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The role of intravenous immune globulin (Ig) therapy in patients with severe sepsis and septic shock is discussed controversially. Low initial IgG levels could help to identify those patients who might benefit from an adjunctive Ig treatment. To investigate the effect of initial serum IgG levels on 28-day mortality in patients with severe sepsis and septic shock. In this retrospective analysis of the SBITS trial data, 543 patients were allocated to four groups (quartiles) depending on their initial serum IgG levels (1: IgG ≤ 6.1 g/l; 2: IgG 6.2–8.4 g/l; 3: IgG 8.5–11.9 g/l; 4: IgG > 11.9 g/l). The third quartile was taken as the reference quartile. For the applied logistic regression model clinically relevant confounders were defined and integrated into further risk-adjusted calculations. Patients with the lowest IgG levels had a mortality rate similar to those patients with initial IgG levels in the second and third quartile, representing the physiological IgG range in healthy people. Surprisingly, patients with the highest IgG levels even showed a significantly higher mortality in a risk-adjusted calculation compared to the reference quartile (OR 1.69, CI 1.01–2.81, p = 0.05). Subgroup analyses revealed that initial IgG levels were of no prognostic value in patients presenting with vasopressor-dependent septic shock on admission as well as in patients with either gram-positive or gram-negative sepsis. Initially low IgG levels do not discriminate between survival and nonsurvival in patients with severe sepsis and septic shock. Therefore, low IgG cannot help to identify those patients who might benefit from an adjunctive IgG sepsis therapy. Whether a high initial IgG serum level is an independent mortality risk factor needs to be investigated prospectively.

Background Statins (HMG CoA reductase inhibitors), in addition to reducing circulating cholesterol and incidence of coronary heart disease, also have pleiotropic, anti-inflammatory effects. Patients with chronic liver diseases, non-alcoholic fatty liver disease (NAFLD) or hepatitis C are often excluded from statin therapy because of adverse effects in a small cohort of patients despite increased cardiovascular risk cholesterol. Ezetimibe, which inhibits cholesterol absorption by inhibition of Niemann-Pick C1 like 1 (NPC1L1) protein in the brush border of intestinal cells, has been suggested as a new therapeutic option in these patients. Methods Effects of ezetimibe on lipoprotein metabolism, hepatic and intestinal lipid content in guinea pigs, an animal model with a lipoprotein profile and pattern similar to humans were investigated. In order to investigate a possible effect of ezetimibe on cholesterol induced inflammation NF-kappaB activation as an indicator for inflammatory processes in liver and gut tissue was measured. Results Lipid enriched diet led to accumulation of lipids in hepatic tissue which caused strong hepatic NF-kappaB activation. Ezetimibe reduced lipid diet induced increase of circulating cholesterol by about 77% and prevent hepatic NF-kappaB activation almost completely. In contrast in intestinal cells Ezetimibe, though lowering diet induced cholesterol accumulation, increased triglyceride content and subsequent NF-kappaB activation. Conclusion In summary these data show, that ezetimibe effectively reduced diet induced circulating cholesterol levels, hepatic lipid accumulation and inflammatory response in our guinea pig model. However this drug elicited a local inflammatory response in intestinal tissue. Whether these diverse effects of ezetimibe on inflammatory parameters such as NF-kappaB have clinical relevance remains to be determined.

ZusammenfassungIn der Diagnostik von Infektionen und inflammatorischen Prozessen ist das C-reaktive Protein (CRP) einer der meistverwendeten Parameter, unter anderem aufgrund der geringen Kosten und der schnellen Verfügbarkeit. Im Zuge der letzten Jahre gewannen jedoch andere Entzündungsparameter, wie zum Beispiel das Interleukin 6 (IL-6) oder Procalcitonin (PCT), zunehmend an Bedeutung. Obwohl diese Parameter im klinischen Alltag noch nicht überall etabliert sind, besitzen sie doch wesentliche Vorteile in der Diagnostik und im Verlaufsmonitoring von entzündlichen Erkrankungen. Beispielsweise ist die Erkennung entzündlicher Komplikationen auf Intensivstationen durch erhöhte IL-6 Spiegel 24 bis 48 Stunden vor einer Erhöhung des CRP möglich. Die deutliche Überlegenheit von PCT gegenüber CRP in der Diagnostik von bakteriellen Infektionen und Sepsis begründet sich in der höheren Spezifität des PCT für bakterielle Infektionen. Der PCT-Verlauf ermöglicht daher eine bessere Beurteilung des Therapieerfolges und Krankheitsverlaufs des Patienten und liefert Hinweise auf eine gegebenenfalls erforderliche Therapieumstellung. Daraus ergibt sich die Frage, ob die Messung des CRP-Spiegels durch IL-6 und/oder PCT ersetzt werden kann. In dieser Übersichtsarbeit wird die derzeitige Bedeutung von CRP im Verhältnis zu den neueren Entzündungsparametern in der Diagnostik von bakteriellen Infektionen, im therapeutischen Monitoring und in seiner Aussagekraft bezüglich der Prognose des Patienten auf Intensivstationen dargestellt.

Zusammenfassung Die Rolle von Procalcitonin (PCT)-Plasmaspiegel bei kritisch kranken Patienten wurde in den vergangenen Jahren intensiv untersucht. Insbesondere zur Erkennung von Infektionen erwiesen sich PCT-Plasmaspiegel in vielen Fällen anderen klinischen und biochemischen Markern überlegen. Neuere Untersuchungen zeigen, dass mit Hilfe der PCT-Spiegel bei bestimmten Erkrankungen die antibiotische Therapie gesteuert und damit der Antibiotika-Verbrauches reduziert werden kann. Für die Beurteilung der Prognose von kritisch kranken Intensivpatienten scheint der Parameter jedoch nur eingeschränkt verwertbar zu sein. Darüber hinaus können in seltenen Fällen falsch positive und falsch negative Werte auftreten. Trotz dieser Einschränkungen werden heutzutage PCT-Plasmaspiegel bereits vielfältig auf Intensivstationen eingesetzt. Die möglichen klinischen Anwendungen dieses Labormarkers als diagnostisches Werkzeug zur Beurteilung kritisch kranker Patienten sollen im Folgenden dargestellt werden.

Despite recent advances in management of patients in intensive care units, sepsis and septic shock are the major causes of morbidity and mortality. Prompt and adequate antibiotic therapy accompanied by surgical removal of the infectious material are the first-line therapy of choice. In addition, various immunomodulatory treatments have been investigated during the past decades. However, despite promising results in studies with animal models, studies in humans with antibodies against lipopolysaccharide (LPS), tumor necrosis factor and interleukin-1 have not been successful. In addition, high doses of steroids, immunoglobulins or antibodies against LPS and cytokines did not reduce mortality, probably owing to timing and dosage of these drugs. Prophylactic administration of immunomodulatory drugs cannot be recommended due to severe adverse effects. However, owing to pleiotropic effects of statins this class of cholesterol lowering drugs has been suggested to be beneficial as adjuvant therapy for sepsis. The present review summarizes the pathophysiology of sepsis as well as experimental and clinical evidence for the use of statins in sepsis.

