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To access publisher's full text version of this article click on the hyperlink at the bottom of the page To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry. Canadian Institutes of Health Research Medical Research Council UK G0601261 Mexico Convocatoria SSA/IMMS/ISSSTE-CONACYT 2012-2 clave 150352 IMSS R-2011-785-018 CONACYT Salud-2007-C01-71068 US National Institutes of Health DK062370 HG000376 DK085584 DK085545 DK073541 DK085501 Wellcome Trust WT098017 WT090532 WT090367 WT098381 WT081682 WT085475 info:eu-repo/grantAgreement/EC/FP7/201413

To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci (P < 5 × 10−8), including variants near the GLP2R, GIP, and HLA-DQA1 genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action–associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.

Determination of renal function is a prerequisite for planning therapy in cancer patients. Limitations of creatinine as marker for the glomerular filtration rate (GFR) led to the proposal of cystatin C as a more accurate biomarker especially in mild renal insufficiency or in patients with low muscle mass. We compared the accuracy of cystatin C- and creatinine-based equations to estimate GFR in head and neck cancer (HNC) patients receiving platinum-based radiochemotherapy.The study population consisted of 52 HNC patients (GFR range, 37-105 mL/min/1.73 m(2) complemented by 17 patients with known renal insufficiency (GFR range, 10-60 mL/min/1.73 m(2)). Intraclass correlation coefficients were calculated between the reference method (51)Cr-EDTA clearance and estimated GFR by creatinine clearance and equations based on creatinine (Cockroft-Gault, modification of diet in renal disease (MDRD), Wright) or cystatin C (Larsson, Dade-Behring, Hoek). In addition, sensitivity and specificity to discriminate GFR > 60 mL/min/1.73 m(2) were evaluated by receiver operating characteristic curve (ROC).The highest correlation coefficients were found for the cystatin C-based estimates in comparison with creatinine-based estimates or creatinine clearance, even though Bland-Altman plots revealed GFR overestimation for all equations tested. The cystatin C-based Hoek formula exhibited the highest overall precision and accuracy. GFR of 60 mL/min/1.73 m(2) for the creatinine-based Wright formula, closely followed by the MDRD formula and cystatin C-based equations of Larsson, Dade-Behring, and Hoek.Cystatin C-based GFR estimates showed the overall strongest correlation to the reference method. Thus, we recommend cystatin C for GFR estimation in HNC patients as an alternative method to the estimated creatinine clearance in clinical practice.

UNLABELLED This study was conducted to evaluate the accuracy and kinetics of interleukin 8 (IL-8) as a test for early-onset bacterial infections (EOBI) in neonates and to examine whether IL-8 would allow "unnecessary" antibiotic therapy to be reduced. First, IL-8 was measured 378 times on admission, along with C-reactive protein (CRP), immature to total neutrophil ratio (IT ratio) and blood cultures, in full-term and preterm neonates with suspected EOBI. Combined culture-proven and clinical EOBI were detected on admission by the combination of IL-8 > or = 70 pg ml(-1) and/or CRP > 10 mg l(-1) with 92% sensitivity and 74% specificity. An increased IL-8 was found in 62% of the infected infants, while CRP was still normal. In a second study period, IL-8 was determined prospectively in 331 infants who presented clinical signs of EOBI or had a birth history of amniotic infection. Antibiotic therapy was restricted to those infants with suspected infection who also had an increased IL-8 and/or CRP (n = 158). Another 39 infants received antibiotics on the basis of clinical signs despite negative IL-8 and CRP. Of 150 non-infected infants in whom IT ratio, IL-8 and CRP were available, treatment would have been indicated for 93 infants based on IT ratio and/or CRP (n = 77) or clinical signs (n = 16), but was only initiated in 55 infants based on IL-8 and/or CRP (n = 28) or clinical signs (n = 27), an apparent reduction in "unnecessary" antibiotic therapy of 40%. CONCLUSION The combination of IL-8 and CRP is a reliable test for the diagnosis of EOBI and may be helpful in enabling antibiotic therapy to be reduced in newborn infants.

To access publisher's full text version of this article click on the hyperlink at the bottom of the page We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease. cademy of Finland 77299 102318 10493 118065 123885 124243 129293 129680 136895 139635 211119 213506 251217 263836 Agence National de la Recherche Association de Langue Francaise pour l'Etude du Diabete et des Maladies Metaboliques Association Diabeete Risque Vasculaire Association Francaise des Diabetiques Association of Danish Pharmacies Augustinus Foundation Becket Foundation British Diabetes Association (BDA) Research British Heart Foundation Central Norway Health Authority Central Finland Hospital District Center for Inherited Disease Research (CIDR) City of Kuopio City of Leutkirch Copenhagen County Danish Centre for Evaluation and Health Technology Assessment Danish Council for Independent Research Danish Heart Foundation Danish Research Councils Deutsche Forschungsgemeinschaft ER 155/6-2 Diabetes Research Foundation Diabetes UK Doris Duke Charitable Foundation Erasmus Medical Center Erasmus University Estonian government SF0180142s08 European Commission ENGAGE HEALTH-F4-2007-201413 FP7-201413 FP7-245536 EXGENESIS LSHM-CT-2004-005272 FP6 LSHM_CT_2006_037197 LSHM-CT-2007-037273 C-Public Health 2004310 European Regional Development Fund Federal Ministry of Education and Research, Germany FKZ 01GI1128 FKZ 01EO1001 Federal Ministry of Health, Germany Finnish Diabetes Association Finnish Diabetes Research Foundation Finnish Foundation for Cardiovascular Research Finnish Medical Society Folkhalsan Research Foundation Foundation for Life and Health in Finland Foundation for Old Servants Fredrick och Ingrid Thuring Foundation French region of Nord-Pas-de-Calais (Contrat de Projets Etat-Region) German Center for Diabetes Research German Research Council GRK1041 German National Genome Research Network Groupe d'Etude des Maladies Metaboliques et Systemiques Health Care Centers in Vasa, Narpes and Korsholm, Finland Health Foundation Heinz Nixdorf Foundation Helmholtz Zentrum Munchen Helsinki University Central Hospital Research Foundation Hospital District of Southwest Finland Ib Henriksens Foundation IngaBritt and Arne Lundberg's Research Foundation 359 Karolinska Institutet Knut and Alice Wallenberg Foundation KAW 2009.0243 Kuopio University Hospital Lundbeck Foundation Magnus Bergvall Foundation Medical Faculty of University Duisburg-Essen Medical Research Council, UK G0000649 G0601261 Ministry for Health, Welfare and Sports, the Netherlands Ministry of Education and Culture, Finland 722 627 Ministry of Education, Culture and Science, the Netherlands Ministry of Health and Prevention, Denmark Ministry of Social Affairs and Health, Finland Ministry of Innovation, Science, Research and Technology of North Rhine-Westphalia, Germany Munich Center of Health Sciences Municipal Health Care Center and Hospital in Jakobstad, Finland municipality of Rotterdam, the Netherlands Narpes Health Care Foundation National Health Screening Service of Norway National Heart, Lung, and Blood Institute, USA HHSN268201100005C HHSN268201100006C HHSN268201100007C HHSN268201100008C HHSN268201100009C HHSN268201100010C HHSN268201100011C HHSN268201100012C N01HC25195 N02HL64278 R01HL087641 R01HL59367 R01HL086694 National Human Genome Research Institute, USA U01HG004402 N01HG65403 National Institute for Diabetes and Digestive and Kidney Diseases, USA R01DK078616 U01DK085526 K24DK080140 R01DK073490 National Institute for Health and Welfare, Finland National Institutes of Health, USA HHSN268200625226C UL1RR025005 R01DK062370 R01DK072193 1Z01HG000024 AG028555 AG08724 AG04563 AG10175 AG08861 U01HG004399 DK58845 CA055075 DK085545 DK098032 Netherlands Genomics Initiative Netherlands Organisation for Health Research and Development Netherlands Organisation of Scientific Research NOW Investments 175.010.2005.011 911-03-012 050-060-810 Nord-Trondelag County Council Nordic Center of Excellence in Disease Genetics Norwegian Institute of Public Health Norwegian Research Council Novo Nordisk Foundation Ollquist Foundation Oxford National Institute for Health Research (NIHR) Biomedical Research Centre Paavo Nurmi Foundation Paivikki and Sakari Sohlberg Foundation Perklen Foundation Pirkanmaa Hospital District, Finland Programme Hospitalier de Recherche Clinique Programme National de Recherche sur la Diabete Research Institute for Diseases in the Elderly 014-93-015 Robert Dawson Evans Endowment, Department of Medicine, Boston University School of Medicine and Boston Medical Center Royal Swedish Academy of Sciences Sarstedt, Germany Signe and Ane Gyllenberg Foundation Sigrid Juselius Foundation Slottery Machine Association, Finland Social Insurance Institution of Finland South OstroBothnia Hospital District state of Baden-Wurttemberg, Germany Stockholm County Council 560183 Swedish Cultural Foundation, Finland Swedish Diabetes Foundation Swedish e-science Research Center Swedish Foundation for Strategic Research Swedish Heart-Lung Foundation Swedish Research Council SFO EXODIAB 2009-1039 521-2010-3490 521-2007-4037 521-2008-2974 ANDIS 825-2010-5983 LUDC 349-2008-6589 8691 Swedish Society of Medicine Tore Nilsson Foundation Torsten and Ragnar Soderbergs Stiftelser MT33/09 University Hospital Essen University of Tromso University College London NIHR Biomedical Research Centre UK NIHR Cambridge Biomedical Research Centre Uppsala University Uppsala University Hospital Vaasa Hospital District Velux Foundation Wellcome Trust GR072960 076113 083948 090367 090532 083270 086596 098017 095101 098051 098381

