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.

Vitamin D Deficiency has no Impact on PSA Reference Ranges in a General University Hospital - A Retrospective Analysis.

BACKGROUND: Vitamin D deficiency has been linked to a higher risk of prostate cancer. We tested the hypothesis that vitamin D levels would have an impact on prostate specific antigen (PSA) levels. METHODS: From our laboratory database we selected 5136 male patients with simultaneously determined vitamin D and PSA levels. Subgroups of several age cohorts with different vitamin D levels were created and PSA 95 percentile values were assessed. The independent effect of vitamin D levels and age on PSA levels was determined with logistic regression. RESULTS: PSA levels increased with age, while no difference was identified in PSA levels in different vitamin D subgroups. CONCLUSION: Vitamin D levels do not have an effect on PSA. Hence, there is no need to adjust PSA reference ranges and threshold values to vitamin D levels during the process of decision making.

[An inverse significant association between thyroid stimulatory hormone (TSH) and prostate specific antigen (PSA) blood levels in males 40-75 years of age 40-75 years of age]. / Szignifikáns inverz kapcsolat a pajzsmirigy-stimuláló hormon (TSH) és a prosztataspecifikus antigén (PSA) vérszintjei között 40­75 éves korú férfiakban.

Introduction: Recent experiments and clinical studies indicate the contribution of thyroid hormones to prostate pathology. Aim: In our retrospective analyzis of university patient population, we evaluated the association between thyroid stimulatory hormone (TSH) and prostate specific antigen (PSA). Method: From the Laboratory Information System we retrieved the data of male patients between 40 and 75 years of age who had been subjected to simultaneous TSH and PSA measurements during the last 12 years (n = 7279). The association between logTSH and logPSA levels was tested with multiple regression analysis and adjusted for age. Results: Significant associations between logPSA and logTSH and age (r = 0.297 and 0.472, respectively) were detected. PSA levels were higher in patients with TSH below (n = 405) than in those with TSH within reference range (TSH 0,35-4,95 mU/ml) (n = 6698) (PSA level: 1.118 [0.639-2.338] vs. 0.920 [0.508-1.826] ng/ml, p<0.016). Based on estimates, a 10% decrease in TSH is associated with a 0.42% increase in PSA levels in our population. This corresponds to a 42% increase in PSA levels in the same patient if he would present with 0.2 mU/ml instead of 2.0 mU/ml TSH. Conclusion: The finding that hyperthyreosis might be associated with higher PSA levels indicates that PSA reference ranges would differ in hyperthyreotic and in euthyreotic patients. Probably the PSA clinical decision limits is also recommended to be modified according to the patient's thyroid status. Orv Hetil. 2019; 160(35): 1376-1379.

[Estrogen metabolism during pregnancy]. / Az ösztrogénmetabolizmus várandósság alatt.

The extensive metabolism of estrogen hormones, where oxidized forms, structural isomers and conjugated products appear in many tissues locally as well as in systemic circulation, is believed to be associated with a number of diseases. Targeted estrogen metabolomic studies have been largely associated with postmenopausal, malignant advert immune conditions. Although the role of estriol in maintaining pregnancy and the biological activity of estrogen metabolites is known, a relatively small number of publications have addressed the formation and transformation of these compounds during pregnancy. The aim of this study is to present in detail the formation and progression of estrogen metabolites during pregnancy and to summarize the knowledge of their role in undesirable processes occurring during gestation. Orv Hetil. 2019; 160(26): 1007-1014.

B7 costimulation and intracellular indoleamine 2,3-dioxygenase expression in umbilical cord blood and adult peripheral blood.

Alterations in the expression of B7 costimulatory molecules and their receptors, as well as differences in the tryptophan (TRP) catabolic pathway, may influence immunological reactivity of umbilical cord blood (UCB) compared with adult peripheral blood (APB) T lymphocytes. We determined the frequency of activated (CD11b(+)) monocytes expressing B7-1, B7-2, B7-H1, and B7-H2, and that of T cells and CD4(+) T helper cells expressing CD28, cytotoxic T lymphocyte antigen 4 (CTLA-4), programmed death-1 receptor, and inducible costimulator of T cells in UCB and APB samples using flow cytometry. We also examined the intracellular expression of indoleamine 2,3-dioxygenase (IDO) applying flow cytometry and plasma levels of TRP, kynurenine (KYN), and kynurenic acid using high-performance liquid chromatography. The level of CTLA-4 expression on CD4 cells was higher in UCB compared with in APB, indicating that the possibility of CD28-mediated costimulation may be decreased. The level of the corresponding costimulator molecule, B7-2, was also elevated. Therefore, this inhibitory relation may function to a higher extent in UCB than in APB. The plasma KYN to TRP (K/T) ratio was 2-fold higher in UCB compared with APB. However, the capacity of UCB monocytes to produce IDO compared with APB monocytes was lower, and reverse signaling via B7-2 in UCB monocytes was found to be immature, which suggests that the observed increase in K/T ratio may be due to placental, rather than fetal, overexpression of IDO in competent cells. These factors may all contribute to the previously observed reduced reactivity of UCB T lymphocytes compared to APB T cells.

