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Although amateur sports have become increasingly competitive within recent decades, there are as yet few studies on the possible health risks for athletes. This study aims to determine the impact of ultra-endurance exercise-induced stress on the number and function of circulating hematopoietic progenitor cells (CPCs) and hematological, inflammatory, clinical, metabolic, and stress parameters in moderately trained amateur athletes. Following ultra-endurance exercise, there were significant increases in leukocytes, platelets, interleukin-6, fibrinogen, tissue enzymes, blood lactate, serum cortisol, and matrix metalloproteinase-9. Ultra-endurance exercise did not influence the number of CPCs but resulted in a highly significant decline of CPC functionality after the competition. Furthermore, Epstein-Barr virus was seen to be reactivated in one of seven athletes. The link between exercise-induced stress and decline of CPC functionality is supported by a negative correlation between cortisol and CPC function. We conclude that ultra-endurance exercise induces metabolic stress and an inflammatory response that affects not only mature hematopoietic cells but also the function of the immature hematopoietic stem and progenitor cell fraction, which make up the immune system and provide for regeneration.

Testing for (1→3)-beta-D-glucan (BDG) is used for detection of invasive fungal infection. However, current assays lack automation and the ability to conduct rapid single-sample testing. The Fungitell assay was adopted for automation and evaluated using clinical samples from patients with culture-proven candidemia and from culture-negative controls in duplicate. A comparison with the standard assay protocol was made in order to establish analytical specifications. With the automated protocol, the analytical measuring range was 8-2500 pg/ml of BDG, and precision testing resulted in coefficients of variation that ranged from 3.0% to 5.5%. Samples from 15 patients with culture-proven candidemia and 94 culture-negative samples were evaluated. All culture-proven samples showed BDG values >80 pg/ml (mean 1247 pg/ml; range, 116-2990 pg/ml), which were considered positive. Of the 94 culture-negative samples, 92 had BDG values

Activated protein C (APC) resistance (Dahlback et al, 1993) is a common risk factor for venous thromboembolism (Bucciarelli et al, 1999). This phenotype is highly associated with the F5 R506Q (F5 rs6025; factor V Leiden, FVL) mutation (Bertina et al, 1994). Heterozygous and homozygous discrepancies between F5 R506Q genotype and phenotype (APC resistance), known as pseudo-homozygosity, have been described (Castaman et al, 1997; Brugge et al, 2005). This incidental phenomenon suggests that, based on APC-resistance testing, there is a homozygous F5 R506Q mutation, yet, genetic testing only shows a heterozygous F5 R506Q mutation (Simioni et al, 1996). In such cases, polymorphisms located on the second factor V (FV) protein coding allele (i.e. wild-type for F5 R506Q) cause intracellular decreased FV protein production, leading to reduced FV activity (Castoldi et al, 1998). In contrast, the phenomenon “pseudo-wild-type” FVL, suggesting a wild-type F5 R506Q according to APC resistance testing but heterozygous F5 R506Q mutation by genetic testing, is infrequently described (Dargaud et al, 2003; Asselta et al, 2004). In these two studies, the polymorphisms responsible for the reduced FV protein levels were found to be located on the same FV protein coding allele, together with the F5 R506Q mutation.

Malondialdehyde (MDA) is considered to be a biomarker for enzymatic degradation and lipid peroxidation of polyunsaturated fatty acids. Usually, MDA determination from different biological materials is performed by reaction with thiobarbituric acid (TBA) followed by high-performance liquid chromatography (HPLC) analysis and fluorometric detection. As this method lacks specificity and sensitivity, we developed a gas chromatography-mass spectrometry (GC-MS) method based on derivatization of MDA with 2,4-dinitrophenylhydrazine. Representative ions in negative ion chemical ionization (NICI) mode were recorded at m/z 204 for MDA and at m/z 206 for the deuterated analogon (MDA-d₂) as internal standard. This stable and precise GC-MS method showed good linearity (r² = 0.999) and higher specificity and sensitivity than the HPLC method and was validated for both total MDA (t-MDA) and free MDA (f-MDA). Within-day precisions were 1.8-5.4%, between-day precisions were 4.8-9.2%; and accuracies were between 99% and 101% for the whole calibration range (0.156-5.0 μmol/L for t-MDA and 0.039-0.625 μmol/L for f-MDA). Although comparison of t-MDA levels from GC-MS and HPLC results using Passing-Bablok regression analysis as well as Bland-Altman plot showed a correlation of the data, a tendency to increased results for the HPLC values was detectable, due to possible formation of unspecific products of the TBA reaction.