Background Several studies have proposed a pathogenic role for oxidized LDL (oxLDL) in atherosclerosis. We tested the hypothesis whether oxLDL modulates dendritic cells (DCs), since these important antigen-presenting cells have been implicated in atherogenesis. We investigated the uptake of oxLDL by DCs, the scavenger-receptors involved and the resulting changes in phenotype and cytokine-spectra. In addition, we analyzed the impact of oxLDL on the nuclear transcription factor-kappa B (NF-κB)-pathway. Methods and results oxLDL (10 μg/ml) increased the expression of the scavenger-receptors CD205 and CD36 and decreased the mannose-receptor expression. The lectin-like oxLDL-receptor (LOX-1)-expression was not affected. The endocytotic capacity of dextran and lucifer-yellow was moderately decreased by oxLDL. Blockage of the scavenger-receptors CD36, LOX-1 and CD205 reduced oxLDL uptake. Furthermore, oxLDL induced DC-maturation and triggered differentiation of DCs in myeloid and plasmacytoid DCs. oxLDL decreased IL-10 secretion and increased IL-6 release. Finally, oxLDL induced an activation of the NF-κB-pathway. Inhibition of IκBα-phosphorylation diminished the oxLDL-induced DC-maturation and -differentiation. Conclusion oxLDL uptake by DCs is mediated by the scavenger-receptors LOX-1, CD36, and CD205. oxLDL induces a proinflammatory cytokine profile in human DCs leading to DC-maturation and -differentiation which can, in part, be explained by an activation of the NF-κB-pathway. These results support the hypothesis that vascular inflammation may be aggravated by oxLDL induced DC-activation.

Zusammenfassung Zur Untersuchung der klinischen Bedeutung von Biomarkern während intensivmedizinischer Betreuung wurden Interleukin-6 (IL-6), Procalcitonin (PCT) and C-reaktives Protein (CRP) bei 38 kritisch kranken Patienten während des ersten Fieberanstieges über 38,3°C gemessen. Bereits zum Zeitpunkt des Fieberanstieges konnten signifikant höhere IL-6-Konzentrationen bei Patienten verzeichnet werden, welche die Erkrankung nicht überlebten. Insbesondere IL-6-Werte >1000 pg/mL waren mit sehr hoher Mortalität assoziiert. Sensitivität, Spezifität, positive and negative Vorhersagewerte zur Beurteilung der Mortalität waren für IL-6 höher als für PCT und CRP. ROC-Analysen zeigten die höchste prognostische Wertigkeit für IL-6-Konzentrationen im Vergleich zu PCT und CRP-Konzentrationen. Diese Daten unterstützen die Hypothese, dass eine deutlich erhöhte IL-6-Konzentration bereits zum Zeitpunkt des ersten Fieberanstieges ein guter Frühmarker zur Erkennung von Hochrisikopatienten mit hoher Mortalität ist.

ZusammenfassungSchwere systemische Entzündungen wie die Sepsis und der septische Schock stellen die häufigste Todesursache auf der Intensivstation dar. Trotz der Entwicklung der modernen Intensivmedizin steigt die Inzidenz weiter an und die Mortalität liegt seit vielen Jahren bei 30–60%. Ursache hierfür ist unter anderem das Fehlen diagnostischer Marker der Sepsis zur Früherkennung, Risikobeurteilung und Verlaufsbeobachtung. Aus diesem Grund wurden in den vergangenen Jahren eine Vielzahl von Biomarkern untersucht, von denen allerdings nur einige Einzug in die klinische Routine gehalten haben. Zu den viel versprechenden Markern gehören Procalcitonin (PCT), einige Zytokine wie das Interleukin-6 und metabolische Marker. In der vorliegenden Übersicht sollen klinische Bedeutung zur Früherkennung und Therapiesteuerung von bereits etablierten und neueren Markern unter Berücksichtigung der Pathophysiologie dargestellt werden.

It is now generally accepted that, in addition to hypercholesterolemia, pro-inflammatory and procoagulatory factors play a major role in atherogenesis. Risk factors such as smoking, hypertension, diabetes and renal diseases alter lipoprotein profile and composition thus rendering them susceptible to modification. Modified lipoproteins induce local inflammation possibly due to activation of nuclear factor (NF-)kappaB and subsequent expression of adhesion molecules, release of pro-inflammatory cytokines, growth factors and mitogens, which are mediators for cell growth, proliferation and lipid deposition. Furthermore, activation of collagenases and proteases in combination with prothrombotic processes attenuate clot formation, plaque rupture and occlusion of vessels. Clinical as well as experimental studies suggest that elevated levels of pro-inflammatory markers may have a diagnostic potential. Thus, a therapeutic approach which modulates circulating cholesterol levels and improves pro-inflammatory and procoagulatory situation may prove beneficial as adjuvant therapy in atherosclerotic disease.

Acute occlusion of a peripheral artery is a serious complication in peripheral arterial disease (PAD). Traditionally open surgical intervention in combination with antithrombotic therapy is the choice for treatment but the beneficial effects of both strategies are limited often by the patient's situation and therapeutic side effects. Heparin-mediated extracorporeal low-density lipoprotein precipitation (H.E.L.P.) apheresis efficiently removes circulating atherogenic lipoproteins, fibrinogen and C-reactive proteins as well as various proinflammatory and procoagulatory factors. We first report H.E.L.P. apheresis treating a PAD patient suffering from repeated postoperative femoropopliteal bypass graft occlusion, first, intensively, followed by weekly intervals. Limb amputation was avoided and the patient is doing well now. Angiography revealed bypass graft remained patent half a year after operation. This case report might help to design the regime for preventing postoperative bypass occlusion in patients with hyperlipidemia or hyperfibrinogenemia.

Cultured primary human keratinocytes were screened for their expression of various members of the toll-like receptor (TLR) family. Keratinocytes were found to constitutively express TLR1, TLR2, TLR3, TLR5, and TLR9 but not TLR4, TLR6, TLR7, TLR8, or TLR10 as shown by polymerase chain reaction analysis. The expression of the crucial receptor for signaling of staphylococcal compounds TLR2 was also confirmed by immunohistochemistry, in contrast to TLR4, which showed a negative staining pattern. Next, we analyzed the activation of the proinflammatory nuclear transcription factor kappaB by Staphylococcus aureus strain 8325-4. Using nuclear extract gel shifts, RelA staining, and luciferase reporter transfection plasmids we found a clear induction of nuclear factor kappaB translocation by the bacteria. This translocation induced the transcription of nuclear factor kappaB controlled genes such as inducible nitric oxide synthetase, COX2, and interleukin-8. Transcription of these genes was followed by production of increased amounts of interleukin-8 protein and NO. Inhibition experiments using monoclonal antibodies and the specific platelet activating factor receptor inhibitor CV3988 showed that nuclear factor kappaB activation by S. aureus was TLR2 but not TLR4 or platelet activating factor receptor dependent. In line, the purified staphylococcal cell wall components lipoteichoic acid and peptidoglycan, known to signal through TLR2, also showed nuclear factor kappaB translocation in human keratinocytes, indicating a crucial role of the staphylococcal cell wall in the innate immune stimulation of human keratinocytes. These results help to explain the complex activation of human keratinocytes by S. aureus and its cell wall components in various inflammatory disorders of the skin.