Aim: To evaluate a new micro-method technique for measurement of interleukin 8 in detergent-lysed whole blood (whole blood IL-8) applicable to capillary blood sampling as a test for bacterial infections in neonates. Methods: Whole blood IL-8 was measured at the first suspicion of infection along with IL-8 determined in plasma (plasma IL-8), C-reactive protein and blood cultures in 154 consecutive newborn infants with clinical signs of bacterial infection. Only 20 μl of whole blood were required for the new assay. Results: Blood culture-proven infections were diagnosed in six infants and clinical infection (defined as a combination of clinical and laboratory signs) in 20 infants. 1000 pg/ml was determined as the suitable threshold for whole blood IL-8 by ROC-curve analysis. At that threshold, whole blood IL-8 detected blood culture-proven infections with a sensitivity of 83% and a specificity of 67%. The areas under the ROC curves were similar for whole blood IL-8 and plasma IL-8. Conclusions: Compared with plasma IL-8, whole blood IL-8 offers the advantages that measurements of whole blood IL-8 require a smaller blood sample volume and are not altered by haemolysis. The diagnostic accuracy of whole blood IL-8 remains to be studied in more detail in the future.

Background and Objective: Although in recent years methods in emergency medicine have been remarkably improved, thoracic trauma remains associated with high mortality. To select adequate treatment in multitrauma patients, early diagnosis of lung contusion is of great importance. Upon hospital admission, however, even modern imaging techniques frequently fail to correctly estimate both severity and extent of chest trauma. Therefore, the aim of our study was to define laboratory markers indicating chest trauma almost immediately after accident. Patients and Methods: 107 trauma patients were enrolled in this prospective study. Blood samples were taken immediately at the site of accident, on hospital admission, after 30 and 60 min, and 2-hourly for an interval of 12 h, then daily. In addition to the biochemical analysis of 20 different substances, the following data were drawn and correlated to the laboratory results: Injury Severity Score (ISS), Polytrauma Score (PTS), Ulm score HTAPE (trauma pattern-specific: head, thorax, abdomen, pelvis, extremities; 0–3 degrees each), Multiple Organ Failure (MOF) score accordings to Goris et al, overall lethality, primary and secondary lethality. All trauma scores were subject to descriptive analysis. Our main analysis focuses on the thorax trauma score including variable selection by logistic regression as well as ROC analysis. Results: In nonsurvivors, overall trauma severity and head injury were remarkably higher (15.9%) than in survivors. Whereas there was a strong correlation between head injury and primary lethality (≤ 3 days), secondary lethality (> 3 days post trauma) was charged by thoracic trauma as well as by limb trauma. Of all mediators investigated, it was interleukin-6 (IL-6) that showed highest correlations (p < 0.0001) to the extent of chest trauma, especially during the first hour after hospital admission. Further correlations, yet clearly less pronounced, were found between IL-6 and PTS, between ISS, abdominal pelvic and limb trauma, but not to head injury. Our findings suggest that there is a correlation between endotoxin and 6-keto-prostaglandin F1α and the severity of thoracic injury, too, but it is of lower statistical impact compared to IL-6. The practical value of both mediators, however, is limited because of the sophisticated and time-consuming laboratory analysis they demand. Conclusion: The study results suggest IL-6 to be an early marker for the extent of chest trauma.

In a prospective clinical study, we investigated the inflammatory response in 88 neonatal subjects (43 boys and 45 girls) who underwent major abdominal surgery owing to congenital malformation involving the gastrointestinal tract and compared it with the response in 20 infants (8 boys, 12 girls; mean age, 4 mo) who underwent elective surgery for resolution of an existing temporary stoma. In both groups, plasma levels of endotoxin, IL-6, and C-reactive protein as well as leukocyte counts were determined during and after surgery. Endotoxin was measured by the Limulus amebocyte test, IL-6 by ELISA, and C-reactive protein by nephelometry. Statistical analyses were performed using the Wilcoxon signed-rank test. A significant increase in circulating endotoxin and a leukocyte shift was observed in the infant group only. Postoperatively, IL-6 levels peaked between 2 and 6 h and C-reactive protein after 24 h in the infant group. In contrast, no significant increase in the levels of endotoxin, IL-6, and C-reactive protein in plasma were observed during and after surgery in the neonatal subjects, except those with gastroschisis. Newborns with gastroschisis developed an inflammatory response after surgery that was less pronounced than the response of infants older than 4 mo. The finding that endotoxemia in newborns does not follow surgical trauma is most likely because of the absence of bacterial colonization of the gastrointestinal tract.

