Reference data on estrogen metabolome in healthy pregnancy.

INTRODUCTION: Estrogen hormones and their metabolites are implicated in the maintenance of healthy pregnancy and adequate fetal development. Abnormal levels were related to increased risk of pregnancy complications, particularly preeclampsia. Our aims were (1) to develop a methodological platform for the comprehensive assessment of estrogen metabolome in pregnancy; (2) to collect healthy reference data for relevant elements of estrogen metabolome in each trimester; (3) to assess unconjugated fractions of the estrogen metabolome, (4) to assess the dominant metabolic pathways of estrogen compounds. METHODS: We enrolled healthy pregnant mothers between gestational week 5-15 (on the confirmation of pregnancy; 79 samples), gestational weeks 19-27 (70 samples), and gestational week 34-39 (54 samples). A method employing liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed to assess estrone, 17-beta-estradiol, estriol levels, and their metabolites as conjugated and unconjugated forms. Descriptive statistics were used to characterize the level of compounds in each trimester. RESULTS: Estrone, 17-beta-estradiol and estriol levels are dramatically increasing with the advancement of pregnancy. Measured levels were in a very wide range. 17-beta-estradiol is neither glucuronated nor sulphated. To the contrary, estriol and estrone are significantly conjugated; unconjugated fraction is <15% of total hormone levels in any trimester. Regarding metabolism, 4-methoxy-estradiol and 17-epiestriol were not detected. CONCLUSION: We concluded that (1) the levels of estrogen compounds and metabolites increase with advancing gestational age; (2) the wide ranges of levels challenge the establishment of a healthy reference range for clinical purposes; (3) 17-beta-estradiol is not conjugated significantly; (4) 4-methylation and 17-epimerization pathways of estrogens are negligible with our LC-MS/MS method.

Interrelationship of hemoglobin A1c level lipid profile, uric acid, C-reactive protein levels and age in a large hospital database.

INTRODUCTION: Hemoglobin A1c (HbA1c) is used to monitor glucose homeostasis and to identify risk for diabetes. As diabetic patients are frequently present with dyslipidaemia, low-grade inflammation and hyperuricemia, we tested whether HbA1c levels can be estimated having the information about lipid profile, uric acid (UA) and C-reactive protein (CRP) levels. We developed formulas to describe the association of these parameters with HbA1c levels. METHODS: Data of 9599 male and 10,817 female patients, measured between 2008 and 2018, were analysed. Patients represented a general hospital patient population with overrepresentation of those with elevated HbA1c over 5.6%. The impact of gender, age, CRP, lipid profile and UA levels on HbA1c % on HbA1c levels was tested with multiple linear regression model. The magnitude of effects of individual factors was used to develop formulas to describe the association between HbA1c and other cardiometabolic parameters. With these formulas we estimated median HbA1c values in each age in both gender and compared them to measured HbA1c levels. RESULTS: The developed formulas are as follow: HbA1c (estimated) in women = 0.752 + 0.237*log10(HDL/cholesterol) + 0.156*log10 (cholesterol) + 0.077*log10 (triglyceride) + 0.025*log10(CRP) +0.001*log10 (age) -0.026*log10(HDL/LDL) -0.063*log10 (uric acid)-0.075*log10 (LDL)-0.199*log10(HDL); HbA1c (estimated) in men = 1.146 + 0.08*log10 (triglyceride) + 0.046*log10(CRP) + 0.01*log10 (cholesterol) + 0.001*log10 (age) -0.014*log10(HDL)-0.018*log10(HDL/LDL)-0.025*log10(HDL/cholesterol) -0.068*log10 (LDL)-0.159*log10 (uric acid) Between 20 and 70 years of age, estimated HbA1c matched perfectly to measured HbA1c in. CONCLUSION: At population level, HbA1c levels can be estimated almost exactly based on lipid profile, CRP and uric acid levels in female patients between 20 and 70 years.

