neurologic, or psychiatric concomitant diseases, advanced age, male gender, high-risk anesthesia scores, number and extent of intraoperative blood pressure fluctuations, and surgery under intubation anesthesia are associated significantly with the incidence of nonsurgical perioperative complications. In contrast, body weight, concomitant metabolic and circulatory diseases, previous surgery on the joint, origin of the articular disease, and the duration of surgery and tourniquet time do not correlate with the probability of a nonsurgical perioperative complication. A significant correlation with the parameters investigated could not be found for the occurrence of specific orthopaedic complications. The current report identifies specific risk factors that define patients with risk of having perioperative complications according to objective criteria. These parameters must be given individual consideration when establishing the indication and planning of surgery.

Adult↗
PubMed2000

Higher expression of glucocorticoid receptor in peripheral mononuclear cells in inflammatory bowel disease.

OBJECTIVE: Glucocorticoids are widely used in the treatment of inflammatory bowel disease (IBD). Up- and down-regulated expression of glucocorticoid receptors (GR) has been reported for different chronic inflammatory diseases. The aim of this study was to investigate the expression of GR and their apparent dissociation constant (Kd) in patients with IBD. METHODS: Thirty-nine patients with IBD (22 with ulcerative colitis, 17 with Crohn's disease) and 35 normal controls were studied. Twenty-five patients did not receive steroids, 14 patients were treated with steroids. Peripheral blood mononuclear cells from patients and controls were isolated using the Ficoll-Hypaque gradient and a whole cell [3H]-dexamethasone binding assay and Scatchard plot analysis were performed to assess GR number and the apparent dissociation constant. Results were expressed as mean +/- standard deviation. RESULTS: Normal controls showed an expression of 3,969 +/- 1,555 GR per cell with an apparent dissociation constant of 6.16 +/- 3.8 nmol/L. IBD patients without steroids had a significant increase both in the expression of GR per cell (6,401 +/- 2,344; p < 0.0001; Wilcoxon-Mann-Whitney test) and in the apparent dissociation constant (11.02 +/- 7.57 nmol/L; p = 0.006). Expression of GR in IBD patients was suppressed to normal levels under steroid treatment (4,594 +/- 2,237; p = 0.024), but Kd remained elevated (13.56 +/- 9.05 nmol/L). Plasma cortisol levels were not different between IBD patients and the control group. CONCLUSIONS: Our data show a systemic increase in GR expression and a decrease in the affinity to the GR in IBD, in contrast to other inflammatory diseases such as rheumatoid arthritis and asthma. These changes point towards a systemic character of IBD, which might be considered in a decision between topical and systemic treatment.

Anti-Inflammatory Agents↗
PubMed2000

Glucocorticoid dose dependent downregulation of glucocorticoid receptors in patients with rheumatic diseases.

OBJECTIVE: The therapeutic success of low doses of glucocorticoids is mediated entirely by classical genomic effects, whereas that of high doses is also mediated to an as yet unknown extent by nongenomic effects. We assessed the relative therapeutic importance of these nongenomic effects in pulse therapy. METHODS: A [3H]dexamethasone radioligand binding assay was used to measure the number of glucocorticoid receptor sites (R, given as number of sites per cell) and glucocorticoid receptor binding affinity (Kd, given in nM) in peripheral blood mononuclear cells isolated from 26 healthy control blood donors and 27 patients with rheumatic diseases. Patients were divided into 4 groups on the basis of their glucocorticoid dose: 0 mg (Group A), < or = 0.25 mg (Group B), 0.25 to 1 mg (Group C), and > 1 mg (Group D) of prednisolone equivalent per kg per day. RESULTS: Sex independent normal values of 3605 +/- 1136 for R and 5.39 +/- 3.4 for Kd were found. At 5407 +/- 1968, the number of receptor sites in patients not receiving glucocorticoid therapy (Group A) was significantly higher than that of controls (p < 0.01). In patients receiving glucocorticoid therapy this value was reduced at 3855 +/- 866 (Group B), 3358 +/- 963 (Group C), and 2685 +/- 962 (Group D). The values in Groups C and D were significantly lower than those in untreated patients (p < 0.02). CONCLUSION: In pulse therapy doses of glucocorticoids that exceed receptor saturation are administered for several days, but in addition significant receptor downregulation occurs. Therefore, we assume an increase in the relative contribution of the nongenomic effects of glucocorticoids to the therapeutic success under these conditions.

Adult↗
PubMed1999

Equivalent doses and relative drug potencies for non-genomic glucocorticoid effects: a novel glucocorticoid hierarchy.

Glucocorticoids have three distinct therapeutically relevant effects (genomic, specific nongenomic, and unspecific non-genomic), raising the hypothesis that the relative potencies of non-genomic and genomic effects of glucocorticoids may differ. Therefore, we measured the unspecific non-genomic potencies of five clinically important glucocorticoids and compared them with the classical (genomic) potencies. We studied the immediate glucocorticoid effects on respiration, on protein synthesis, and on Na+-K+-ATPase and Ca2+-ATPase in concanavalin A-stimulated rat thymocytes. We titrated the respiration of the cells with methylprednisolone, prednylidene, dexamethasone, prednisolone or betamethasone, and then interpolated the glucocorticoid concentrations needed to inhibit concanavalin A-stimulated respiration back to normal. These "equivalent doses" produced equal inhibition of respiration, of specific energy-consuming pathways, and of the concanavalin A effect on quiescent cells. The relative drug potencies were calculated as the inverse of the equivalent doses normalized to methylprednisolone and were: prednylidene (3.0) > dexamethasone (1.2) > methylprednisolone (1.0) > prednisolone (0.4) > betamethasone (0.2). This hierarchy is completely different from that for the classical effects. These new data are of crucial relevance for in vitro experiments and clinical use, especially in glucocorticoid high-dose therapy. Examples are the choice between methylprednisolone and prednisolone in pulse therapy, and the completely different clinical usage of dexamethasone and betamethasone, despite their similar affinities for nuclear receptors.

Adenosine Triphosphate↗