[A 52-year-old patient with positive troponin, iron deficiency anemia and known sarcoidosis]. / 52-jährige Patientin mit positivem Troponin, Eisenmangelanämie und bekannter Sarkoidose.

We report on a 52-year-old female patient with recurrent neurosarcoidosis and an "atypical" course of celiac disease, with mild clinic features, positive IgA-antibodies and histology. In our patient, the IgA-antibodies led to a false positive troponin I test, and we initially suspected an acute coronary syndrome. With dietary treatment of the celiac disease, the antibodies decreased and the troponin I test became negative. The coincidental occurrence of sarcoidosis and "potential" celiac disease (positive antibodies only) has been reported. The coincidence of an "atypical" celiac disease and sarcoidosis is rare.

The impact of antithymocyte globulin on short-term toxicity after allogeneic stem cell transplantation.

Antithymocyte globulin (ATG) is commonly used in allogeneic haematopoietic stem cell transplantation (HSCT). Little information is available, however, as to the optimal protocol for use and the side-effects occurring if ATG is administered in high daily doses (10-30 mg/kg). We report our experience with ATG Fresenius (ATG-F) in conditioning for allogeneic HSCT. During a period of 3 days, 47 patients received doses between 10 and 30 mg/kg either over 4 h preceded by 1-1.5 mg/kg prednisolone 30 min before the start of ATG-F (protocol A) or alternatively, over 12 h with 3-4 mg/kg prednisolone being administered before and 6 h after start of ATG (protocol B). During treatment with ATG-F, the side-effects observed included inflammation, disseminated intravascular coagulation, hyperdynamic circulation and renal dysfunction. Although these complications caused substantial morbidity, they were reversible within a few days. Side-effects were significantly more severe in patients treated according to protocol A than in those treated according to protocol B. As prolonged infusion of ATG-F does not reduce T cell clearance due to the long half-life of ATG-F, and since less cytokine release during conditioning might have beneficial long-term effects, we recommend administering ATG-F over 12 h preceded by high-dose steroid treatment.

GH therapy in juvenile chronic arthritis: results of a two-year controlled study on growth and bone.

Disturbance of growth frequently occurs in children suffering from juvenile chronic arthritis (JCA). Recognition of growth impairment is important because reduced final height is one of the permanent consequences. The aim of this study was to evaluate the efficacy and safety of human GH (hGH) in growth-retarded prepubertal children with JCA. Thirty-five children were tested for GH deficiency (GHD) and randomly assigned to a study and an untreated control group; five were GH deficient and were part of the GHD group. All received glucocorticoids. The study group was treated with 1 IU/kg BW.wk hGH; the GHD group was given 0.5 IU. During 2 yr of hGH treatment growth velocity and height SD score increased compared with baseline values. There was a marked increase in growth velocity in the treated groups, but also some increase in the control group. Plasma levels of IGF-I and IGF-binding protein-3 increased with GH treatment. These results suggest that hGH might be useful in the treatment of growth impairment in JCA. GH may counteract the adverse effects of glucocorticoid therapy, but its effect is dependent on the disease activity. Long-term controlled studies are needed to determine the risks and benefits of GH therapy in JCA.

The impact of chemotherapy on Leydig cell function in long term survivors of germ cell tumors.

BACKGROUND: Because patients with germ cell tumors expect an additional life span of around 50 years after successful treatment, attention is now focused on potential long term toxicity. Limited data are available on Leydig cell function in long term survivors. METHODS: The authors measured testosterone, sex hormone binding-globulin (SHBG), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) levels in 244 patients with germ cell tumors. Patients were divided into three groups: Group 1 had received no chemotherapy (n = 58 patients), Group 2 had received cumulative doses of cisplatin < or = 400 mg/m(2) (n = 117 patients), and Group 3 had received cumulative doses of cisplatin > 400 mg/m(2) (n = 69 patients). The median times from chemotherapy were 74 months and 75 months in Groups 2 and 3, respectively. RESULTS: Subnormal testosterone levels (< 10 nmol/L) were found in 5%, 11%, and 20% in Groups 1, 2, and 3, respectively (Group 1 vs. Group 3; P = 0.02). The mean testosterone level and the testosterone/SHBG ratio did not differ significantly between Groups 1 and 2; however, they did differ between Groups 1 and 3 (testosterone: 17.0 nmol/L vs. 14.9 nmol/L, respectively; P = 0.02; testosterone/SHBG ratio: 0.70 vs. 0.59; P < 0.05). There was a significant inverse correlation between the testosterone/SHBG ratio and LH (correlation coefficient [r] = -0.25; P = 0.0002). A significant positive correlation was found for LH and FSH (r = 0.78; P < 0.0001), indicating a strong association between Leydig cell dysfunction and germinal epithelial damage. CONCLUSIONS: Standard doses of cisplatin-based chemotherapy do not lead to a significant deterioration of Leydig cell function in long term survivors of germ cell tumors. In contrast, high cumulative doses of chemotherapy cause a significant and persistent impairment of Leydig cell function. More data are needed regarding the clinical relevance of moderate testosterone deficiency. Further research is necessary to determine whether some patients may benefit from testosterone replacement.