Background: For the treatment of aortic aneurysm, stent-graft implantation is an alternative method to open surgery. There is no study comparing both methods with regard to endotoxaemia, the acute phase cascade, and clinical outcome. Methods: In this prospective study, we enrolled 40 patients (34 males, 6 females; mean age 72.1±7.5 [58–92] years) with infrarenal abdominal aortic aneurysm who underwent aortic surgery. Comparable groups of patients were treated with open (n=20) or endovascular (n=20) stent-graft implantation. To characterize the inflammatory response, plasma levels of endotoxin, endotoxin-neutralizing capacity (ENC), interleukin-6 (IL-6), C-reactive protein (CRP), and white blood cell count were determined. In all patients, measurements were performed on admission, skin suture, 4 h and from the first to fifth postoperative day. As parameters for the clinical outcome, we assessed daily temperature, lung function, pain, duration of postoperative hospital stay, and morbidity. Wilcoxon rank test was used for statistical analysis. Results: In both groups, a significant increase of endotoxin plasma levels and a decrease of ENC was found already after skin incision. IL-6 levels peaked 4 h postoperatively in both groups, whereas CRP rose at the first postoperative day, reaching a maximum at day 2. Conventionally operated patients had significantly higher plasma levels of endotoxin, IL-6, and CRP and lower ENC during and after surgery than patients with stent-graft implantation. Moreover, patients with endovascular stent grafting had significant less postoperative pain, less restriction of total vital capacity, a shorter hospital stay, and a lower morbidity. Conclusions: Endovascular stent grafting of infrarenal aortic aneurysm seems to be superior not only in terms of the inflammatory response but also in overall clinical outcome.

Several studies have been demonstrated that endotoxin is a potent stimulus of the acute inflammatory response following traumatic injury. Although numerous studies have indicated that the extent of surgical intervention correlates well with the inflammatory response, the potential role of endotoxin as a trigger under those conditions still remains unknown. Therefore, the aim of this study was to elucidate whether or not the up-regulated inflammatory mediators are paralleled by increased endotoxin plasma levels during and following surgery, and whether the extent of surgical intervention represents a crucial factor under those conditions. To study this, plasma was collected at various time points during and after surgery from 52 patients subjected to abdominal surgery (i.e., major surgery) and 25 patients subjected to thyroid surgery (i.e., minor surgery). Plasma was assessed for endotoxin, endotoxin neutralizing capacity (ENC), and inflammatory mediators (leucotriene-C4 [LTC4]-, 6-keto-prostaglandin-F-1-alpha [PGF]-, thromboxane-B2 [TxB2], interleukin-6 [IL-6], and C-reactive protein [CRP]). Furthermore, splanchnic blood circulation was measured by determination of the intraluminal pH of the stomach and sigma (pHi) by intraluminal tonometry. Mesenteric lymph nodes were also collected at the time point of organ mobilization in the major surgery group and were assessed for bacterial translocation. Among all parameters investigated, endotoxin showed the most rapid changes. A significant increase in plasma levels of endotoxin and a decrease of ENC were found in the major surgery groups following induction of anesthesia and in the minor surgery groups after skin incision. Moreover, the incidence of elevated endotoxin levels was significantly higher (89% with elevated endotoxin levels) than the incidence of bacterial translocation (35% with gram-negative bacteria) in mesenterial lymph nodes of the major surgery group. pHi decreased significantly in both groups after skin incision, but no difference was observed between the major and minor surgery groups. Plasma mediators of the arachidonic acid cascade (LTC4, PGF, and TxB2) were only elevated in individual patients during and following surgery in both groups. Conversely, the post-operative increase in the acute phase mediators was significantly different in the major and minor surgery groups. IL-6 plasma levels peaked higher and earlier after major surgery than after minor surgery and the delayed increase of CRP was significantly greater in the major surgery group. In conclusion, the results indicate that plasma levels of endotoxin significantly correlate with the severity of the surgical intervention and may play an important role in inducing mediators of the acute phase reaction under such conditions.

The aim of this clinical study was to investigate the time sequence between intraoperative and postoperative endotoxemia, changes in intramucosal pHI, mediator release, and acute phase proteins and their relationship to postoperative infections. In 60 patients (median age 61 [33-72] years, male/female: 50/10) plasma levels of endotoxin, endotoxin neutralizing capacity (ENC), leukotriene-C4 (LTC4), 6-ketoprostaglandin-F-1α (PGF), thromboxane-B 2 (TxB2), inter leukin-6 (IL-6), and C-reactive protein (CRP) were measured before, during, and after cardiac surgery. The intraluminal pHI of the stomach was assessed as a marker of splanchnic blood circulation. Patients were divided in one group with postoperative infections (group A, n=8) and another groups without infections (group B, n = 52). Among all measured parameters, endotoxin plasma levels showed the most rapid changes. A significant increase of endotoxin plasma levels and a decrease in ENC appeared after the induction of anesthesia, culminating in a peak after reperfusion. Endotoxin showed a significantly higher increase in group A (14fold) compared to group B (sixfold, p < 0.001 ), whereas ENC decreased by eightfold in both groups. The parameters of the arachidonic cascade increased and pHI decreased, however, there were no significant differences between both groups. The latest increase was observed for the acute phase proteins IL-6 and CRP. IL-6 levels peaked 6 hours postoperatively with a 20fold (group B) and 30fold (group A) increase (p < 0.001 vs baseline; no differences between groups), whereas CRP rose at the first postoperative day with a 21fold (group B) and 25fold (group A) increase at day 2 (p < 0.001 vs baseline, no difference between groups). Differences between both groups appeared at the second postoperative day for IL-6 (median values group A/B: 421/219 pg/mL; p < 0.05) and at the fifth postoperative day for CRP (median values group A/B: 321/81 mg/L; p < 0.05). In conclusion, endotoxin seems to be the earliest trigger of the mediator cascade in acute phase response and may indicate infections in the postoperative course.

Drug administration via the endotracheal tube is recommended as a second-line approach in emergency settings such as cardiac arrest. It is unknown what amount of drugs are absorbed when they are given through the laryngeal mask airway as compared with the endotracheal tube. We administered lidocaine at a dose of 2 mg/kg diluted in 10 mL normal saline to 20 anesthetized patients undergoing routine surgical procedures. Ten patients received lidocaine into the endotracheal tube and 10 patients received lidocaine into the laryngeal mask airway. Blood samples were taken for measurement of lidocaine plasma concentrations, and the pharmacokinetics were calculated. Therapeutic plasma concentrations (>1.4 microg/mL) could be achieved in 10 of 10 patients after endotracheal tube instillation but in only 4 of 10 patients after laryngeal mask instillation (P < 0.05). Peak lidocaine concentrations (2.47 and 1.09 microg/mL) (P < 0.05) and the area under the time versus plasma concentration curve (117.7 and 91.2 microg x min x mL(-1)) (P < 0.05) were higher after lidocaine administration into the endotracheal tube than into the laryngeal mask airway. In conclusion, the laryngeal mask airway is not a reliable route for the recommended dose of endobronchial lidocaine administration compared with the endotracheal tube.

Trauma may cause a relevant reduction in antithrombin (AT) III activity, which is associated with adverse events. The very early changes in AT III activity after accident trauma are still unclear and possible relations with Interleukin (IL)-6, which is known to interact with AT III, have not been investigated so far. Upon approval of the IRB/IEC, 30 patients were enrolled with multiple injuries (ISS 9-75). Groups were performed according to injury severity, IL-6 concentration, and survivors versus non-survivors. Blood samples were collected at the scene of accident then at 2, 4, 6, 12, and 24 h and at day 3, 5, 10 and 15. No patient received AT III concentrates. In all groups a reduction in AT III activity occurred, which was most pronounced in very severe injuries. The activity re-increased spontaneously and steadily in all groups regardless of the IL-6 concentration. There was no clear impact of the AT III activity on survival.