Short term ciprofloxacin and clindamycin combination antibiotic therapy before and after transrectal ultrasound scan and prostate biopsy: Its impact on major components of gut microbiome.

The perturbation of gut microbiome is a risk factor for a number of adverse conditions. Among other factors antibiotic therapy is a common culprit. We characterized the short-term alteration of gut microbiome after antibiotic therapy. Nine patients (age (median [range]): 67 [57-75 years]) were subjected to prostate biopsy. Ciprofloxacin and clindamycin, 500 mg and 150 mg, respectively, were administered twice a day; this combination therapy was started the day before and continued until 5th and 8th day, respectively, following biopsy. 16s RNA sequencing data from fecal swabs taken before antibiotic therapy and 14 days after biopsy were analysed. At phylum level, the abundance of Actinobacteria and Firmicutes decreased, while that of Bacteroides and Proteobacteria increased after antibiotic therapy. The ratio of Firmicutes:Bacteroides inversed (from 2.81 to 0.74, p = 0.035). At order level, the abundance of Bacteroidales and Veillonellales increased, while that of Clostridiales and Coriobacteriales decreased. At genus level the abundance of Bacteroides increased, while those of Roseburia, Faecalibacterium and Collinsella decreased. These findings indicate that short-term antibiotic exposure skews gut microbiome composition. The current level of knowledge does not allow to decide whether this skewness is detrimental and has any long-term effect on disease including prostate pathology.

A High-Throughput Clinical Laboratory Methodology for the Therapeutic Monitoring of Ibrutinib and Dihydrodiol Ibrutinib.

Ibrutinib (IBR) is an oral anticancer medication that inhibits Bruton tyrosine kinase irreversibly. Due to the high risk of adverse effects and its pharmacokinetic variability, the safe and effective use of IBR is expected to be facilitated by precision dosing. Delivering suitable clinical laboratory information on IBR is a prerequisite of constructing fit-for-purpose population and individual pharmacokinetic models. The validation of a dedicated high-throughput method using liquid chromatography-mass spectrometry is presented for the simultaneous analysis of IBR and its pharmacologically active metabolite dihydrodiol ibrutinib (DIB) in human plasma. The 6 h benchtop stability of IBR, DIB, and the active moiety (IBR+DIB) was assessed in whole blood and in plasma to identify any risk of degradation before samples reach the laboratory. In addition, four regression algorithms were tested to determine the optimal assay error equations of IBR, DIB, and the active moiety, which are essential for the correct estimation of the error of their future nonparametric pharmacokinetic models. The noncompartmental pharmacokinetic properties of IBR and the active moiety were evaluated in three patients diagnosed with chronic lymphocytic leukemia to provide a proof of concept. The presented methodology allows clinical laboratories to efficiently support pharmacokinetics-based precision pharmacotherapy with IBR.

Urine soluble urokinase plasminogen activator receptor as a potential biomarker of lupus nephritis activity.

There is a lack of non-invasive biomarkers to identify lupus nephritis (LN). Soluble urokinase plasminogen activator receptor (suPAR) is a sensitive biomarker of ongoing inflammation and a potential marker of podocyte dysfunction. The aim of this study was to assess urine and plasma suPAR in LN. 14 systemic lupus erythematosus (SLE) patients with newly diagnosed LN, 8 active SLE patients (SLEDAI >8) without LN and 31 healthy individuals were enrolled. Urine and plasma samples were taken before the initiation of LN induction therapy, and monthly thereafter. Global and renal disease activity were defined using the SLEDAI-2K and the SLEDAI-2K renal domain score, respectively. suPAR concentrations were measured with the suPARnostic Flex ELISA assay. Urine and plasma suPAR levels were elevated in SLE patients with active LN compared with resolved LN and healthy controls. Urine suPAR levels were comparable to healthy controls in active SLE without LN. Urine and plasma suPAR levels were higher before than after the initiation of LN induction therapy. Prospective follow-up measurements also suggested that urine suPAR levels raised again in patients with a relapse of LN according to SLEDAI-2K renal domain score, whereas plasma suPAR levels did not correlate with renal disease activity. Urine suPAR is a promising LN activity biomarker, given its isolated elevation in urine in active LN and pronounced decrease with LN improvement.