The mechanisms underlying the pathogenesis of obesity-related atherosclerosis remain to be clarified. To investigate the preclinical phase, interleukin-6 (IL-6) plasma levels were analyzed together with clinical, anthropometric, inflammatory, and metabolic variables in a well-defined cohort of 677 young and middle-aged overweight/obese and normal-weight subjects. In the juvenile and adult overweight/obese study group, IL-6 levels were increased significantly compared with normal-weight, age-matched controls (P0.001). In both juveniles and adults, higher levels of IL-6 were observed in obese compared with overweight participants. Subjects with metabolic syndrome (MS) had significantly higher IL-6 levels than those without MS. In juveniles, leptin, and in adults, the waist-to-height ratio, turned out to be the best predictor of IL-6 plasma levels in a multiple stepwise regression model. Taken together, in every age group, interleukin-6 is associated positively with the grade of overweight. Interestingly, leptin, which is the best known adipokine, is associated predictively with interleukin-6 plasma levels only in juveniles, which may indicate an important role of this molecule in the initiation of obesity-related inflammation.

Aim: Mild hypothermia (MH) after cardiac arrest attenuates hypoxic brain injury and improves survival. As MH increases contractility in normal hearts, we hypothesized that MH improves cardiovascular function after cardiac arrest. Methods: In 16 anaesthetized pigs (64 ± 2 kg), ventricular fibrillation was induced electrically for 5 min. At 10 min after resuscitation and return of spontaneous circulation (ROSC), pigs were assigned to normothermia (NT, 38 °C, n = 8) or MH (33 °C, n = 8, intravascular cooling). Results: At ROSC 6 h vs. baseline, heart rate (HR) was unchanged in NT, but decreased in MH. Cardiac output (CO, l min−1) decreased in MH (3.5 ± 0.2 vs. 5.5 ± 0.4, P

Kniepeiss D, Renner W, Trummer O, Wagner D, Wasler A, Khoschsorur GAli, Truschnig-Wilders M, Tscheliessnigg K-H. The role of CYP3A5 genotypes in dose requirements of tacrolimus and everolimus after heart transplantation. Clin Transplant 2011: 25: 146–150. © 2009 John Wiley & Sons A/S. Abstract: Background: tacrolimus and everolimus are immunosuppressive drugs metabolized by enzymes of the CYP3A subfamily. A common variant of the CYP3A5 gene, CYP3A5*3, results in strongly decreased CYP3A5 activity and has been shown to influence Tacrolimus blood concentrations, but its role for the pharmacogenetics of Everolimus remains unclear. Aim of the study was to examine the role of CYP3A5*3 variant in tacrolimus and everolimus dose and drug levels after heart transplantation. Methods: The present study comprised 15 patients with Tacrolimus and 30 patients with Everolimus-based maintenance therapy after heart transplantation. CYP3A5 genotypes were determined and correlated with clinical data. Results: In the Tacrolimus group, 13 subjects were CYP3A5 non-expressors (*3/*3 genotype) and two were heterozygous expressors (*1/*3 genotype). Average Tacrolimus dose was significantly higher in subjects expressing CYP3A5 compared to non-expressors. Tacrolimus levels were not significantly different at any point of time. In the Everolimus group, 27 subjects were CYP3A5 non-expressors (*3/*3 genotype) and three were heterozygous expressors (*1/*3). Neither Everolimus dose nor levels were significantly different between CYP3A5 expressors and non-expressors at any point of time. Discussion: We conclude that in adult patients after heart transplantation, CYP3A5 genotypes have a strong influence on Tacrolimus, but not Everolimus dose requirement.

The development of atherosclerotic lesions leading to myocardial infarction (MI) or stroke encompasses a cascade of cellular and molecular events that can well be characterized as a chronic immune-mediated inflammation occurring preferentially in the biologic surrounding of the so called metabolic syndrome. Adipokines, chemokines, cytokines, and their receptors are critically involved in the initiation and perpetuation of atherosclerosis, and they play important roles at all levels in the pathogenesis of this disease. Metabolic risk profiles associated with sedentary lifestyle, obesity, especially intra-abdominal fat accumulation, insulin resistance, and dyslipidemia pave the way for a chronic, immune-mediated vascular inflammation around vascular lipid deposits. In the present article, the impact of adiponectin, monocyte and T-cell associated cytokines (with emphasis on Neopterin), individual adipose tissue - distribution and pleiotropic drug effects on the individual course of atherosclerosis and associated cardiovascular disease are reviewed.