Effects of troglitazone on insulin sensitivity in HIV-infected patients with protease inhibitor-associated diabetes mellitus.

Antiretroviral therapy (ART) is frequently associated with metabolic alterations, including insulin resistance and diabetes mellitus. In this pilot study, we evaluated the effect of the PPARgamma activator troglitazone on ART-associated insulin resistance in HIV-infected patients with ART-associated diabetes mellitus. Six patients with protease inhibitor (PI)-associated diabetes mellitus, lipodystrophy and dyslipidemia were treated with troglitazone 400 mg q.d. for 3 months. Previous oral antidiabetics were discontinued prior to the study. At baseline and after 3 months, insulin sensitivity (intravenous insulin tolerance test), body composition (multifrequence bioelectrical impedance analysis) and fat distribution (CT scan quantification) were assessed. Glycaemic control (fasting and postprandial blood glucose, fructosamine, glycosylated haemoglobin) and serum lipid status were determined monthly. In four of the six patients, there was a clear improvement in insulin sensitivity, resulting in a reversal of insulin resistance in two of these patients. Overall, there was an increase in lean body mass and a decrease in total body fat. The volume of visceral adipose tissue decreased whilst the volume of subcutaneous adipose tissue increased. Total cholesterol, LDL and HDL cholesterol increased, and total triglycerides and VLDL-cholesterol decreased. No adverse effects such as hepatotoxicity were observed. Treatment with troglitazone 400 mg q.d. can ameliorate and in some cases even reverse ART-associated insulin resistance. Therefore, further studies including non-diabetic patients with ART-associated insulin resistance may be helpful in evaluating the long-term effects of thiazolidinediones on ART-associated insulin resistance and other metabolic complications, such as adipose maldistribution and dyslipidaemia.

Time-dependent efficacy of initial reperfusion with 2,3 butanedione monoxime (BDM) on release of cytosolic enzymes and ultrastructural damage in isolated hearts.

BACKGROUND: Reperfusion injury after cardioplegia may not be sufficiently addressed by conventional cardioplegic techniques in open heart surgery. 2,3-butanedione monoxime (BDM) has the potential to reduce myocardial reperfusion injury by uncoupling myocyte contraction from the intracellular calcium concentration, thus reducing reperfusion contracture. The aim of this study was to investigate the effects of different application periods of BDM during initial reperfusion on myocardial tissue injury after cardioplegia. METHODS: Isolated guinea-pig hearts underwent 50 min of cardioplegic arrest in St. Thomas' Hospital II solution at 37 C. Control hearts (n = 8) were immediately reperfused with normal Krebs-Henseleit solution for 30 min. In the therapy groups BDM-5, BDM-20, and BDM-40 (n = 8, each), hearts were initially reperfused with BDM (20mmol/L) for either 5, 20, or 40 min, respectively, followed by 30 min of reperfusion with normal Krebs-Henseleit solution. Coronary venous effluent was collected to estimate myocardial tissue damage through release of cytosolic enzymes (LDH and CK) and cardiac troponin 1. Ultrastructural alterations were qualitatively assessed by electron microscopy. RESULTS: Initial reperfusion with BDM markedly reduced LDH and CK release, as long as BDM was present. After washout of the protective agent a rebound of enzyme release occurred in BDM-5 hearts which was effectively reduced in BDM-20 and BDM-40 hearts. Troponin I release was similarly increased in all groups at the onset of reperfusion and rapidly decreased thereafter. Myocardial ultrastructural damage was most pronounced in control hearts, intermediate in BDM-5 and BDM-40 hearts, but markedly attenuated in BDM-20 hearts. CONCLUSIONS: Both 20 and 40 min of initial reperfusion effectively protected the hearts from reperfusion damage as indicated by cytosolic enzyme release, while 5 min of treatment were clearly insufficient. Toxic effects of BDM during the longer treatment period of 40 min or induction of edema by the long-term perfusion of non-beating hearts in this group may account for the worse preservation of myocardial ultrastructure in BDM-40 hearts. Thus, contraction uncoupling during initial reperfusion by BDM or similarly acting drugs may prove a viable principle for reduction of myocardial reperfusion injury. However, the ideal duration of treatment for the best therapeutic effect must be carefully evaluated.