Sensitive, High-Throughput Liquid Chromatography-Tandem Mass Spectrometry Analysis of Atorvastatin and Its Pharmacologically Active Metabolites in Serum for Supporting Precision Pharmacotherapy.

The antihyerlipidemic drug atorvastatin (ATR) is used worldwide as part of the strategy to prevent cardiovascular events. The high prevalence of patient nonadherence remains an important challenge which could be addressed efficiently by precision pharmacotherapy based on therapeutic drug monitoring (TDM). ATR is metabolized to pharmacologically active metabolites, and evidence shows that the sums of ATR acid and lactone form concentrations (ATR + ATRL), or of ATR and hydroxylated metabolites (ATR + MET) should be assayed. A method is presented for the analysis of these substances in serum. Method validation included the estimation of the quantitative relationship between the concentrations and the standard deviations (SD), which supports the optimal incorporation of TDM results into nonparametric pharmacokinetic models. The concentrations of the analytes were evaluated in human subjects receiving ATR. The method's performance improved by taking the sums of acid and lactone concentrations into account. The concentration-SD relationship was linear, and we recommend applying Theil's regression for estimating the assay error. All analytes could be detected by 2 h post dose in the samples of human subjects. The changes in metabolite/parent drug concentration ratios in time depended on the dose. The method is suitable for the TDM of ATR with a focus on precision pharmacotherapy.

Identification of disease- and headache-specific mediators and pathways in migraine using blood transcriptomic and metabolomic analysis.

BACKGROUND: Recent data suggest that gene expression profiles of peripheral white blood cells can reflect changes in the brain. We aimed to analyze the transcriptome of peripheral blood mononuclear cells (PBMC) and changes of plasma metabolite levels of migraineurs in a self-controlled manner during and between attacks. METHODS: Twenty-four patients with migraine were recruited and blood samples were collected in a headache-free (interictal) period and during headache (ictal) to investigate disease- and headache-specific alterations. Control samples were collected from 13 age- and sex-matched healthy volunteers. RNA was isolated from PBMCs and single-end 75 bp RNA sequencing was performed using Illumina NextSeq 550 instrument followed by gene-level differential expression analysis. Functional analysis was carried out on information related to the role of genes, such as signaling pathways and biological processes. Plasma metabolomic measurement was performed with the Biocrates MxP Quant 500 Kit. RESULTS: We identified 144 differentially-expressed genes in PBMCs between headache and headache-free samples and 163 between symptom-free patients and controls. Network analysis revealed that enriched pathways included inflammation, cytokine activity and mitochondrial dysfunction in both headache and headache-free samples compared to controls. Plasma lactate, succinate and methionine sulfoxide levels were higher in migraineurs while spermine, spermidine and aconitate were decreased during attacks. CONCLUSIONS: It is concluded that enhanced inflammatory and immune cell activity, and oxidative stress can play a role in migraine susceptibility and headache generation.

Looking beyond linear regression and Bland-Altman plots: a comparison of the clinical performance of 25-hydroxyvitamin D tests.