Bei familiarer Hypercholesterinamie erfordert die koronare Herzkrankheit im Kindesalter sowohl eine medikamentose Therapie als auch den Einsatz der LDL-Apherese. Im vorgestellten Fall konnte bei einem 10-jahrigen Patienten ein Verschluss des Ramus descendens anterior der linken Koronararterie nachgewiesen werden. Wegweisend war die pathologische Ergometrie. Mit Hilfe der LDL-Apherese wird die maximal erreichbare Senkung der Lipidparameter und des Fibrinogens bei Senkung der Plasmaviskositat angestrebt. Erstaunlicher Weise wird diese Behandlung auch von Kindern gut toleriert, die notigen Gefaszugange sind ausreichend, Shunt-Operationen nicht unbedingt erforderlich. Die Effizienz dieses Verfahrens zeigte sich an den beeindruckenden Veranderungen der Hauteffloreszenzen. Die weiteren angiographischen Kontrollen und der klinische Verlauf werden Aufschluss geben uber den Nutzen der Behandlungsstrategie der maximalen Lipidtherapie und die erhoffte Prognoseverbesserung.

Serum cholesterol procalcitonin (PCT) and C-reactive protein (CRP) levels were measured consecutively in 76 critically ill patients at admission to the intensive care unit. The presence of infection was defined according to the CDC (Centers for Disease Control and Prevention) criteria; in-house mortality, underlying diseases, and severity of sepsis were monitored. Nonsurvivors had significantly lower cholesterol levels compared with survivors (69 mg/dL [range, 37-88 mg/dL] vs. 96 mg/dL [range, 71-132 mg/dL], P = 0.006) whereas no significant differences were noted for serum PCT and CRP levels. In a cohort of patients with cholesterol levels of 50 mg/dL or less, 82% did not survive as compared with patients with cholesterol levels of 100 mg/dL or greater (mortality, 21%). In a control group without infection, no difference of cholesterol, PCT, or CRP was found between survivors and nonsurvivors. Our data show that low cholesterol levels in patients with infectious disease have a prognostic value and may be useful markers to identify high-risk patients already at admission.

In Deutschland erkranken etwa 500–800.000 Patienten wahrend ihres Krankenhausaufenthaltes an Infektionen. Eine gefurchtete Komplikation stellt die Sepsis mit einer sehr hohen Mortalitat von 50% und etwa 75.000 Todesfallen in Deutschland dar. Durch eine kaskadenartigen Aktivierung der verschiedenen Immunprozesse kommt es dabei zur Entgleisung der Immunreaktion bis zum septischen Schock. Da dieser Prozess um so schlechter therapeutisch zu beeinflussen ist je weiter die Immunreaktion fortgeschritten ist, wurde nach diagnostischen Parametern gesucht, die bereits in der fruhen Entwicklung des Immunprozesses nachweisbar sind. Zytokine haben eine zentrale Bedeutung bei der Pathogenese inflammatorischer Erkrankungen. Zunachst wirken Zytokine lokal mit dem Ziel der Infektabwehr. Eine uberschiesende Freisetzung fuhrt zu einer systemischen Reaktion des Organismus mit nachweisbaren Plasmaspiegeln der Zytokine. Neben der zentralen Rolle der Zytokine im pathophysiologischen Geschehen konnte die diagnostische Wertigkeit zirkulierender Zytokinspiegel sowohl als Fruhmarker als auch Marker der Schwere der Erkrankung in vielen Studien gezeigt werden. Besonders das Auftreten der Zytokine vor allen anderen klinischen und klinisch-chemischen Markern erlaubt die fruhe Erkennung infektioser oder inflammatorischer Komplikationen bei Hochrisikopatienten oder Patienten auf Intensivstationen. Experimentelle Studien zeigen, dass TNF als eines der ersten Zytokine im Plasma nachweisbar ist. Allerdings ist die Halbwertszeit von TNF sehr kurz und unter klinischen Bedingungen oft nicht mehr nachweisbar. Proinflammatorische Zytokine wie IL-6 und IL-8 sowie losliche Zytokinerezeptoren wie TNF-R oder IL-2R verbleiben langer in der Zirkulation. Mit Verfugbarkeit von automatisierten Messmethoden konnen Zytokinspiegel innerhalb weniger Stunden gemessen werden. Daher konnen sie in klinisch-diagnostische und auch therapeutische Entscheidungen mit einbezogen werden. Die mogliche klinische Bedeutung der Bestimmung von Zytokinplasmaspiegeln im Rahmen inflammatorischer Erkrankungen soll im Folgenden dargestellt werden.

Hyperlipoproteinemia can aggravate glomerulosclerosis and chronic tubulointerstitial (ti) damage in kidneys without primary immunologic disease. We evaluated whether the effect of hyperlipidemia on progression of renal damage differed between kidneys without preexisting glomerular disease and kidneys with mesangioproliferative glomerulonephritis and whether the renal actions of hyperlipidemia were dependent on oxidant-antioxidant balance. Hyperlipidemia was induced by high-fat and high-cholesterol diet in uninephrectomized rats. In rats without glomerulonephritis, hyperlipidemia led to a rise in glomerular and ti generation of reactive oxygen species (ROS). Oxygen radicals were mainly generated by enhanced xanthine oxidoreductase (XO), which rose with protein concentration and activity during hyperlipidemia; concurrently, glomerulosclerosis and chronic ti injury were noticed during hyperlipidemia [ti damage (% of total tubulointerstitium (TI) after 150 days): normolipidemia 0.1 ± 0% vs. hyperlipidemia 3.4 ± 0.9%; P < 0.05]. In mesangioproliferative Thy-1 nephritis, ti injury was significantly accelerated by hyperlipidemia (ti damage after 150 days: normolipidemic Thy-1 nephritis 2.5 ± 0.6% vs. hyperlipidemic Thy-1 nephritis 12.5 ± 3.1%; P < 0.05). Antioxidant enzyme activities decreased and XO activity rose markedly in the TI (XO activity in TI after 150 days: normolipidemic Thy-1 nephritis 2.2 ± 0.5 vs. hyperlipidemic Thy-1 nephritis 4.5 ± 0.7 cpm/μg protein; P < 0.05). In hyperlipidemic Thy-1 nephritis rats, which had a higher urinary protein excretion than normolipidemic rats, hypochlorite-modified proteins, an indirect measure for enhanced myeloperoxidase activity, were detected in renal tissue and in urine, respectively. During hyperlipidemia, chronic damage increased in renal TI. Enhanced generation of ROS, rise in oxidant enzyme activity, and generation of hypochlorite-modified proteins in renal tissue and urine were noticed. These data suggest that oxidant stress contributed to the deleterious effects of hyperlipidemia on the renal TI.