OBJECTIVE We tested whether mild hypothermia impacts on circulatory and respiratory dysfunction during experimental endotoxemia. DESIGN Randomized controlled prospective experimental study. SETTING Large animal facility, Medical University of Graz, Austria. SUBJECTS Thirteen anesthetized and mechanically ventilated pigs. INTERVENTIONS Lipopolysaccharide was administered for 4 hours. With the beginning of lipopolysaccharide infusion, animals were assigned to either normothermia (38°C, n = 7) or mild hypothermia (33°C, n = 6, intravascular cooling) and followed for 8 hours in total. MEASUREMENTS AND MAIN RESULTS At the end of the protocol, cardiac output was lower in mild hypothermia than in normothermia (4.5 ± 0.4 L/min vs 6.6 ± 0.4 L/min, p < 0.05), but systemic vascular resistance (885 ± 77 dyn·s/cm vs 531 ± 29 dyn·s/cm, p < 0.05) and (Equation is included in full-text article.)(77% ± 6% vs 54% ± 3%, p < 0.05) were higher. Indices of left ventricular contractility in vivo were not different between groups. The high-frequency band in spectral analysis of heart rate variability indicated a better preserved vagal autonomic modulation of sinuatrial node activity in mild hypothermia versus normothermia (87 ± 5 vs 47 ± 5, normalized units, p < 0.05). Plasma norepinephrine levels were elevated compared with baseline in normothermia (2.13 ± 0.27 log pg/mL vs 0.27 ± 0.17 log pg/mL, p < 0.05) but not in mild hypothermia (1.02 ± 0.31 vs 0.55 ± 0.26, p = not significant). At 38°C in vitro, left ventricular muscle strips isolated from the mild hypothermia group had a higher force response to isoproterenol. SaO2 (100% ± 0% vs 92% ± 3%, p < 0.05) and the oxygenation index (PO2/FIO2, 386 ± 52 mm Hg vs 132 ± 32 mm Hg, p < 0.05) were substantially higher in mild hypothermia versus normothermia. Plasma cytokine levels were not consistently different between groups (interleukin 10) or higher (tumor necrosis factor-α and interleukin 6 and 8) during mild hypothermia versus normothermia. CONCLUSION The induction of mild hypothermia attenuates cardiac and respiratory dysfunction and counteracts sympathetic activation during experimental endotoxemia. This was not associated with lower plasma cytokine levels, indicating a reduction of cytokine responsiveness by mild hypothermia.

Endogenous thrombin generation (ETP) may be critically involved in obesity associated thromboembolism.Three hundred and one participants of the STyrian Juvenile OBesity (STYJOBS)/Early DEteCTion of Atherosclerosis (EDECTA) study cohort (age, 16-58years) were analysed. ETP was measured by the new CE-IVD marked Siemens-Innovance(®) ETP test on a BCS-XP analyser, and correlated to clinical findings and extended lipometry-based anthropometric data, biomarkers, and coagulation parameters.In the overweight/obese study group, ETP and fibrinogen levels were significantly higher compared to controls (p0.001). In a multiple stepwise regression including all subjects, subcutaneous adipose tissue thickness of upper back, cholesterol and ultrasensitive C-reactive protein were the best predictors for ETP.Trunk weighted obesity together with low grade inflammation and hypercholesterolemia enhance thrombin generation.

Obesity related dyslipidemia, chronic inflammation and oxidative stress were associated with atherosclerotic sequels. We analysed oxidized low-density lipoprotein (oxLDL) plasma levels of 797 participants of the STyrian Juvenile OBesity (STYJOBS) / Early DEteCTion of Atherosclerosis (EDECTA) Study cohort aged from 5 to 50 years. The rationale of STYJOBS/EDECTA is to investigate the preclinical phase of obesity by a well defined cohort of young and middle aged overweight/obese and normal weight subjects.Plasma oxLDL was analysed by ELISA (Mercodia, Sweden). In the overweight/obese (OW/OB) study group, oxLDL levels were significantly increased compared to normal weighted controls (p0.001). Probands with metabolic syndrome (MS) had significantly higher oxLDL levels than probands without MS; between overweight and obese participants, and between females and males, no significant difference was seen. In a multiple stepwise regression analysis including all study subjects, age, gender, anthropometric data, presence of metabolic syndrome, systolic, diastolic blood pressure, carotis communis intima media thickness, lipids, adipokines, metabolic, and inflammatory biomarkers, decreased high-density lipoprotein (HDL-cholesterol) and increased total cholesterol were the best predictors for increased oxLDL levels.Decreased HDL-cholesterol is an important determinant of lipid peroxidation irrespective of obesity, age, gender, SAT distribution, and inflammatory/metabolic biomarkers.