Background The value of exercise electrocardiography in the prediction of perioperative cardiac risk has yet to be defined. This study was performed to determine the predictive value of exercise electrocardiography as compared with clinical parameters and resting electrocardiography. Methods A total of 204 patients at intermediate risk for cardiac complications prospectively underwent exercise electrocardiography before noncardiac surgery. Of these, 185 were included in the final evaluation. All patients underwent follow-up evaluation postoperatively by Holter monitoring for 2 days, daily 12-lead electrocardiogram, and creatine kinase, creatine kinase MB, and troponin-T measurements for 5 days. Cardiac events were defined as cardiac death, myocardial infarction, minor myocardial cell injury, unstable angina pectoris, congestive heart failure, and ventricular tachyarrhythmia. Potential risk factors for an adverse event were identified by univariate and multivariate logistic regression analysis. Results Perioperative cardiac events were observed in 16 patients. There were 6 cases of myocardial infarction and 10 cases of myocardial cell injury. The multivariate correlates of adverse cardiac events were definite coronary artery disease (odds ratio, 8.8; 95% confidence interval [CI], 1.1--73.1; P = 0.04), major surgery (odds ratio, 4.7; 95% CI, 1.3--16.3; P = 0.02), reduced left ventricular performance (odds ratio, 2.0; 95% CI, 1.1--3.8; P = 0.03), and ST-segment depression of 0.1 mV or more in the exercise electrocardiogram (odds ratio, 5.2; 95% CI, 1.5--18.5; P = 0.01). A combination of clinical variables and exercise electrocardiography improved preoperative risk stratification. Conclusions This prospective study shows that a ST-segment depression of 0.1 mV or more in the exercise electrocardiogram is an independent predictor of perioperative cardiac complications.

The long-term outcome of trauma patients basically depends on the relation between the clearance capacity of the organism, e.g., the lungs, and the antigenic (inflammatory) load in relation to the amount of damaged and perfused tissue. It is necessary to determine quality and quantity of fracture and soft-tissue damage by clinical means as early as possible. It is unknown whether biochemical markers and the impact of soft-tissue trauma correlate and whether there is a predictive value on clinical outcome.A total of 107 trauma patients were prospectively enrolled in the study. Blood samples were collected immediately at the site of accident, at hospital admission, and every 2 hours for an interval of 24 hours, then daily. In addition to the biochemical analysis of 20 different substances, the following data were collected and correlated to the laboratory results: Injury Severity Score, polytrauma score of Hannover, modified fracture index, and soft-tissue index. These primary clinical findings as well as the laboratory data were correlated to criteria of clinical outcome such as length of stay in the intensive care unit, length of hospital stay, infections, systemic inflammatory response syndrome, sepsis, multiple organ failure score according to Goris, and finally to primary (72 hours), secondary (72 hours), and overall lethality. The determination of individual extent and severity of soft-tissue trauma is based on standard partial body volumes derived from healthy volunteers. In addition, clinical estimation of the degree of soft-tissue damage according to the usual classifications was performed.Significant (p0.05) correlations were found between fracture as well as soft-tissue trauma and intensive care unit stay, hospital stay, infections, systemic inflammatory response syndrome, multiple organ failure score, serum concentrations/activities of serum interleukin-6 and -8 and creatine kinase during the first 24 hours after trauma. Severe soft-tissue trauma was related to secondary lethality, however, without statistical significance.The amount of fracture and soft-tissue damage can be estimated early by analysis of serum interleukin-6 and creatine kinase and is of great importance with regard to long-term outcome after trauma.

Intravenous administration of vasopressin during cardiopulmonary resuscitation (CPR) may be more effective than optimal doses of epinephrine. The main purpose of this study was to determine whether intraosseous vasopressin achieves serum drug levels comparable with intravenous doses during CPR and, additionally, to evaluate the effects of intraosseous vasopressin during CPR.Prospective, randomized laboratory investigation using an established porcine model with instrumentation for measurement of hemodynamic variables, blood gases, and return of spontaneous circulation.University hospital laboratory.Twelve domestic pigs.After 4 mins of untreated ventricular fibrillation and 3 mins of CPR, 12 pigs were randomized to be treated with intravenous administration of vasopressin (0.8 unit/kg vasopressin; n = 6) or intraosseous vasopressin (0.8 unit/kg vasopressin; n = 6). Defibrillation was performed 5 mins after drug administration to attempt the return of spontaneous circulation.At both 90 secs and 5 mins after drug administration, intravenous and intraosseous administration of vasopressin resulted in comparable mean (+/-SEM) coronary perfusion pressure (43+/-4 vs. 44+/-3 and 30+/-2 vs. 37+/-2 mm Hg, respectively) and vasopressin plasma concentrations (13,706+/-1,857 vs. 16,166+/-3,114 pg/mL and 10,372+/-883 vs. 8246+/-2211 pg/mL, respectively). All animals in both groups were successfully resuscitated; pigs that received intraosseous vasopressin had a significantly higher (p.05) mean arterial (92+/-6 vs. 129+/-12 mm Hg) and coronary perfusion pressure (84+/-11 vs. 119+/-11 mm Hg) at 5 mins of return of spontaneous circulation.Intraosseous vasopressin resulted in comparable vasopressin plasma levels, hemodynamic variables, and return of spontaneous circulation rates as did intravenous vasopressin. Intraosseous vasopressin may be an alternative for vasopressor administration during CPR, when intravenous access is delayed or not available.

Objective: To investigate the effect of preoperative ibuprofen administration on renal function during and after infrarenal aortic surgery under thoracolumbar epidural anaesthesia (EPA). Design: A prospective randomised, double-blinded clinical study. Setting: Operation room and intensive care unit in a university hospital. Patients: Twenty-six consecutive patients scheduled for elective infrarenal aortic surgery. Interventions: The patients were prospectively randomised to receive 400 mg ibuprofen intravenously (i. v.) or a placebo aliquot before surgery. Measurements and results: We assessed renal function by calculating creatinine clearance, and fractional sodium excretion before surgery (baseline), 1 h after cross-clamping (intraoperative), 6 h after cross-clamping (postoperative) and 24 h after cross-clamping (on the 1 st postoperative day). At each point in time, we additionally registered haemodynamics and determined the plasma concentration of 6-keto-PGF1α (stable metabolite of prostacyclin, PGI2), bicyclic PGE2 (stable metabolite of PGE1 E2), active renin, aldosterone and vasopressin by radioimmunoassays. Throughout the observation period the renal function parameters mostly remained within the normal range without a significant difference between ibuprofen- and placebo-treated patients (creatinine clearance: baseline 41 ± 3 vs 38 ± 6, intraoperative 57 ± 8 vs 64 ± 11, postoperative 64 ± 9 vs 56 ± 9, first postoperative day 43 ± 5 vs 47 ± 6 ml · min · m−2, means ± SEM). The plasma levels of 6-keto-PGF1α (68 ± 8 vs 380 ± 71* ng · 1−1), bicyclic PGE2 (57 ± 5 vs 88 ± 9* ng · 1−1) and vasopressin (14 ± 7 vs 45 ± 10* ng · 1−1,p < 0.0125), however, were significantly higher during the intra-operative period in the placebo-treated patients. Conclusion: The inhibition of endogenous prostaglandin release by ibuprofen does not substantially impair renal function during infrarenal aortic surgery under EPA.