BACKGROUND: The systematic evaluation of the clinical concordance of various 25-hydroxyvitamin D (25OHD) testing methods is presented. The need for this approach is raised by the discrepancies in the analytical performance of the available assays. METHODS: The analytical and clinical performance of six automated 25OHD assays and an in-house liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was investigated. Leftover serum samples (n=162, SA: n=114) were analyzed and all 21 assay combinations were evaluated. The utility of Cohen's κ values was assessed by transforming them into minimum percentage agreement (MPA). McNemar's hypothesis test was employed for testing the symmetry of the disagreeing classification outcomes within each method pair. RESULTS: Depending on the assay method, the ratio of results classified as positive (<20 ng/mL) was 13.5%-40.0%. The percentage agreement (PA) was 74.1%-92.6%. Compared to other methods, significantly more hypovitaminosis cases were delivered by DiaSorin Liaison® 25 OH vitamin D Total (DL) and significantly fewer by IDS-iSYS 25-Hydroxy Vitamin DS (II). The strongest clinical concordance was exerted by II vs. LC-MS/MS. The κ-derived MPA showed close similarity to the PA scores. McNemar's tests confirmed the asymmetry of the disagreement in the classification in 14 method combinations. CONCLUSIONS: The presented approach allows the prediction of the clinical consequences of a 25OHD method transfer. Differences in the clinical classification of assay results are likely encountered when transferring to a new method, even between assays standardized according to the Vitamin D Standardization Program (VDSP) Reference Method Procedure (RMP).

Endocrine Factors Determining Immune Polarization during Perinatal Transition.

In utero the skewness of the adaptive immune system towards Th2 ('antiinflammatory') direction and low of Th1/Th2 cell ratio defend the fetus against rejection by the maternal immune system. Th2 dominance at birth is also of importance as it prevents uncontrolled inflammatory processes during parturition. This condition should change rapidly after birth. In an extrauterine milieu that is inherent with exposure to microorganisms, Th1 ('proinflammatory') polarization (i. e. increased Th1 cytokine production along with high Th1/Th2 ratio) are required to maintain an efficient immune response. After birth, maternal hormone supplies including estrogen, progesterone, testosterone, and antiinflammatory prostaglandins cease abruptly. As these hormones have an immune modulatory action favoring Th2, and inhibiting Th1 polarization, their low level supports the strengthening of Th1-type immunity. During parturition a dramatic but transient increase of several hormones (oxytocin, thyorid hormones, and catecholamines) occurs. Again, the net effect of high hormone levels favors Th2 activation, followed by Th1 polarization when hormonal levels reach their postnatal levels. The perinatal change of these components results in the quick cessation of Th1 inhibition and supports the maturation of adaptive immunity to provide an effective response against extrauterine microorganisms.

[The biological and clinical relevance of estrogen metabolome]. / Az ösztrogénmetabolom biológiai és klinikai jelentosége lokális folyamatokban.

Considerable knowledge has been gathered on the physiological role of estrogens. However, fairly little information is available on the role of compounds produced in the breakdown process of estrone and estradiol wich may play a role in various diseases associated with estrogen impact. To date, approximately 15 extragonadal estrogen-related compounds have been identified. These metabolites may exert protective, or, instead, pro-inflammatory and/or pro-oncogenic activity in a tissue-specific manner. Systemic and local estrogen metabolite levels are not necesserily correlated, which may promote the diagnostic significance of the locally produced estrogen metabolites in the future. The aim of the present study is a bibliographic review of the extragonadal metabolome in peripheral tissues, and to highlight the role of the peripheral tissue homeostasis of estrogens as well as the non-hormonal biological activity and clinical significance of the estrogen metabolome. Orv Hetil. 2017; 158(24): 929-937.

Expression of lymphocyte activation markers of preterm neonates is associated with perinatal complications.