Efficacy of contraction uncoupling by 2,3-butanedione monoxime during initial reperfusion versus cardioplegic arrest for protection of isolated hearts.

The efficacy of 2,3-butanedione monoxime (BDM) as additive to St. Thomas Hospital II solution (STH) as compared to initial BDM reperfusion with regard to myocardial ischaemia/reperfusion injury was investigated in isolated guinea pig hearts. Isolated guinea pig hearts were perfused with Krebs-Henseleit buffer in the Langendorff technique at constant pressure of 55 mmHg. After cardioplegic arrest with STH solution, global ischaemia was induced for 50 min and recovery of myocardial function was monitored during 30 min reperfusion. Control hearts (n = 8) received no further treatment. In BDMCP hearts (n = 8), 20 mM BDM were added to STH only. BDMREP hearts (n = 8) were treated with 20 mM BDM during the initial 20 min of reperfusion. BDMCP/REP hearts (n = 8) received BDM during cardioplegic arrest as well as during initial reperfusion. Left ventricular systolic function as assessed by developed pressure (LVDP) was depressed to 47 +/- 3% of pre-ischaemic baseline in control. Only initial BDM reperfusion (BDMREP) resulted in improved recovery of LVDP to 66 +/- 5%. Similar data were obtained for dP/dtmax and dP/dtmin. Reperfusion contracture was attenuated in both groups receiving initial BDM reperfusion (BDMREP and BDMCP/REP). BDM in STH did not protect hearts from cellular injury as assessed by release of lactate dehydrogenase (LDH) during reperfusion. In contrast, no increase in LDH release occurred during initial BDM reperfusion in BDMREP and BDMCP/REP hearts, followed by a mild rebound after washout of the drug. Addition of BDM to the cardioplegic STH solution did not protect isolated hearts from cellular injury or depression of post-ischaemic function. In contrast, initial BDM reperfusion alone attenuated reperfusion contracture, prevented LDH release, and improved recovery of systolic and diastolic myocardial function. The combination of BDM treatment during cardioplegic arrest with initial BDM reperfusion provides no additional protection from reperfusion injury.

Effect of antithrombin III supplementation on inflammatory response in patients with severe sepsis.

Antithrombin III (AT III) is an important inhibitor of thrombin activity, as well as of many other proteases of the coagulation system. AT III administration showed beneficial effects on septic multiple organ dysfunction in clinical and experimental studies. It was the aim of this study to determine whether continuous long-term AT III supplementation alters the systemic inflammatory response in patients with severe sepsis. In a prospective study, 29 surgical patients with severe sepsis were randomly assigned to receive either conventional intensive care treatment (n = 15, control group) or additional AT III supplementation to achieve a plasma AT III activity >120% during a 14 day study period (n = 14, AT III group). Plasma concentrations of interleukin (IL)-6 and IL-8 and of the circulating soluble adhesion molecules sICAM-1 and sE-selectin, as well as of PMN elastase, were determined daily. Additionally, total leukocyte count and C-reactive protein (CRP) were measured daily, and body temperature was registered. Compared to control patients, a down-regulation of plasma IL-6 was observed in the AT III group (p < or = .01). AT III supplementation prevented the continuous increase in sICAM-1 plasma concentration observed in control patients and led to a significant fall in soluble sE-selectin and CRP concentration (p < or = .01). This fall corresponded to a down-regulation of body temperature over time (p < or = .01). There was no AT III effect on IL-8, PMN-elastase concentration, or total leukocyte count. Our results show that long-term AT III supplementation attenuates the systemic inflammatory response in patients with severe sepsis. The down-regulation of IL-6 may also explain the fall in endothelium-derived adhesion molecules and may represent the molecular basis by which AT III exerts its beneficial effects on organ function.

Optimizing the oxygen balance during initial reperfusion with 2,3-butanedione monoxime attenuates cardiac reperfusion injury.

The effect of 20 mmol/L butanedione monoxime on myocardial ischemia/reperfusion damage was studied in isolated guinea pig hearts. Three groups of hearts (n = 8) were perfused in the Langendorff mode and cardioplegic arrest was induced with St. Thomas Hospital II solution (STS) at 37 degrees C for 50 min. Myocardial oxygen demand, recovery of myocardial function, and creatine kinase release during 30 min of reperfusion were monitored. Preservation of myocardial ultrastructure was determined by electron microscopy. Control (C) hearts underwent cardioplegic arrest and reperfusion without treatment. BDM was added during cardioplegic arrest in BDMSTS hearts, or to the initial (20 min) reperfusate in BDMREP hearts. BDM during initial reperfusion markedly reduced O2 demand and prevented creatine kinase release from cardiac myocytes, resulting in improved recovery of myocardial function and attenuation of myocardial ultrastructural damage after washout of the drug. In contrast, addition of BDM to the cardioplegic solution provided no protection from ischemic or reperfusion injury.