Sepsis with multiple organ failure is frequently associated with a substantial decrease of cholesterol levels. This decrease of cholesterol is strongly associated with mortality suggesting a direct relation between inflammatory conditions and altered cholesterol homeostasis. The host response during sepsis is mediated by cytokines and growth factors, which are capable of influencing lipid metabolism. Conversely lipoproteins are also capable of modulating cytokine production during the inflammatory response. Therefore the decrease in circulating cholesterol levels seems to play a crucial role in the pathophysiology of sepsis. In this review the interaction between cytokines and lipid metabolism and its clinical consequences will be discussed.

Recent studies suggest that release of cytokines during inflammatory states such as septic shock leads to hypocholesterolemia. To examine whether tumor necrosis factor alpha (TNF), which is the major cytokine in inflammatory disease, causes hypocholesterolemia, we measured serum levels of total (bioactive and receptor-bound) TNF, cholesterol, Apo B, and Apo A1 in seven patients with septic shock over a period of 8 days. Since elevated serum TNF levels are accompanied by the release of soluble TNF receptors, levels of TNF receptors p55 and p75 were also measured. Patients with septic shock had significantly higher serum TNF and TNF receptor levels compared with healthy controls. Increased cytokine levels were accompanied by a significant decline in total serum cholesterol apolipoprotein A1 and B. In vitro studies with cultured human skin fibroblasts, human umbilical vein endothelial cells, and HepG2 hepatoma cells showed that TNF increased the degradation of 125I-labeled low-density lipoprotein in all the cell lines tested. Recombinant soluble TNF receptors inhibited the TNF-induced stimulation of low-density lipoprotein receptor in a concentration-dependent manner. However, the calculated ratio of TNF receptors to total TNF measured in serum of these patients was not able to counteract the stimulatory effect of TNF, possibly due to the higher molar excess of TNF receptors required to achieve this effect in vitro. Our data strengthen the hypothesis that serum values of total TNF determine the extent of hypocholesterolemia during sepsis and septic shock despite the presence of a high concentration of TNF receptors. Studies with recombinant TNF also confirm the role of TNF in hypocholesterolemia in inflammation.

To investigate the prognostic value of interleukin 6 (IL-6), procalcitonin (PCT), and C-reactive protein (CRP) in critically ill patients during the first increase of fever, serum levels were measured in 38 patients admitted to intensive care unit of the Department of Medicine, Klinikum Grosshadern, University of Munich, immediately after increase of body temperature more than 38.3 degrees C. Ten healthy controls were also included for comparison. The onset of fever was accompanied by elevated circulating levels of all the 3 markers in comparison with healthy controls. However, only IL-6 levels were significantly higher (P < 0.05) in nonsurvivors (n = 21) compared with survivors. Sensitivity, specificity, positive, and negative predictive values calculated from median levels was higher for IL-6 compared with PCT and CRP. Areas under receiver characteristic operating curves revealed the highest area under the curve for IL-6 in contrast to PCT and CRP. These data suggest that IL-6 rather than PCT or CRP may be an early predictor of mortality in patients with onset of fever and identify patients, who need intensive monitoring to initiate appropriate therapy at an early stage.

C-reactive protein (CRP) currently constitutes one of the most widely used parameters for the diagnosis of infections and inflammatory processes, due to simple methods and low costs. However, in recent years, other parameters, such as interleukin 6 (IL-6) and procalcitonin (PCT), have gained in importance. Although these parameters are presently not established everywhere in clinical routine, they provide significant advantages in the diagnosis and monitoring of inflammatory diseases. For instance, in intensive care, the increase in IL-6 levels may indicate inflammatory complications 24 to 48 h prior to the increase in circulating CRP levels. In contrast to CRP, PCT shows a higher specifity for bacterial infections, which facilitates the diagnosis of bacterial infections and sepsis. PCT measurements further allow assessment of therapeutic success and indicate necessary changes in antibiotic therapy. These points raise the question whether CRP measurements should at least in part be replaced by PCT and/or IL-6. Thus, this review seeks to examine the value of CRP in relation to PCT and IL-6 for the diagnosis of bacterial infections, in therapeutic monitoring, and regarding prognosis in critical care patients.

Lipoproteins labeled with 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI) are widely used to visualize LDL-and scavenger-receptor activity in cultured cells. The purpose of this study was to evaluate a new single-step fluorometric assay with high sensitivity for the quantitative determination of the LDL- or scavenger-receptor activity in adherent and non-adherent cells. We used an aqueous solution of 1 g/l SDS dissolved in 0.1 M NaOH to lyse the cells after incubation with DiI-LDL or DiI-acetylated LDL. This allows for the first time the determination of fluorescence intensity and cell protein in the same sample without prior lipid extraction of the fluorochrome. Fluorescence of the cell lysates was determined in microtiter plates with excitation-emission set at 520 and 580 nm, respectively. This rapid method demonstrates high specificity for determining the LDL- and scavenger-receptor activity in cultured cells (e.g., human skin fibroblasts from patients with and without familial hypercholesterolemia; human U-937 monocyte and murine P388 D1 macrophage cell lines). The validity of our fluorescence assay is demonstrated by comparison of cellular uptake and metabolism of lipoproteins labeled with both, DiI and 125iodine. The rapidity and accuracy of this assay allows its routine application for studying receptor-mediated lipoprotein uptake in various cell types.

Eine Vielzahl von experimentellen und klinischen Studien zeigt, daβ Zytokine eine zentrale Rolle bei der Entstehung der Sepsis spielen. Im Rahmen von Entzündungsreaktionen werden Zytokine freigesetzt, die als Signaltransmitter die verschie-denen Komponenten des Immunsystems zu einer zielgerichte-ten Immunantwort koordinieren. Obwohl an der komplexen Entstehung der Sepsis viele Zytokine beteiligt sind, können im Serum septischer Patienten nur wenige Zytokine wie Interleukin-1 (IL-1), Interleukin-6 (IL-6) und Tumor-Nekrose-Faktor-alpha (TNF) sowie neuerdings auch Interleukin-8 (ΓL-8) und Interleukin-10 (IL-10) verläβlich bestimmt werden. Dariiber hinaus wurden für einige Zytokinantagonisten – wie lösliche TNF-Rezeptoren und der IL-1-Rezeptor-Antagonist (IL-1RA) – ebenfalls meβbare Serumspiegel gefunden. Die höchste prognostische Aussagekraft in der Beurteilung der Sepsis ergibt sich für IL-6-Serumspiegel, die dariiber hinaus mit dem Schweregrad der Organdysfunktion korrelieren. Die klinische Wertigkeit von TNF-Messungen im Serum septischer Patienten ist eingeschränkt, da die TNF-Serumspiegel relativ groβe Variationen aufweisen. Neuere Befunde zeigen aber, daβ lösliche TNF-Rezeptoren auf Grund ihrer längeren biologischen Halbwertzeit besser zur Prognose-Beurteilung (Letalitäts-Risi-ko) geeignet sind. Sowohl für die TNF-Rezeptoren als auch für einige andere Zytokine stehen heute automatisierte Testsyste-me zur Verfügung, die eine Messung innerhalb weniger Stun-den ermöglichen und somit klinisch anwendbar sind.