Background—Infection of pancreatic necrosis has a major impact on clinical course, management, and outcome in acute pancreatitis. Currently, guided fine needle aspiration is the only means for an early and accurate diagnosis of infected necrosis. Procalcitonin (PCT), a 116 amino acid propeptide of calcitonin, and interleukin 8 (IL-8), a strong neutrophil activating cytokine, are markers of severe inflammation and sepsis.Aims—To analyse the clinical value of PCT and IL-8 as biochemical parameters for predicting infected necrosis in acute pancreatitis.Patients and methods—Fifty patients with acute pancreatitis entered this prospective study and were stratified into three groups according to morphological and bacteriological findings: 18 patients with oedematous pancreatitis (group I), 14 patients with sterile necrosis (group II), and 18 patients who developed infected necrosis a median of 13.5 days after the onset of symptoms (group III). After admission serum samples were drawn daily for two weeks. Concentrations of PCT and IL-8 were measured by chemoluminescent immunoassays (upper reference range 0.5 ng/ml for PCT and 70 pg/ml for IL-8). The routine parameter C-reactive protein was determined by laser nephelometry (upper reference range 10 mg/l).Results—Median concentrations of PCT and IL-8 were significantly higher in patients with infected necrosis than in those with sterile necrosis during the observation period, whereas there was no difference in C-reactive protein. In oedematous pancreatitis overall median concentrations of all three parameters were low. By receiver operating characteristics best cut off levels for predicting infected necrosis or persisting pancreatic sepsis were 1.8 ng/ml for PCT and 112 pg/ml for IL-8. If these cut off levels were reached on at least two days, sensitivity, specificity, and accuracy for the prediction of infected necrosis were 94%, 91%, and 92% for PCT and 72%, 75%, and 74% for IL-8, respectively. After surgical treatment of infected necrosis median PCT and IL-8 values continued to be significantly higher in patients with persisting pancreatic sepsis (n=11) compared with those having an uneventful postoperative course (n=7). For the preoperative differentiation between infected necrosis and sterile necrosis guided fine needle aspiration was performed in 24 patients with necrotising pancreatitis and reached a diagnostic accuracy of 84% compared with 87% for PCT, and 68% for IL-8. There was no correlation between the aetiology of acute pancreatitis or the extent of necrosis and PCT or IL-8.Conclusion—PCT and IL-8 are found in high concentrations in infected necrosis and associated systemic complications in patients with acute pancreatitis. The course of PCT shows the closest correlation with the presence of infected necrosis. Monitoring of serum PCT is a potential new marker for the non-invasive and accurate prediction of infected necrosis as well as for the selection of patients with persisting septic complications after surgical debridement.

To extend understanding of the genetic architecture and molecular basis of type 2 diabetes (T2D), we conducted a meta-analysis of genetic variants on the Metabochip, including 34,840 cases and 114,981 controls, overwhelmingly of European descent. We identified ten previously unreported T2D susceptibility loci, including two showing sex-differentiated association. Genome-wide analyses of these data are consistent with a long tail of additional common variant loci explaining much of the variation in susceptibility to T2D. Exploration of the enlarged set of susceptibility loci implicates several processes, including CREBBP-related transcription, adipocytokine signaling and cell cycle regulation, in diabetes pathogenesis. © 2012 Nature America, Inc. All rights reserved.

Objective Insulin-like growth factor (IGF)-1, -2 and Insulin like growth factor binding proteins (IGFBP) are involved in the proliferation and differentiation of cells. It has never been evaluated, if the IGF-system can serve as a tumor marker in neoplasms. Methods In our prospective study 163 patients with colorectal cancer (22), prostate cancer (21), head and neck tumors (17), lymphomas (20), lung cancer (34) and other entities (49) were analysed for their IGF and IGFBP serum levels at the beginning and the end of radiotherapy and compared to 13 healthy people. Subgroups of patients with local tumor disease versus metastatic disease, primary and recurrent therapy and curative versus palliative therapy were compared. Results The serum levels of IGF-2 were significantly elevated in patients with prostate and colorectal cancer. However, sensitivity and specificity were only 70%. IGFBP-2 serum levels were elevated in patients with head and neck tumors. Again sensitivity and specificity were only 73%. A difference between local disease and metastatic disease could not be found. A difference between IGF serum levels before and after radiotherapy could not be detected. Conclusion The IGF-system cannot serve as a new tumor marker. The detected differences are very small, sensitivity and specificity are too low. IGF measurement is not useful for the evaluation of the success of radiotherapy in malignancies.

Background Animal experiments have shown a protective effect of vitamin C on the formation of gallstones. Few data in humans suggest an association between reduced vitamin C intake and increased prevalence of gallstone disease. The aim of this study was to assess the possible association of regular vitamin C supplementation with gallstone prevalence. Methods An observational, population-based study of 2129 subjects aged 18-65 years randomly selected from the general population in southern Germany was conducted. Abdominal ultrasound examination, completion of a standardized questionnaire, compilation of anthropometric data and blood tests were used. Data were collected in November and December 2002. Data analysis was conducted between December 2005 and January 2006. Results Prevalence of gallstones in the study population was 7.8% (167/2129). Subjects reporting vitamin C supplementation showed a prevalence of 4.7% (11/232), whereas in subjects not reporting regular vitamin C supplementation, the prevalence was 8.2% (156/1897). Female gender, hereditary predisposition, increasing age and body-mass index (BMI) were associated with increased prevalence of gallstones. Logistic regression with backward elimination adjusted for these factors showed reduced gallstone prevalence for vitamin C supplementation (odds ratio, OR 0.34; 95% confidence interval, CI 0.14 to 0.81; P = 0.01), increased physical activity (OR 0.62; 95% CI, 0.42 to 0.94; P = 0.02), and higher total cholesterol (OR 0.65; 95% CI, 0.52 to 0.79; P < 0.001). Conclusion Regular vitamin C supplementation and, to a lesser extent, increased physical activity and total cholesterol levels are associated with a reduced prevalence of gallstones. Regular vitamin C supplementation might exert a protective effect on the development of gallstones.

Aim of the study was to determine reference values for the soluble Transferrin Receptor (sTfR) in a cross sectional population sample.For the determination of reference values, using a standard calibrated fluorescence-immunoassay, the samples (990 females; 1060 males; 13 - 65 years old) were divided into five groups according to age and sex. Soluble transferrin receptor and ferritin were measured by a fluorescence-immunoassay with AIA-21 (TOSOH BIOSCIENCE, Tessenderlo, Belgium). The sTfR/logFer-Index was calculated by dividing the sTfR by the logarithm of ferritin, the logsTfR/Fer-Index by dividing the logarithm of sTfR by ferritin.Mean sTfR concentration was 1.75 +/- 0.39 mg/l in group I (13-17 years), 1.65 +/- 0.34 mg/l in group II (18-30 years), 1.60 +/- 0.39 mg/l in group III (31-40 years), 1.54 +/- 0.39 mg/l in group IV (41-50 years), and 1.59 +/- 0.34 mg/l in group V (51-65 years), respectively. A gender-specific difference between the groups was observed: sTfR concentrations were lower in group I (p0.005) and group II (p = 0.01) for women. The mean sTfR-concentration decreased consecutively in the age group I-IV (13-50 years).This is the first cross sectional population based study to determine reference values for sTfR-concentrations. Our results demonstrated age- and gender-specific differences.