tacrolimus and everolimus are immunosuppressive drugs metabolized by enzymes of the CYP3A subfamily. A common variant of the CYP3A5 gene, CYP3A5*3, results in strongly decreased CYP3A5 activity and has been shown to influence Tacrolimus blood concentrations, but its role for the pharmacogenetics of Everolimus remains unclear. Aim of the study was to examine the role of CYP3A5*3 variant in tacrolimus and everolimus dose and drug levels after heart transplantation.The present study comprised 15 patients with Tacrolimus and 30 patients with Everolimus-based maintenance therapy after heart transplantation. CYP3A5 genotypes were determined and correlated with clinical data.In the Tacrolimus group, 13 subjects were CYP3A5 non-expressors (*3/*3 genotype) and two were heterozygous expressors (*1/*3 genotype). Average Tacrolimus dose was significantly higher in subjects expressing CYP3A5 compared to non-expressors. Tacrolimus levels were not significantly different at any point of time. In the Everolimus group, 27 subjects were CYP3A5 non-expressors (*3/*3 genotype) and three were heterozygous expressors (*1/*3). Neither Everolimus dose nor levels were significantly different between CYP3A5 expressors and non-expressors at any point of time.We conclude that in adult patients after heart transplantation, CYP3A5 genotypes have a strong influence on Tacrolimus, but not Everolimus dose requirement.

(Headache 2010;50:109-116) Background.— The group of catecholamines, which include dopamine, adrenaline, and noradrenaline, are neurotransmitters which have been considered to play a role in the pathogenesis of migraine. However, the impact of catecholamines, especially dopamine on migraine as well as the exact mechanisms is not clear to date as previous studies have yielded in part conflicting results. Objective.— This study aimed to produce a comprehensive examination of dopamine in migraineurs. Methods.— Catecholamines and various parameters of the homocysteine, folate, and iron metabolism as well as cyclic guanosine monophosphate (cGMP) and inflammatory markers were determined in 135 subjects. Results.— We found increased dopamine levels in the headache free period in female migraineurs but not in male patients. Increased dopamine is associated with a 3.30-fold higher risk for migraine in women. We found no significant effects of aura symptoms or menstrual cycle phases on dopamine levels. Dopamine is strongly correlated with cGMP and the homocysteine—folate pathway. Conclusion.— We show here that female migraineurs exhibit increased dopamine levels in the headache free period which are associated with a higher risk for migraine.

Congenital human cytomegalovirus (hCMV) infection is the most common intrauterine viral disease in western countries. Little is known about hCMV virus load in various body fluids of congenitally infected children.To determine virus load in various body fluids. To assess the impact of hCMV virus load to predict the outcome of congenitally infected newborns and efficacy of antiviral therapy.Cord vein blood, urine, and cerebrospinal fluid (CSF) of congenitally hCMV-infected children were investigated and hCMV load was determined by quantitative polymerase chain reaction (PCR). Fourteen of 30 children had clinical symptoms and/or pathological laboratory results and 16 had none of them at birth. Ganciclovir was given to 21 children (10 of them with symptoms, 11 of them without symptoms). Viral load before and after therapy was measured.There was a significant difference between median virus load in cord vein blood (2.3 x 10(3) copies per ml) and in urine (4.2 x 10(5) copies per ml; P0.001) at diagnosis of congenital hCMV infection. At that time, no significant difference of virus load was found between the various groups (symptomatic vs. asymptomatic; with therapy vs. without therapy), neither in serum nor in urine. Comparing median virus load in urine before (3.0 x 10(5) copies per ml) and after therapy (2.0 x 10(3) copies per ml), a significant decrease was observed (P0.001). Virus load in CSF was always found to be less than 400 copies per ml, and only those children with symptoms showed a positive result.At birth, virus load in urine seems to be superior to that in cord vein blood to reflect the situation in the organs precisely. As predicting factor for the risk of developing symptoms, only hCMV detection in the CSF appears to be promising. The significant decrease of virus load in children with therapy may reflect the efficacy of therapy. Studies including a greater number of children are needed.

Although cytomegalovirus infection is the most common infection transmitted via the placenta, there are no guidelines for routine screening to detect children congenitally infected with cytomegalovirus. From 1993 to 1997, maternal serum and cord vein blood of newborns was screened for HCMV-IgM (n = 21,183). Urine was examined for HCMV-excretion during the first postnatal week to prove HCMV infection in children who expressed HCMV-IgM in cord vein blood (n = 13) or who were born to mothers positive for HCMV-IgM in the serum (n = 234), or when both cord vein blood and maternal serum were positive for HCMV-IgM (n = 6). Congenital HCMV infection was detected in 17 newborns. To determine the incidence of congenital HCMV infection, only those mother/child pairs were selected in whom serum and cord vein blood were investigated (n = 5967 mother/child pairs). In this group 13 newborns were infected. The observed incidence for congenital HCMV infection is 0.21%. It is concluded that that this screening programme will detect those children at risk for congenital HCMV infection. These children have to be examined for virus excretion in the urine. Although the observed incidence is only 0.21%, congenital HCMV infection is a problem that can no longer be neglected because of its long-term sequelae.