The role of procalcitonin (PCT) plasma levels as a diagnostic tool for intensive care patients has been intensively investigated during the past years. In particular for recognition of bacterial infections, PCT levels have been shown to be superior to other clinical and biochemical markers. Furthermore, some very recent studies show that in patients with lower respiratory tract infections PCT guided antibiotic therapy reduces antibiotic use and thereby may also reduce duration of stay of patients in hospital and thus cut hospitalisation costs. However, various studies indicate that the value of PCT as a prognostic marker is limited because of false positive or negative values. Despite these limitations PCT plasma levels are currently measured in intensive care units. The present study summarises the possible clinical uses of this laboratory marker as a diagnostic tool for the assessment of critically ill patients.

Clinical observations show that severe illness often leads to hypocholesterolemia. To verify this finding and to define the relationship between serum cholesterol and a patient's prognosis, a study was conducted in two large hospital populations. Of 24,000 and 61,463 adult patients (populations I and II) an average of 3.8% and 3.6% died in hospital, respectively. The mean serum cholesterol levels of patients who died was significantly lower than that of those who survived (163.6 mg/dl versus 217.8 mg/dl; P0.0001). The average cholesterol of surviving patients was similar to that of 6,543 healthy controls. During hospitalization serum cholesterol levels ofor = 100 mg/dl were encountered in 1.2% and 3.6% of patients of populations I and II, respectively. The mortality of these hypocholesterolemic patients was about tenfold higher than average and showed a strong, inverse, linear relationship with serum cholesterol concentrations. Patients whose serum cholesterol level dropped to less than 45 mg/dl did not survive. These data show that in severely ill patients serum cholesterol may decline to very low concentrations, and the prognosis is reflected by the degree of hypocholesterolemia, which thus may serve as a clinically useful prognostic parameter.

Hyperlipidemia and lipoprotein abnormalities are often encountered in patients with nephrotic syndrome or chronic renal disease and also in those undergoing haemodialysis and with renal transplant. Even though the significance of lipid deposition in renal tissue and the role of lipoproteins in the pathogenesis of renal disease in man is unclear, experimental and clinical data indicate a possible damaging effect of a disturbed lipid metabolism on the kidney. In humans, glomerular lipid deposition is observed in genetic diseases such as Fabry's disease, lecithin:cholesterol acyltransferase activity (LCAT) deficiency and arteriohepatic dysplasia, and in diseases with acquired disturbance of lipid metabolism such as nephrotic syndrome and cholestatic liver disease. Studies on animals with lupus nephritis, aminonucleoside nephrosis, reduced renal mass, diabetes mellitus or systemic hypertension have shown that cholesterol can increase the incidence of glomerulosclerosis. As most of these studies have been performed in the rat, which has a different lipoprotein profile to that of man, these results should be carefully interpreted with regard to their relevance for humans. In vitro cell culture studies on human glomerular cells have given some preliminary insights into the cellular mechanisms of lipid induced glomerular damage. Apo E-containing lipoproteins, which are pathologically elevated in many renal diseases, are avidly taken up by human mesangial cells. These cells seem to play a central role in the initiation of glomerulosclerosis by inducing proliferation and production of excess extracellular matrix. Lipoproteins are able to stimulate DNA synthesis in these cells, and increase the synthesis of mitogens and extracellular matrix protein. The pathogenic role of oxidized lipoproteins has not yet been defined. Human mesangial cells do not seem to take up these modified lipoproteins. However, macrophages infiltrate glomeruli and may constitute the stimulus for the generation of minimally modified lipoproteins and their cellular uptake. The data from animal experiments suggest that treatment that corrects hyperlipidemia may have an ameliorative effect on renal function. Thus, there are strong indications that lipoproteins may play a critical role in mediating the development of glomerulosclerosis.

Renal diseases are often associated with hyperlipoproteinemia and dyslipoproteinemia. Total serum cholesterol and triglycerides are increased in nephrotic syndrome regardless of etiology. Approximately 40 to 50% of patients with renal insufficiency requiring hemodialysis show hypertriglyceridemia and dyslipoproteinemia. During chronic hemodialysis, high doses of unfractionated heparin deplete post-heparin lipolytic activity and aggravate dyslipoproteinemia. Hypercholestrolemia and hyperlipoproteinemia are often encountered in patients taking glucocorticoids and cyclosporin A after renal transplantation. Observations in experimental animals and in patients with genetically determined and acquired hyperlipidemias suggest that lipids can damage the kidney and lead to glomerulosclerosis. In vitro cell-culture studies of human glomerular cells have been useful in providing information on lipid-induced glomerular damage. Thus, there are strong indications that lipoproteins may play a critical role in the development of mesangial cell damage and progressive renal disease. Therapeutic measures that reduce and correct dyslipoproteinemia in renal disease may have long-term beneficial effects on the amelioration of renal disease.

The concentration of lipoprotein (a) in plasma is under stringent genetic control and raised concentrations are strongly linked to coronary heart disease, in particular when low density lipoprotein levels are also increased. We serially monitored serum Lp(a) in 14 hypercholesterolemic patients who were treated with Pravastatin over a period of two years. C-reactive protein levels were also quantified to exclude a possible ‘acute-phase’ response as a reason for a sudden increase in the Lp(a) concentration. No significant changes were seen in mean Lp(a) levels after 24 months of therapy. Considerable fluctuations of serum Lp(a) levels occurred during the course of treatment. These were in some cases associated with raised C-reactive protein concentrations and might therefore be attributable to an ‘acute-phase’ response. We conclude that the HMG-CoA reductase inhibitor Pravastatin has no long-lasting effects on Lp(a) levels in hypercholesterolemic patients suffering from coronary heart disease.