Antithrombin III supplementation in severe sepsis: beneficial effects on organ dysfunction.

Activation of thrombin and of the coagulation system plays an important role in the pathophysiology of sepsis-associated organ dysfunction. Antithrombin III (AT III) is a natural inhibitor of thrombin, a central procoagulatory factor with pleiotropic activities. Experimental supplementation of AT III improved coagulation parameters and ameliorated organ dysfunction. To determine whether long-term AT III supplementation has beneficial effects on organ function, we conducted a randomized, prospective study in surgical patients with severe sepsis. The study evaluated the long-term effect of AT III supplementation (duration of treatment: 14 days). After randomization (AT III vs. control group), AT III was infused continuously over 14 days to obtain plasma AT III activities > 120%. Forty consecutive patients were recruited (20 AT III/20 control group). Eleven patients had a rapid fatal course and did not met the criterion of a 14 day treatment period. From these 11 patients, 8 patients (5 AT III/3 control group) died within 72 h due to septic shock. The remaining 14 AT III patients and 15 controls survived 14 days and showed no differences in baseline parameters of organ function. AT III caused a disappearance of disseminated intravascular coagulation (DIC) in all patients with DIC, whereas in control patients, the frequency of DIC remained constant (p < .05). In AT III patients a progressive increase in oxygenation index (PaO2/FiO2 ratio) and a continuous decrease in pulmonary hypertension index (mean pulmonary artery pressure/mean arterial pressure (PAP/MAP) ratio) indicated an improvement of lung function (p < .05 vs. control). AT III prevented the continuous rise in total serum bilirubin concentration observed in control patients and diminished the frequency of artificial renal support therapy (p < .05). Long-term supplementation with AT III may improve lung function and prevent the development of septic liver and kidney failure in patients with severe sepsis.

Serum pharmacology of amphotericin B applied in lipid emulsions.

Application of amphotericin B in lipid emulsions (AmB/L) reduced membrane toxicity in vitro and decreased amphotericin B-associated toxic side effects in vivo when compared to that of amphotericin B applied in 5% glucose (AmB/G). Therefore, a comparative analysis of the pharmacological parameters of AmB/L and AmB/G was performed. Thirteen patients were analyzed, and nine of these patients received a subsequent treatment with AmB/G and AmB/L. In patients in both treatment groups amphotericin B showed a biphasic elimination from serum, with a prolonged terminal half-life of approximately 27 h. Patients treated with AmB/L showed significantly lower peak concentrations (44.2%; P = 0.008) and correspondingly lower area under the drug concentration-time curve (AUC) values (64.3%; P = 0.015) compared to the values for the same patients treated with AmB/G at a dose range of 0.6 to 1.5 mg/kg of body weight. The enhanced clearance of AmB/L may be due to a faster initial elimination of amphotericin B-lipid aggregates by the reticuloendothelial system. Lower peak concentrations and AUC values in serum and a correspondingly faster deposition of AmB/L in tissues may at least partly explain the lower toxicity of AmB/L. A comparative pharmacokinetic analysis with data for a single patient treated with AmB/L demonstrated that hemodialysis did not significantly affect the disposition of amphotericin B.

Ticarcillin/clavulanate in the treatment of severe peritonitis.

A prospective study was performed on 50 consecutive patients with secondary peritonitis. All patients received ticarcillin/clavulanate 5.2 g three times daily as initial antibiotic therapy. In 30 patients a primary perforation was found in the gastro-intestinal tract and 20 had post-operative peritonitis. In two thirds of the patients a diffuse peritonitis was found which affected the whole abdomen. Thirty-six patients underwent one or two laparotomies and 11 patients had more than three laparotomies. Subsequently, 17 patients died. The cause of death was a therapeutic failure as a result of the surgical procedure in ten patients (nine patients with persisting intestinal fistulae, one patient with bleeding), whereas in seven cases antibiotic therapy failed. Micro-organisms found in the latter patients were producers of type 1 beta-lactamase (Pseudomonas aeruginosa, Enterobacter sp., Citrobacter sp., Serratia marcescens) and enterococci. Ticarcillin/clavulanate is characterized by its broad antimicrobial spectrum against anaerobic and aerobic bacteria and seems, therefore, to be well suited for initial chemotherapy in patients with diffuse peritonitis.