BACKGROUND: Inappropriate activation of T lymphocytes plays an important role in perinatal complications. However, data on T lymphocyte activation markers of preterm infants is scarce. We investigated the association between gender, gestational and postnatal age, preeclampsia (PE), premature rupture of membranes (PROM) as well as prenatal steroid treatment (PS) and the frequency of activated T lymphocyte subsets (HLA-DR+, CD69+, CD25+, CD62L+) and major T lymphocyte subpopulations (CD4, CD8, Th1, Th2, naïve, memory) in peripheral blood during the first postnatal week in preterm infants. RESULTS: Cord blood and peripheral blood samples were collected from 43 preterm infants on the 1st, 3rd, and 7th days of life. We assessed the frequency of the above T lymphocyte subsets using flow cytometry. The 'mixed effect model' was used to analyze the effects of clinical parameters on T lymphocyte markers. The frequency of CD25+ T lymphocytes was higher in PROM. The frequency of CD4+ and CD8+ cells and the CD4+/CD8+ cell ratio was decreased in PE. The frequency of CD62L+ T lymphocytes was higher in male compared with female infants. PS did not affect the frequency of the investigated markers. CD4+ CD25+ cells had a lower frequency at birth than on day 7. Th2 lymphocytes had a lower frequency on postnatal days 1 and 3 when compared to day 7. CONCLUSIONS: Our observations indicate that alterations affecting the expression of T lymphocyte activation markers are associated with the above factors and may play a role in the development of perinatal complications.

Circulating periostin level in asthmatic pregnancy.

OBJECTIVE: Asthma often complicates pregnancy and represents a risk for complications. Periostin is considered as a biomarker of asthma; however, as it also plays a role in normal gestation, pregnancy may influence circulating periostin levels. This is the first study assessing periostin in asthmatic pregnancy. METHODS: Plasma periostin levels were investigated in asthma (asthmatic non-pregnant, ANP; N = 19) and asthmatic pregnancy (AP; N = 14), compared to healthy non-pregnant controls (HNP; N = 12) and healthy pregnant women (HP; N = 17). The relationship between periostin levels and asthma control determinants was also evaluated. The diagnostic efficacy of periostin to detect uncontrolled asthma was analyzed using ROC analysis. RESULTS: Plasma periostin levels were similar in the HNP and ANP (55.68 [37.21-67.20] vs. 45.25 [32.67-64.55], p > 0.05), and elevated in the HP (68.81 [57.34-98.84] ng/mL, p = 0.02 vs. HNP) and AP groups (54.02 [44.30-74.94] ng/mL, p = 0.0346 vs. ANP). Periostin levels of the two pregnant groups were similar (p > 0.05). In AP women periostin correlated negatively with FEV1 (r = -0.5516) and positively with Raw (r = 0.5535; both p < 0.05). CONCLUSIONS: Pregnancy itself increases circulating periostin levels and this elevation is detectable in asthmatic pregnancy as well. Although periostin correlates with lung function in asthmatic pregnancy, periostin as a biomarker has to be handled with caution in pregnant patients due to the influence of pregnancy on its plasma level.

Alterations of the thrombin generation profile in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disorder resulting in the erosion of the cartilage and bone. Systemic involvement including the cardiovascular system with the risk of atherosclerosis may also occur. Calibrated automated thrombogram (CAT), a commercially available thrombin generation assay is suitable for the general assessment of the functionality of coagulation system. In this study we performed CAT assay in RA patients and in non-affected control subjects (matched for age, sex and comorbidities). Among the CAT parameters Velocity Index increased (from 60 to 83 nM/min), Lag Time and Time to Peak decreased (from 3.47 to 2.83 min and from 6.98 to 5.58 min respectively) in RA. On the other hand, Endogenous Thrombin Potential values decreased (from 1242 to 1108 nM min). The observed alterations were not associated with the applied therapy. These results indicate that the velocity of thrombin formation is increased, while the thrombin generating capability is reduced in RA.

[Measurement of hemoglobin A1c: analytical principles and their significance in clinical decision making]. / Hemoglobin-A-1c-szint-mérés: analitikai vonatkozások és ezek jelentosége a klinikai döntéshozatalban.