Statins, which are effective lipid-lowering drugs, also possess anti-inflammatory potential. However, circulating lipoproteins may also play a protective role during acute inflammatory diseases because of their ability to bind bacterial toxins. Low cholesterol levels have been reported in inflammatory conditions, and plasma cholesterol concentrations inversely correlate with severity and clinical outcome in septic patients. It is thus paradoxical that statins, which drastically reduce circulating cholesterol levels, should be beneficial in patients with inflammatory disease who are already hypocholesterolemic. We investigated the effect of simvastatin on LPS-induced nuclear factor kappaB (NF-kappaB) activation, TNF release, and mortality in guinea pigs, an animal model with a lipoprotein profile and pattern similar to humans. In the present study, simvastatin reduced circulating total and low-density lipoprotein cholesterol levels by 68% and 76%, respectively, and LPS-induced mortality from 73% to 20%. This reduction was accompanied by a significant reduction of NF-kappaB activation in the liver tissue, splenocytes, and plasma TNF levels by about 80%, 50%, and 77%, respectively. Our data suggest that simvastatin, despite lowering circulating low-density lipoprotein cholesterol, decreased LPS toxicity by reduction of NF-kappaB activation and subsequent release of TNF by modulating 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and therefore deserves consideration as a possible adjuvant therapy in acute inflammatory disease.

Serum levels of interleukin 6 (IL-6), procalcitonin (PCT), and C-reactive protein (CRP) were measured in 38 critically ill patients immediately after an increase in body temperature above 38.3°C. Ten healthy controls were also included for comparison. The onset of fever was accompanied by elevated circulating levels of all the 3 markers in comparison to healthy control subjects. However, only IL-6 levels were significantly higher (p

Background/Aims: Pravastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, has been shown to inhibit growth and to induce apoptosis in human hepatocellular carcinoma (HCC) cells. However, the potential benefit of pravastatin in HCC patients has still not been characterized, which prompted us to test the efficacy of pravastatin in patients with advanced HCC. Methods: We investigated prospectively a cohort of 183 HCC patients who had been selected for palliative treatment by transarterial chemoembolization (TACE). Fifty-two patients received TACE combined with pravastatin (20–40 mg/day) and 131 patients received chemoembolization alone. Six independent predictors of survival according to the Vienna survival model for HCC were equally distributed in both groups. Results: During the observation period of up to 5 years, 31 (23.7%) out of 131 patients treated by TACE alone and 19 (36.5%) out of 52 patients treated by TACE and pravastatin survived. Median survival was significantly longer in HCC patients treated by TACE and pravastatin (20.9 months, 95% CI 15.5–26.3, p = 0.003) than in HCC patients treated by TACE alone (12.0 months, 95% CI 10.3–13.7). Conclusion: Combined treatment of chemoembolization and pravastatin improves survival of patients with advanced HCC in comparison to patients receiving chemoembolization alone.

A 7-year-old girl with homozygous familial hypercholesterolaemia and plasma low-density lipoprotein (LDL)-cholesterol levels of 820 mg/dl (21.2 mmol/l) and progressive xanthomata was treated with heparin extracorporeal low-density lipoprotein precipitation (HELP) to lower her plasma LDL. On weekly HELP treatment she maintained her pre-HELP treatment LDL-cholesterol levels at 409 mg/dl (10.6 mmol/l). The long-term HELP treatment was well tolerated and led to regression of her xanthomata. Subsequently, lovastatin [Mevacor; Merck Sharp & Dohme, Westpoint, Pa., USA (20 mg/day)] was added to the regimen, causing a further 20% decrease in her pre-HELP treatment plasma LDL-cholesterol levels. Lovastatin alone did not sufficiently lower her plasma LDL and could not replace the weekly HELP therapy. Our data show that lovastatin is an effective adjunctive therapy for lowering plasma LDL-cholesterol in a homozygous patient, once plasma LDL levels have already been lowered by regular HELP treatment.

Receptor mediated uptake of apo B and apo E rich lipoproteins by glomerular epithelial cells. Various pathological disorders are accompanied by the deposition of lipids into glomerular cells. To gain insight into these disorders, it is essential to know if glomerular cells possess lipoprotein receptors. We therefore characterized the activity of lipoprotein receptors in cultured epithelial cells of the human glomerulus. Podocytes were chosen as they are directly exposed to lipoproteins in pathological states like in glomerular proteinuria (such as, nephrotic syndrome). Isolated human glomeruli (purity >95%) were incubated in bufifered RPMI 1640 medium supplemented with 20% heat-inactivated fetal bovine serum at 37°C and 5% C0 2 . Outgrowing cells were vimentin and keratin positive. Monolayer cultures of human glomerular epithelial cells upon incubation in lipoprotein deficient serum for 48 hours expressed a receptor-dependent uptake of lipoproteins. These cells showed about 10% of the maximal capacity for LDL uptake as compared to fibroblasts; however, the K m values for binding, internalization and degradation were similar in the cultures of glomerular epithelial cells and fibroblasts. The K m values for degradation of LDL, chylomicron remnants, β-VLDL from cholesterol-fed rabbits and VLDL from familial LCAT-deficiency patients were 14.2, 4.9, 2.9, 4.5 µg protein/ml medium, respectively, for glomerular epithelial cells. The avid uptake of 125 I-labeled apo E-containing lipoproteins was further substantiated by their poor displacement by a 25-fold excess of unlabeled LDL and their ability to down regulate the apo B,E receptor activity. LDL as well as βVLDL were able to suppress the incorporation of 14 C acetate into sterols and to stimulate 3 H-cholesterylester formation. These experiments show that cultured glomerular epithelial cells express lipoprotein receptor activity. Plasma concentrations of apo E-containing lipoproteins are increased in certain renal diseases (such as, nephrotic syndrome); these lipoproteins could be rapidly removed by glomerular epithelial cells and lead to lipid deposition in glomeruli.

Human Lp[a] can be fractionated into two species with different affinities for lysine-Sepharose. Forty to 81% of the total Lp[a] in the density fraction 1.055-1.15 g/ml from five individuals was retained by this affinity column. The remaining unretained Lp[a] species with no apparently functional lysine binding site was similar to the retained species in its electrophoretic mobility, lipid, protein, and apolipoprotein composition, and the heterogeneity was not related to apo[a] size polymorphism. Interaction of the two species with the low density lipoprotein (LDL) receptor was studied in human fibroblasts. Using gold-labeled lipoproteins and an immunochemical procedure, both Lp[a] species could be located in clusters on the cell surface, but the extent of labeling was far lower than that seen with LDL. Both Lp[a] variants were less effective than LDL in 1) down-regulation of LDL-receptor activity; 2) suppression of cellular sterol synthesis; and 3) stimulation of cholesteryl ester formation in human fibroblasts. Although degradation of both species of Lp[a] by the perfused rat liver was stimulated after estrogen induction of hepatic LDL-receptor activity, the stimulation amounted to only a quarter of that seen with LDL. The heterogeneity of Lp[a] with respect to the ability to bind epsilon-aminocarboxylic acid will need to be considered in studying the physiological role of this lipoprotein. Both Lp[a] species exhibited a similar interaction with the LDL-receptor in vitro, and confirmed previous investigations that Lp[a] is only a poor ligand for the LDL-receptor.