In patients with chronic renal failure, secondary hyperparathyroidism (sHPT) is a common problem requiring surgical parathyroidectomy (PTX) if medical treatment with active vitamin D and calcimimetics fails. To minimize the risk for recurrence, we perform total PTX (tPTX) without autotransplantation. From October 1997 to January 2004, 46 patients (31 men and 15 women) underwent tPTX without autotransplantation (median age 51 years; range 19–80 years; median dialysis time before PTX 5 years; range 0–25 years). Indications for PTX were hyperparathyroid bone disease in 41 cases and calciphylaxis in 5 cases. Postoperatively, all patients were supplemented with vitamin D analogues, both calcitriol and cholecalciferol. Patients were followed up for 4–107 months (median 63 months). Although tPTX was intended in all cases, we saw recurrent or persistent hyperparathyroidism in 26% and supernumerary glands in 15% of cases. In 7 patients (15%), five or more glands were documented and in another four suspected confirming the clinical relevance of intraoperative parathyroid hormone (PTH) measurement. In our study, the positive predictive value of a low intraoperative PTH (

Overweight and obesity among children and adolescents are increasing. Fatty liver disease (FLD) is an emerging problem in this age group. We investigated prevalence of overweight and non-invasive FLD and associated clinical characteristics in a representative population-based sample of 378 children and adolescents aged 12–20 years who were randomly selected from the general population in Leutkirch, Southern Germany. Overweight was defined as having a body mass index above the 90th percentile for the respective age and sex. About 15% of female (29 out of 194) and 12% of male participants (22/182) were overweight. Among females, only one non-overweight individual showed signs of FLD but in more than one third of the overweight males (8/22) signs of FLD were present. Overweight subjects in general had an unfavourable lipid profile and abnormal concentrations of obesity-related hormones such as significantly lower concentrations of adiponectin and increased levels of inflammatory markers including C-reactive protein and fibrinogen. Overweight males with signs of FLD showed even more severe altered metabolic responses compared to those who were overweight without signs of liver injury. FLD was not explained by alcohol consumption or other chronic liver disease. In this sample of children and adolescents representative of the general population a high prevalence of non-alcoholic fatty liver disease (NAFLD) is found in overweight males. These individuals showed the most severe metabolic alterations compared to non-overweight and overweight individuals without NAFLD indicating even higher risk for future overweight and obesity-related diseases such as type 2 diabetes and cardiovascular disease.

Objective Interleukin-8 (IL-8, also known as neutrophil-activating peptide 1, NAP1 and CXCL8, CXC chemokine ligand 8) is recognized as a potent effector of neutrophil functions. IL-8 is a major response factor following NfkB activation by cytokines or lipopolysaccharide and several different cell types T lymphocytes, monocytes, epithelial and endothelial cells secrete this polypeptide. IL-8 is not to be determined at significant concentrations in plasma due to its receptor binding but may play a major role in tissues. The prediction of sepsis is a major and current field of research in the treatment of surgical patients. The aim of this study was to compare the determination of IL-8 in whole blood cell lysates (whole blood IL-8) and in plasma for the prediction of sepsis in postoperative intensive care. Design Whole blood IL-8, IL-8 in plasma, and CRP were measured in the daily routine monitoring of 84 patients in a surgical intensive care unit. Sepsis was defined by the criteria of the Society of Critical Care Medicine (SCCM). For comparison the APACHE II score (APACHE = Acute Physiology and Chronic Health Evaluation) was calculated. The diagnostic value of the three tests was compared by receiver operating characteristic (ROC) curves. Results Whole blood IL-8 showed higher areas under the curve (AUC) than IL-8 in plasma and CRP. The ROC curves for the APACHE II scores gave similar results. Conclusions Sepsis is a complex disease and is induced by systemic infection of patients suffering from systemic inflammatory response syndromes (SIRS). Therefore, the identification of infection or the host response to infection is of crucial importance. The prediction of an individual marker or interleukin or its binding to surface proteins is not necessarily indicative for sepsis. In cases with unequivocally identified bacterial infections, the current results suggest that whole blood IL-8 may have a similar diagnostic accuracy as plasma levels. Of note, this technique needs less blood and is not being affected by hemolysis.

The metabolic syndrome is a highly prevalent multifaceted clinical entity. Obesity, which is part of the metabolic syndrome, is the fastest growing health‐related problem worldwide. Since currently prevalence data of the metabolic syndrome are lacking from Germany, we have applied ATP III‐criteria in two urban and rural cohorts. Our population‐based studies provide evidence that the prevalence of the metabolic syndrome increases with age. It was found to be more prevalent in a rural population and in this group it clustered in males. As a consequence of our population‐based studies evidence that especially the rural population is at high risk for future macrovascular complications is substantiated. The urgent need for preventive measures aimed at reducing the significantly increased health risk is underscored.

We compared the manually performed LUMItest® procalcitonin (PCT) assay with the newly developed fully mechanized Kryptor® PCT assay and determined the essential assay characteristics of this assay. The new Kryptor® PCT assay was evaluated according to modified NCCLS EP-10/EP-6 protocols in five different laboratories. Samples from 696 patients were assayed using the original LUMItest® PCT assay and the new Kryptor® PCT assay. Possible interference by hemoglobin, triglycerides and bilirubin was evaluated by spiking patient plasma with the appropriate substances. The functional assay sensitivity (FAS) was determined by analyzing samples with low PCT concentrations. The FAS of the new Kryptor® PCT assay was 0.04 ng/ml and the imprecision within- and between-series below 5% and below 10%, respectively. Within the smallest range of determination, from 0.3 ng/ml to 50 ng/ml, common to the LUMItest® PCT assay (x) and the Kryptor® PCT assay (y) the values correlated well: y=0.64+0.94x, s. xy =2.78 ng/ml. The performance characteristics of the Kryptor® PCT assay are fully compatible with the intended clinical use. The assay allows determination of PCT in a turnaround time (TAT) of about 20 minutes and thus is adequate for STAT analyses.

Peritonitis is a severe illness with a high mortality rate and different treatment modalities. Over a time period of 12 years 510 patients with peritonitis treated with continuous peritoneal lavage (CPL) were retrospectively analyzed. 315 of 510 patients with a mean age of 57.4 and a mean APACHE-II-Score of 10.2 on admission had a diffuse four quadrant peritonitis. 195 had a local and diffuse peritonitis due to perforation of the appendix. 232 of 315 patients with diffuse peritonitis (73.7%) had a secondary peritonitis, mostly due to organ perforation. The most frequent comorbidities were congestive heart failure (36.8%), pulmonary diseases (26%), diabetes mellitus (18.7%), chronic renal failure (16.8%), chronic liver diseases (9.5%) and a history of alcohol abuse (12.4%). On admission 18.7% had pulmonary insufficiency, 18.4% renal failure, 14.3% congestive heart failure and 13.3% hepatic insufficiency. 14% had one organ-, 6.7% two organ-, 2.5% three organ- and 5% four organ failure. The mean duration of lavage was 5.1 days with a fluid amount of 8-24 l/day. 81.3% of all patients could be treated successfully. 46 patients were reoperated due to persistent peritonitis. The mortality rate of the primarily treated patients was 15.6% compared to 37.0% of patients who had to be reoperated. The mortality rate of all patients was 18.7%. The prognosis of the clinical outcome was significantly influenced by preexisting organ failure and by the duration of the peritonitis on admission. Our results on CPL for diffuse peritonitis are in accordance with results from other treatment modalities; a direct comparison was not possible due to the different patient groups.