Appropriate care and monitoring of the condition of patients with diabetes is indispensable from the regular measurement of hemoglobin A1c levels. Under well defined criteria hemoglobin A1c levels may also support the diagnosis of diabetes. This review provides a short description of the major principles of methods used for hemoglobin A1c determination and it reviews conditions interfering with the results. It also presents cut-off values for therapeutic decision making. As the results of world-wide efforts for standardization of hemoglobin A1c values obtained with different tests in different laboratories, the hemoglobin A1c results are comparable and can be used for clinical decisions. However, hemoglobin A1c should be considered with a particular caution in patients with hemoglobinopathies and in those with conditions affecting the average life-time of red cells.

Increased plasma soluble urokinase plasminogen activator receptor levels in systemic sclerosis: possible association with microvascular abnormalities and extent of fibrosis.

BACKGROUND: Urokinase plasminogen activator receptor (uPAR) is a key component of the fibrinolytic system involved in extracellular matrix remodeling and angiogenesis. Novel animal models supported the key role of uPAR not only in fibrosis but also in systemic sclerosis (SSc)-related microvascular abnormalities. The aim of this study was to investigate plasma soluble uPAR (suPAR) levels in SSc, and their association with organ-specific involvement. METHODS: suPAR concentrations were measured by ELISA in SSc patient (n=83) and in healthy controls (n=29). Simultaneously, CRP and ESR were assessed. Detailed clinical data including skin, lung, heart and microvascular characteristics were evaluated at sampling. RESULTS: suPAR values were higher in SSc patients than in controls. Subgroup analysis showed higher suPAR values in diffuse cutaneous- than in limited cutaneous SSc and correlated with anti-Scl-70+. suPAR levels also associated with pulmonary function test parameters of fibrosis, presence of microvascular lesions (e.g., Raynaud phenomenon, naifold capillaroscopic abnormalities and digital ulcers) and arthritis. CONCLUSIONS: Our data indicate that suPAR might be a valuable early diagnostic marker of SSc which also correlates with disease severity.

[Focusing on tissue biomarkers. Estrogens as key players in the immune response and autoimmunity]. / Fókuszban a szöveti biomarkerek. Az ösztrogének mint a szövetspecifikus immunválasz és autoimmunitás modulálásának kulcsszereploi.

Estrogens modulate the immune response as well as the risk and progression of autoimmune disorders. Their effects are mediated by nuclear receptors (i.e. estrogen receptor alpha and beta), membrane receptors, and are influenced by their interactions with other hormones. Locally produced hormones and cytokines are the main factors in maintaining tissue homeostasis. The response of immune cells to estrogens is related to their developmental stage. The diverse effects of estrogens on various autoimmune disorders are the result of the versatility of their pathomechanism. In general, progression of B-cell mediated disorders is aggravated by estrogens. Their effects on T-cell mediated disorders, on the other hand, are driven by Th1 or Th2 dominance. As estrogens promote the escalation of the Th2 immune response, Th2-dominant disorders are aggravated, while Th1-dominant disorders are ameliorated upon high estrogen levels. Inflammation on its own also modulates the impact of estrogens. Inflammatory cytokines alter the expression of the alpha and beta estrogen receptors as well as the activity of estrogen metabolizing enzymes. Monitoring the local, tissue-wide interaction between hormones and immune cells would provide a better tool for identification and characterization of molecules involved in this system. To date, routinely used laboratory methods have a limited role in monitoring the local effects of estrogens. In this current paper the authors summarize the role of estrogens in immune system and overview those novel methods which are useful in the investigation of local endocrine milieu.

Different calcium influx characteristics upon Kv1.3 and IKCa1 potassium channel inhibition in T helper subsets.