Preeclampsia is a pregnancy-related hypertensive disease resulting in substantial maternal and neonatal morbidity and mortality. Until today there is no satisfactory treatment to stop disease progression except immediate delivery of the fetus. Heparin-mediated extracorporeal low density lipoprotein (LDL) precipitation (H.E.L.P.) apheresis removes simultaneously circulating LDL, lipoprotein(a) [Lp(a)], fibrinogen, C-reactive protein (CRP) and various proinflammatory and procoagulatory factors. This study was to test the feasibility of H.E.L.P. apheresis in preeclamptic patients and its potential effects on blood and placental markers of preeclampsia. We applied H.E.L.P. apheresis to nine preeclamptic patients and it was well tolerated. Their gestational ages could be continued by 17.7 (3-49) more days. Eight of the nine neonates did well during their neonatal stage. One infant died of late-onset sepsis. H.E.L.P. apheresis reduced significantly circulating levels of triglycerides, total and LDL-cholesterol, Lp(a), fibrinogen, hs-CRP, TNFalpha, sVCAM-1, E-selectin, lipopolysaccharide binding protein (LBP), homocysteine and plasma viscosity. We conclude that H.E.L.P. apheresis reduced maternal circulating levels of proinflammatory and coagulatory markers and plasma viscosity without overt maternal or neonatal clinical side effects.

It is now generally accepted that, in addition to hypercholesterolemia, pro-inflammatory and procoagulatory factors play a major role in atherogenesis. Risk factors such as smoking, hypertension, diabetes and renal diseases alter lipoprotein profile and composition thus rendering them susceptible to modification. Modified lipoproteins induce local inflammation possibly due to activation of nuclear factor (NF-)kappaB and subsequent expression of adhesion molecules, release of pro-inflammatory cytokines, growth factors and mitogens, which are mediators for cell growth, proliferation and lipid deposition. Furthermore, activation of collagenases and proteases in combination with prothrombotic processes attenuate clot formation, plaque rupture and occlusion of vessels. Clinical as well as experimental studies suggest that elevated levels of pro-inflammatory markers may have a diagnostic potential. Thus, a therapeutic approach which modulates circulating cholesterol levels and improves pro-inflammatory and procoagulatory situation may prove beneficial as adjuvant therapy in atherosclerotic disease.

Various radical measures for the treatment of severe hypercholesterolemia such as partial ileal bypass, portocaval shunt, liver transplantation and plasma exchange have been tested in patients in whom drug and diet failed or were insufficient. Although effective, most of these treatments have severe side effects and are not routinely used. For hypercholesterolemic patients LDL-apheresis has proved to be the most promising and safe way as an adjuvant therapy. Several LDL-apheresis procedures with a varying degree of selectivity and efficiency have subsequently been developed. One of them is the H.E.L.P. system which was introduced in 1984 and has now been widely used. Besides the marked reduction of LDL particles by all techniques it has become apparent that only the H.E.L.P. system results in an equally significant change in hemostaseology, hemorheology and vasomotion because of its simultaneously removal of LDL, Lp(a), fibrinogen and CRP. This contribution reviews the application of the H.E.L.P. system as a valuable therapeutic tool for the treatment of various atherothrombotic and microcirculatory disorders such as prevention of early graft occlusion after coronary artery bypass grafting, treatment of peripheral vascular disease, stroke and preeclampsia.

In addition to hypercholesterolemia, proinflammatory and prothrombotic markers have been suggested to play an important role in atherogenesis. We examined whether heparin-mediated extracorporeal low-density lipoprotein precipitation (HELP) therapy modulates the circulating levels of proinflammatory and prothrombotic markers. Twenty-two coronary heart disease (CHD) patients undergoing regular HELP-apheresis (18 males, 4 females, mean age 57.3 +/- 10.9 years) were enrolled in this study. A single HELP therapy treatment significantly decreased the circulating levels of high sensitivity C-reactive protein (hs-CRP), soluble vascular adhesion molecule-1 (sVCAM-1), soluble E-selectin, lipopolysaccharide binding protein (LBP), endothelin-1 (ET-1), and monocyte chemoattractant protein-1 (MCP-1) on average by 67, 37, 24, 27, 24, and 15%, respectively. Prothrombotic factors including fibrinogen, tissue factor (TF), soluble CD40 ligand (sCD40L), and homocysteine were decreased by 66, 27, 16, and 22%, respectively. In accordance with previous studies HELP therapy reduced total cholesterol, low density lipoprotein (LDL) cholesterol, and Lp(a) mass by 50, 61, and 62%, respectively. Our data suggest that simultaneous reduction of proinflammatory and prothrombotic factors together with atherogenic lipoproteins by HELP-apheresis may contribute to improvement of endothelial dysfunction and thereby inhibit progression of atherosclerotic lesions and stabilize the existing plaque.

Interest has recently focused on the use of neurohormonal markers such as atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) as indices of left ventricular systolic dysfunction and prognosis in heart failure. Also, peptides belonging to the interleukin-6 (IL-6) family have been shown to induce ANP and BNP secretion. We hypothesized that BNP and ANP spillover in the peripheral circulation reflects left ventricular dysfunction and IL-6 production in septic shock.Retrospective, clinical study in the medical intensive care unit of a university hospital.17 patients with septic shock and 19 control subjects.Collection of clinical and demographic data in relation to ANP, BNP, IL-6, and soluble TNF receptors (sTNF-R-p55, sTNF-R-p75) in plasma over a period of 4 days.In septic shock we found a significant increase in ANP (82.7+/-9.9 vs. 14.9+/-1.2 pg/ml) and BNP (12.4+/-3.6 vs. 5.5+/-0.7 pg/ml). Plasma ANP peaked together with IL-6. Peaks of ANP and IL-6 were significantly correlated (r=0.73; p0.01). BNP was inversely correlated to cardiac index (r=-0.56; p0.05).ANP and BNP increase significantly in patients with septic shock. BNP reflects left ventricular dysfunction. ANP is related to IL-6 production rather than to cardiovascular dysfunction.