An assay is described for the determination of interleukin 8 (IL-8) in whole blood lysate instead of plasma or serum. EDTA-anticoagulated umbilical cord blood or capillary blood was added to a detergent-containing lysing reagent. This sample was used directly for determination of IL-8 using the Immulite IL-8 assay kit (DPC, Bad Nauheim, Germany) and the Immulite Analyzer. Linearity was confirmed for cord blood as well as for venous blood, at a whole blood to lysing agent ratio from 1:20 to 1:1. IL-8 was stable in whole blood hemolysate at 4 degrees C for at least 3 days; thereafter, concentrations decreased remarkably to 32% of the initial concentration after 8 days. Storage of whole blood prior to hemolysis led to increases in IL-8 concentrations of up to 4 fold the original values. The intra-assay CV was 3.4% (at 234 ng/l) and 7.4 % (at 1080 ng/l) using hemolysate samples. Inter-assay CVs of 13.3% (at 108 ng/l) and 11.7 % (at 506 ng/l) were found using control material. Concentrations of IL-8 in whole blood were significantly higher than in the corresponding plasma. In 70% of 135 apparently healthy neonates' cord blood samples, plasma IL-8 concentrations were below the detection limit of the assay (5 ng/l), whereas a range of 69 - 3150 ng/l IL-8 (median, 266 ng/l) was found in the hemolysate samples of these neonates. A preliminary reference range for IL-8 in whole blood may be set at 132 to 820 ng/l (5th and 95th percentile). In 78 neonates, IL-8 concentrations in hemolysate from capillary blood ranged from 120 ng/l to 2000 ng/A (median, 416 ng/l). The fact that concentrations of IL-8 can be determined using only a very small sample volume (10 microl of whole blood) makes the assay format especially suitable for use in neonatal intensive care.

In 65 patients with hemophagocytic lymphohistiocytosis (HLH), we found an as yet undescribed heterogeneity of defects in cellular cytotoxicity when assay conditions were modified by the incubation time, the presence of mitogen, or interleukin-2 (IL-2). The standard 4-hour natural killer (NK) test against K562 targets was negative in all patients. In patients deficient in type 1 (n = 21), type 2 (n = 5), and type 4 (n = 8) HLH, negative NK function could be reconstituted by mitogen, by IL-2, or by prolongation of the incubation time (16 hours), respectively. Most patients (n = 31) displayed the type 3 defect, defined by a lack of any cellular cytotoxicity independent of assay variations. The characteristic hypercytokinemia also concerned counterregulatory cytokines, such as proinflammatory interferon-γ (IFN-γ), simultaneously elevated with suppressive IL-10 in 38% of types 1–, 2–, and 4–deficient patients and in 71% of type 3–deficient patients. Elevated IFN-γ alone correlated with high liver enzymes, but sCD95-ligand and sCD25 did not—though these markers were expected to indicate the extent of histiocytic organ infiltration. Outcome analysis revealed more deaths in patients with type 3 deficiency (P = .017). Molecular defects were associated with homozygously mutated perforin only in 4 patients, but other type 3 patients expressed normal transcripts of effector molecules for target-cell apoptosis, including perforin and granzyme family members, as demonstrated by RNase protection analysis. Thus, target-cell recognition or differentiation defects are likely to explain this severe phenotype in HLH. Hyperactive phagocytes combined with NK defects may imply defects on the level of the antigen-presenting cell.

Chemokines mediate the migration of leukocytes to sites of inflammation. Changes in the plasma concentration of interleukin (IL)-8 and macrophage inflammatory protein (MIP)-1beta have not been investigated in the very early phase starting immediately after unintentional trauma. Enrolled in the study were 94 patients with multiple blunt injuries. Blood samples were collected at the scene of accident, then at regular intervals for 24 h. IL-8 and MIP-1beta plasma levels were determined by commercial test kits. Patients were grouped according to trauma severity, pattern of injury, as well as survivors vs. nonsurvivors. Serious casualties [Injury Severity Score (ISS)or = 32] revealed a significant increase in IL-8 compared to only a slight elevation in individuals with an ISS32. Nonsurvivors showed a highly significant (P0.005) increase in IL-8 levels beginning immediately after admission. Trauma resulted in a modest activation of MIP-1beta production without differences regarding trauma severity, pattern of injury, or survival. A very strong trauma stimulus is necessary to activate IL-8 production. In contrast to MIP-1beta, IL-8 levels were significantly elevated in nonsurvivors compared to survivors. Therefore, IL-8 might be an early predictor of survival.

Our objective was to evaluate the influence of pre-operative oral application of an immunoglobulin-enriched milk preparation on endotoxin translocation and mediator release during and after abdominal surgery. Forty patients who had been treated by partial (n = 4) or total gastrectomy (n = 8) or pancreatic resection (n = 28) were enrolled in a placebo-controlled pilot study. Pre-operatively, patients were randomly treated for 3 days by oral application of a bovine milk preparation (lactobin 56g/day, n = 20) or placebo (n = 20). In both groups, endotoxin translocation and mediator release was studied pre- and intraoperatively by measuring endotoxin, endotoxin-neutralizing capacity (ENC), interleukin 6, C-reactive protein, transferrin, alpha-2-macroglobulin, albumin, apoliprotein-A1/-B, IgG, IgA, and IgM. The clinical course was followed up by daily evaluation of the Apache-II-score. Clinical data were comparable in both groups. The lactobin group showed significantly lower levels of endotoxin and ENC compared to the placebo group. Acute phase response, endotoxin-binding proteins, and clinical outcome did not differ between both groups. We conclude that prophylactic oral application of lactobin reduces perioperative endotoxemia and prevents reduction of ENC, suggesting a stabilization of gut barrier during abdominal surgery.

In a prospective observational study of 133 neutropenic episodes, interleukin (IL)-8 serum levels > 2000 pg/mL at the onset of fever had a sensitivity of 53% and a specificity of 97% as a predictor of gram-negative bacteremia (GNB; positive predictive value, 73%; negative predictive value, 94%). The rates of early death differed significantly between patients with high and those with low IL-8 levels (3/11 vs. 1/122; P< .01). Serum IL-8 levels at the onset of fever define a low-risk subgroup of patients who can safely be treated with monotherapy.

Objective.To examine whether the determination of interleukin 8 (IL-8) and C-reactive protein (CRP) in neonates with suspected nosocomial bacterial infection (NBI) is feasible and cost-effective in reducing antibiotic therapy.Methods.Between April 1996 and May 1997, IL-8 was measured 260 times along with blood cultures, CRP, and immature-to-total-neutrophil (IT) ratio for suspected NBI in term and preterm neonates. All infants were retrospectively analyzed for NBI. Sensitivity, specificity, positive and negative predictive values, and 95% confidence intervals were calculated for IL-8, CRP, and IT ratio. Receiver-operating characteristic curves were analyzed to determine optimal thresholds. Between June 1997 and June 1998, IL-8 was measured 215 times in newborn infants with suspected NBI and the decision to start antibiotic therapy was based on increased IL-8 and/or CRP values. A cost-effectiveness analysis was performed and sensitivity, specificity, and receiver-operating characteristic curves were reevaluated.Results.At the first suspicion of NBI, the combination of IL-8 ≥ 53 pg/mL and/or CRP >10 mg/L detected culture-proven NBI with 96% sensitivity. The combined culture-proven and clinical NBI were detected with 93% sensitivity and 80% specificity. The use of IL-8 reduced unnecessary antibiotic therapy for suspected NBI by 73% and was cost-effective when compared with initiating antibiotic therapy based on clinical signs alone or based on clinical signs and an increased IT ratio and/or CRP.Conclusions.The combination of IL-8 and/or CRP is a reliable and early test for the diagnosis of NBI in newborn infants. Using the combination of IL-8 and/or CRP to restrict antibiotic therapy to truly infected infants reduces unnecessary antibiotic therapy and is cost-effective.