Functional imbalance between T helper subsets plays important role in the pathogenesis of autoimmune disorders. Transient increase of cytoplasmic calcium level, and sustention of negative membrane potential by voltage sensitive Kv1.3 and calcium-dependent IKCa1 potassium channels are essential for short-term lymphocyte activation, thus present possible target for selective immunomodulation. We aimed to investigate calcium influx sensitivity to the inhibition of potassium channels in the main T helper subsets. Peripheral blood from 11 healthy individuals was drawn and calcium influx kinetics following activation with phytohemagglutinin in Th1, Th2, Th17, and Treg cells were evaluated. Alteration of calcium influx induced by specific inhibitors of Kv1.3 and IKCa1 potassium channels, and the expression of Kv1.3 channels were also assessed. Highest cytoplasmic calcium concentration was observed in stimulated Th1 cells, while the lowest level was measured in Treg cells. In Th1 and Th17 cells, inhibition of both investigated potassium channels decreased calcium influx. In Th2 cells only the inhibitor of Kv1.3 channels, while in Treg cells none of the inhibitors had significant effect. Upon the inhibition of IKCa1 channels, short-term activation of proinflammatory cells was specifically decreased without affecting anti-inflammatory subsets, indicating that selective immunomodulation is possible in healthy individuals.

Relevance of novel inflammatory markers in stroke-induced immunosuppression.

BACKGROUND: Acute ischemic stroke (AIS) has a biphasic effect on the peripheral immune system. The initial inflammatory response is followed by systemic immunosuppression, referred to as stroke-induced immunosuppression (SIIS), leading to severe complications in stroke patients. We aimed to identify an inflammatory marker that best represents this biphasic immunological response after AIS. METHODS: We investigated the alteration of CRP, WBC, neutrophil count, suPAR levels, CD4+ CD25high Tregs, CD64+ and CD177+ neutrophils and monocytes in 12 acute ischemic stroke patients free of infection within 6 hours and one week after the insult. As controls, 14 age-matched healthy individuals were included. RESULTS: CRP, WBC and neutrophil count values were comparable in stroke patients within 6 hours and controls, however, they were elevated in stroke one week after the insult. suPAR levels were higher in both stroke groups compared to controls. The prevalence of CD64+ neutrophils was higher in stroke patients within 6 hours than in controls and it decreased in stroke one week after the insult below the level in controls (5.95 [5.41-8.75] % vs. 32.38 [9.21-43.93] % vs. 4.06 [1.73-6.77] %, p < 0.05). CONCLUSIONS: Our pilot study identified that the prevalence of CD64+ neutrophils may reflect a biphasic alteration of the immune response following AIS. Since its level decreases below baseline after one week of the CNS insult in stroke patients without infection, it might serve as a reliable candidate to identify the developing inflammatory response due to infection after stroke in the future.

[Thrombin generation assays and their clinical application]. / Trombingenerációs vizsgálatok és klinikai alkalmazásuk.

Thrombin is a key enzyme of the coagulation system, having both pro- and anticoagulant functions. Thus, the generation of thrombin is one of the most important steps in coagulation. Global haemostasis assay, the so-called thrombin generation test is appropriate for its assessment. Since thrombin generation is sensible for both pro- and anticoagulant processes it can be applied for the general characterisation of the risk of thrombosis and bleeding, too. Clinical studies confirmed augmented thrombin generation in patients with high risk of venous or arterial thrombosis. Anticoagulant therapy (also novel oral anticoagulant treatment) can be monitored by thrombin generation. In case of haemophilia thrombin generation assays reflect bleeding severity. It is applicable for monitoring of both conventional haemophilia treatment and inhibitor-bypassing therapy, which is needed when inhibitors develop in patients. Standardization of thrombin generation methods and determination of cut off values are required before its application in clinical practice.

[Effects and significance of estradiol in men]. / Az ösztradiol hatásai és jelentosége férfiakban.

The most important estrogen is estradiol in both men and women. In men elevated estradiol levels and associated metabolic disorders have been implicated in the development of common diseases including cardiovascular disorders, insulin resistance and type 2 diabetes mellitus, as increased estradiol associated with decreased testosterone levels increases the risk of these diseases. In this review the authors summarize the causes and consequences of androgen deficiency and estradiol excess, and they review recent studies on potential therapeutic strategies to correct increased estradiol levels in men.