Hypocholesterolemia, which often accompanies infectious diseases has been suggested to serve as a prognostic marker in hospitalized patients. Even though patients with chemotherapy-induced leukopenia are at high risk of infection and mortality, only limited information is available on serum cholesterol levels in these patients. We therefore measured serum cholesterol levels in 17 patients with hematological malignancies during chemotherapy-induced neutropenia and correlated it with clinical outcome. Patients with fever (>38.5 °C) showed a significant decrease in serum cholesterol levels within 24 hours. Eight days after onset of the fever non-survivors had significantly lower serum cholesterol levels (median 2.09 mmol/l, range 0.49‐2.79, n=6) compared to survivors (median 3.23 mmol/l, range 1.68‐4.86, n=11). Cholesterol levels in survivors returned to baseline levels at the time of discharge from the hospital. At the onset of fever, serum levels of inflammatory cytokines interleukin-6, tumor necrosis factor (TNF) and soluble TNF receptors p55 and p75 were elevated in all patients, but only TNF and TNF receptor p75 levels were significantly different in survivors and non-survivors. Our data suggest that a decrease in serum cholesterol levels is a prognostic marker in neutropenic patients with fever. Release of inflammatory cytokines may in part be responsible for hypocholesterolemia in these patients. Clin Chem Lab Med 2002; 40(3):304‐307

Serum levels of Interleukin-6 (IL-6), a proinflammatory cytokine, are increased in early stages of inflammatory diseases such as infection and sepsis. Assay systems which permit its measurement within a few hours and as a single measurement have not been reported so far. We therefore evaluated a now commercially available automated method for IL-6 measurement on the Cobas Core®immunological analyzer (Roche Diagnostic Systems) which enables single IL-6 measurement within about 1 hour. The automated assay correlates well with an established, manual microtiter plate assay (Biosource GmbH) which uses the same antibodies and reagents (r=0.98). Accuracy of the automated method was established by adding known amounts of IL-6 international reference preparation. Recovery of the international standard was in the range of 92–104 %. The automated assay had a precision of singletons below 6% and was linear up to 2800 pg/ml. This automated assay provides a suitable, convenient and time saving method for measurement of IL-6 serum levels in the routine clinical laboratory.

Abstract Nuclear factor-κB (NF-κB)/Rel transcription factors may be involved in atherosclerosis, as is suggested by the presence of activated NF-κB in human atherosclerotic lesions. The aim of the present study was to investigate the effects of oxidized LDL (oxLDL) on the NF-κB system in human THP-1 monocytic cells as well as adherent monocytes. Our results demonstrate that short-term incubation of these cells with oxLDL activated p50/p65 containing NF-κB dimers and induced the expression of the target gene IL-8. This activation of NF-κB was inhibited by the antioxidant and H 2 O 2 scavenger pyrrolidine dithiocarbamate and the proteasome inhibitor PSI. The oxLDL-induced NF-κB activation was accompanied by an initial depletion of IκB-α followed by a slight transient increase in the level of this inhibitor protein. In contrast, long-term treatment with oxLDL prevented the lipopolysaccharide-induced depletion of IκB-α, accompanied by an inhibition of both NF-κB activation and the expression of tumor necrosis factor-α and interleukin-1β genes. These observations provide additional evidence that oxLDL is a potent modulator of gene expression and suggest that (dys)regulation of NF-κB/Rel is likely to play an important role in atherogenesis.

Objective : To investigate the prognostic value of increased serum concentrations of soluble tumor necrosis factor (TNF) receptors in patients at high risk for sepsis. Design : Prospective study. Setting : Cardiac surgical intensive care unit in a University Hospital. Patients : Those 27 of 870 consecutive postcardiac surgical patients who met a previously validated high-risk criterion for imminent sepsis (Acute Physiology and Chronic Health Evaluation II [APACHE II] score of ≥24 on the first postoperative day [day 1]). In this population, systemic inflammatory response syndrome was present in 96% of the patients and the inhospital mortality rate was 30%. In addition, ten postcardiac surgical patients with an uncomplicated course (mortality rate 0%) were studied for comparison. Interventions : Blood sampling for measurements of serum concentrations of TNF and soluble TNF receptors 55 kilodalton (TNF receptor-p55) and 75 kilodalton (TNF receptor-p75) on days 1, 2, 3, and 5. Measurements and Main Results : Compared with the ten patients with an uncomplicated course (group A), the high-risk patients had significantly higher baseline (day 1) serum concentrations of soluble TNF receptor-p55 (9.2 vs. 4.2 ng/mL) and soluble TNF receptor-p75 (9.2 vs. 5.5 ng/mL). These high-risk patients could be further differentiated into two subgroups : one (B) with a prompt decrease in APACHE II score and a good prognosis (mortality rate 0%) and another (C) with a persisting high risk of sepsis and mortality rate (40%, p

Arterial hypertension is a dominant pathogenetic factor for glomerulosclerosis. Nevertheless metabolic factors such as hyper- or dyslipoproteinemia may significantly modify and accelerate the process of glomerular scarring. Hyperlipidemia and lipoprotein abnormalities are often encountered in patients with nephrotic syndrome and chronic renal disease. Although the significance of lipid deposition in renal tissue and the role of lipoproteins in the pathogenesis of renal disease in man has not yet been clearly defined, experimental and clinical data indicate a damaging effect of disturbed lipid metabolism on the kidney. In humans glomerular lipid deposition is observed in several genetic diseases, including lecithin-cholesterol acyltransferase activity deficiency. Studies on animals with reduced renal mass, diabetes mellitus or arterial hypertension have shown that hypercholesterolemia increases the incidence of glomerulosclerosis. Especially the interaction of arterial hypertension and dyslipoproteinemia leads to a rapid and pronounced development of glomerulosclerosis. As most of these studies have been performed in the rat, which has a different lipoprotein profile than man, these results should be carefully interpreted with regard to their relevance for humans. In vitro cell culture studies on human glomerular cells have provided insight into the possible cellular mechanisms of lipid-induced glomerular damage. Apoprotein E containing lipoproteins that are pathologically elevated in many renal diseases are avidly taken up by human glomerular cells. Mesangial cells seem to play a central role in the initiation of glomerulosclerosis by proliferation and production of excess extracellular matrix. Lipoproteins are able to stimulate DNA synthesis in these cells and increase the synthesis of mitogens and matrix proteins. The pathogenetic role of modified, oxidized lipoproteins has not yet been elucidated.(ABSTRACT TRUNCATED AT 250 WORDS)

We investigated long-term hypolipidemic effects and clinical safety of simvastatin, a new competitive inhibitor of 3-hydroxy-methylglutaryl coenzyme A reductase in 24 patients with familial and non-familial hypercholesterolemia. Patients received up to 40 mg simvastatin for a period of 30 months. Significant decreases were noted in plasma cholesterol (30%), plasma triglycerides (25%), very low density lipoprotein-cholesterol (26%), and low density lipoprotein-cholesterol (40%), whereas an increase in plasma high density lipoprotein-cholesterol (11%) was observed. Furthermore, the percentage decrease in plasma low density lipoprotein cholesterol was independent of individual baseline concentrations. Simvastatin did not alter the composition of low density lipoproteins or high density lipoproteins. The percentage decrease in total plasma and low density lipoprotein-cholesterol was independent of apoprotein E isoforms and low density lipoprotein-receptor activity as assayed in cultured fibroblasts. The drug therapy was well tolerated and clinical examinations revealed no adverse effects. Clinical chemistry indices and hematological, as well as endocrinological parameters remained within normal limits and ranges.