To evaluate procalcitonin (PCT) as a test for early diagnosis of bacterial infections (BI) in newborn infants and to compare the results of PCT with those of interleukin 8 (IL-8), C-reactive protein (CRP) and differential white blood cell count.PCT was prospectively measured along with IL-8, CRP and differential white blood cell counts and blood cultures in 197 newborn infants at the first suspicion of bacterial infection. PCT, IL-8, CRP and differential white blood cell counts were analyzed for sensitivity, specificity and positive and negative predictive values after receiver operating characteristic curve analysis for best thresholds. The kinetics of PCT was determined in infants with and without BI.Forty-six infants were diagnosed clinically as having BI, of whom 9 had BI with positive blood cultures. At a cutoff value of 0.50 microg/l, PCT detected combined culture-proved and clinical BI with a sensitivity of 57% (95% confidence interval, 41%, 71%) and a specificity of 66% (95% confidence interval, 57%, 74%). The combination of IL-8or =70 ng/l and/or CRP10 mg/l achieved a sensitivity of 91% (95% confidence interval, 79%, 98%) and a specificity of 73% (95% confidence interval, 64%, 81%). PCT values of infected and not infected infants tended to rise for 24 h after initial evaluation and then decreased.The combination of IL-8 and CRP is more reliable than PCT as a test for early diagnosis of BI in newborn infants.

We assessed the predictive value of procalcitonin (PCT) serum levels in neutropenic patients with fever and various types of infection, using a prospective 3 times weekly blood sampling protocol during 103 patient episodes. Compared with pre-fever levels, median PCT levels increased after fever onset from 0.16 ng/ml (day -1) to 0.34 ng/ml (day +1). In samples obtained within 32 h after fever onset, PCT levels differed significantly between (clinically or microbiologically) documented infection and unexplained fever (median 0.51 vs. 0.26 ng/ml), between bacteraemia and non-bacteraemic infection (median 0.8 vs. 0.27 ng/ml) and between Gram-negative bacteraemia and all other episodes (median 1.28 vs. 0.31 ng/ml). Receiver-operating-characteristic (ROC) curves indicated that the discriminatory power of PCT was best for predicting bacteraemia vs. non-bacteraemic infection (sensitivity 73%; specificity 86%; area under the ROC curve 0.795; cut-off value 0.5 ng/ml). Compared with interleukin-8 (IL-8) serum levels, test characteristics were similar in the prediction of bacteraemia vs. non-bacteraemic infection and in the prediction of documented infection vs. unexplained fever, while IL-8 was better than PCT in the prediction of Gram-negative bacteraemia (area under the ROC curve 0.965 vs. 0.758).

We investigated and compared serum levels of cardiac troponins I(cTnI) and cardiac troponin T (cTnT) in 85 renal patients (chronic renal impairment n = 23, continuous ambulatory peritoneal dialysis n = 20, hemodialysis n = 42). Patients with the following conditions were excluded: myocardial infarction, angina pectoris, liver disease, malignant neoplasms, enforced physical activity, skeletal muscle trauma, myositis, rhabdomyolysis and seizures. Troponin T was measured by the second generation cTnT-ELISA with a cutoff value = 0.1 μg/l. Troponin I was measured by a cTnI immunoassay analyser with a cut-off value = 2.0 μg/l. Additionally, creatine kinase (CK), CK-MB activity, CKMB mass concentration and myoglobin levels were measured. Specificity was determined as the fraction of true-negative cases compared to the total number of false-positive and true-negative cases. Specificity for cTnT was 96 % [78–100] in patients with renal impairment (creatinine > 150 μmol/l), 95 % [75–100] in continuous ambulatory peritoneal dialysis patients, but in hemodialysis patients it was 75 % [53–92] for short-term hemodialysis (< 1 year) and 46 % [24–68] for long-term hemodialysis (> 1 year). There was a weak correlation between cTnT levels and duration of hemodialysis therapy (r = 0.35, n = 34, p < 0.04). Specificity for cTnI in renal impairment patients was 96 % [78–100] and 100 % [84–100] in continuous ambulatory peritoneal dialysis and all hemodialysis patients. None of the studied markers showed higher specificity than cTnI. Only myoglobin was less specific than cTnT in hemodialysis patients. Different clearances of the troponins during dialysis (investigated by pre-hemodialysis and post-hemodialysis levels) cannot explain the discordant results of cTnT and cTnI. Conclusion: Cardiac troponin I exhibits higher specificity than cardiac troponin T in hemodialysis patients. Uremic myopathy could explain falsely elevated troponin T levels in hemodialysis patients.

18 Background: Insulin-like growth factor (IGF)-1, -2 and insulin-like growth factor binding proteins (IGFBP) are involved in the proliferation and differentiation of cells. It has never been evaluated if the IGF-system can serve as a tumor marker in neoplasms. Methods: In our prospective study, 163 patients with colorectal cancer (22), prostate cancer (21), glioblastoma (12), head and neck tumors (17), lymphomas (20), lung cancer (34), and other entities (37) were analysed for their IGF and IGFBP serum levels at the beginning and the end of radiotherapy and compared with 13 healthy people. Subgroups of patients with local tumor disease versus metastatic disease, primary and recurrent therapy and curative versus palliative therapy were compared. Results: The serum levels of IGF-2 were significantly elevated in patients with prostate and colorectal cancer. However, sensitivity and specificity were only 70%. IGFBP-2 serum levels were elevated in patients with head and neck tumors. Again, sensitivity and specificity were only 73%. A difference between local disease and metastatic disease could not be found. A difference between IGF serum levels before and after radiotherapy could not be detected. Conclusions: The IGF-system cannot serve as a new tumor marker. The detected differences are very small and sensitivity and specificity are too low. IGF measurement is not useful for the evaluation of the success of radiotherapy in malignancies.

5592 Background: Determination of renal function is a prerequisite for planning therapy in cancer patients. Limitations of creatinine as marker for the glomerular filtration rate (GFR) led to the p...

Hypothesis: Interleukin 6 (IL-6), a multifunctional cytokine, is expressed by various cells after many stimuli and underlies complex regulatory control mechanisms. Following major trauma, IL-6 release correlates with injury severity, complications, and mortality. The IL-6 response to injury is supposed to be uniquely consistent and related to injury severity. Therefore, we designed a prospective study starting as early as at the scene of the unintentional injury to determine the trauma-related release of plasma IL-6 in multiple injured patients. Patients and Methods: On approval of the local ethics committee, 94 patients were enrolled with different injuries following trauma (Injury Severity Score [ISS] median, 19; range, 3-75). The patients were rescued by a medical helicopter. Subsets were performed according to the severity of trauma—4 groups (ISS, ,9, 9-17, 18-30, and .32)—and survival vs nonsurvival. The first blood sample was collected at the scene of the unintentional injury before cardiopulmonary resuscitation, when appropriate. Then, blood samples were collected in hourly to daily intervals. Interleukin 6 plasma levels were determined using a commercial enzyme-linked immunosorbent assay test. The short-term phase protein, Creactive protein, was measured to characterize the extent of trauma and to relate these results to IL-6 release. Results: As early as immediately after trauma, elevated IL-6 plasma levels occurred. This phenomenon was pronounced in patients with major trauma (ISS, .32). Patients with minor injury had elevated concentrations as well but to a far lesser extent. In surviving patients, IL-6 release correlated with the ISS values best during the first 6 hours after hospital admission. All patients revealed increased C-reactive protein levels within 12 hours following trauma, reflecting the individual injury severity. This was most pronounced in patients with the most severe (ISS, .32) trauma. Conclusions: To our knowledge, this is the first study that elucidates the changes in the IL-6 concentrations following major trauma in humans as early as at the scene of the unintentional injury. The results reveal an early increase of IL-6 immediately after trauma. Moreover, patients with the most severe injuries had the highest IL-6 plasma levels. There is strong evidence that systemic IL-6 plasma concentrations correlate with ISS values at hospital admission. Therefore, IL-6 release can be used to evaluate the impact of injury early regardless of the injury pattern.