Serum maternal hepcidin levels 3 days after delivery are higher compared to those measured at parturition.

AIM: Our aim was to investigate the levels of hepcidin at parturition and 3 days after delivery and to relate hepcidin levels to parameters of iron homeostasis. MATERIALS AND METHODS: We measured hepcidin levels with mass spectrometry in serum samples of 38 term pregnant women taken just prior to and 3 days after vaginal delivery (n = 23) or cesarean section (CS) (n = 15). Hepcidin levels were related to iron homeostasis parameters and interleukin (IL)-6 levels. Parameters measured before and after delivery were compared with the Wilcoxon test. RESULTS: Serum iron levels (median, interquartile range) decreased (14.3, 9.6-21.1 vs. 8.9, 6.8-11.5 µmol/L, P < 0.01), while hepcidin levels increased (2.73, 2.2-3.45 vs. 10.62, 6.70-15.89 µg/L, P < 0.01) by the third day after parturition compared to those measured before delivery. IL-6 levels were comparable before and after delivery. No direct association between serum hepcidin and iron homeostasis parameters or IL-6 levels was found. CONCLUSIONS: Factors triggering hepcidin synthesis dominate 3 days after delivery. Studies are needed to assess the contribution of hepcidin to iron homeostasis during the periparturition period.

[Increased hepcidin levels three days after gynecological interventions]. / Emelkedett hepcidinszint nogyógyászati mutéteket követo harmadik napon.

UNLABELLED: Hepcidin is an endogenous substance that inhibits iron absorption and plasma iron levels. Due to technical reasons its levels are not routinely assessed and data regarding its clinical relevance are limited. We analyzed the alteration of hepcidin levels following gynecological interventions. Hepcidin levels were determined by mass spectrometry, along with the levels of interleukin-6, the main inductor of hepcidin with ELISA in 17 women undergoing gynecological intervention just prior to and three days after the surgery. The results were related to iron homeostasis parameters. A decrease in serum iron (median, interquartile range) (17.85 [15.25-24.9] versus 10.1 [7.6-15.0] µmol/l, p<0.01) and transferrin levels (60.3 [55.93-67.18] versus 53.1 [49.7-60.0], p< 0.01) µmol/l, simultaneously with an increase in hepcidin (2.75 [2.24-3.51] versus 8.01 [6.8-9.67] µg/l, p<0.01) and interleukin-6 levels (ND = not detected) (ND [ND - 2.2] versus 8.15 [2.31-12.86], p<0.01). CONCLUSION: As with other acute phase proteins postoperative hepcidin levels dramatically increase, simultaneously with other changes in iron homeostasis. These results indicate a possible causative relationship between increased hepcidin and decreased iron levels. In clinical practice, determination of hepcidin levels may be indicated for characterization and, possibly, prediction of postoperative iron homeostasis. However, measurement of hepcidin level in clinical practice is unlikely in the near future due to the lack of available kits for routine clinical laboratories.

T-lymphocyte calcium influx characteristics and their modulation by Kv1.3 and IKCa1 channel inhibitors in the neonate.

Cytokine production in activated T lymphocytes of the term neonate is reduced compared with adults. We aimed to characterize the calcium influx kinetics of activated T lymphocytes in the neonate and to test the functionality and expression of Kv1.3 and IKCa1 lymphocyte potassium channels, important regulators of calcium influx. We isolated lymphocytes from the peripheral blood of nine adults and cord blood of nine term neonates. We measured the calcium influx kinetics with flow cytometry in the T(h)1, T(h)2, CD4 and CD8 T-lymphocyte subsets activated with PHA. We determined the sensitivity of calcium influx to specific inhibitors of the Kv1.3 and IKCa1 channels. We also measured Kv1.3 channel expression using specific antibody. With the exception of the CD4 subset, calcium influx kinetics was decreased upon activation in neonatal T lymphocytes compared with adults. Neonatal T lymphocytes were found to be less sensitive to the specific inhibition of Kv1.3 and IKCa1 channels. The expression of Kv1.3 channels was higher on major T-lymphocyte subsets of newborns except for T(h)1 lymphocytes. Our findings suggest that the characteristics of short-term activation of major neonatal T-lymphocyte subsets are altered compared with adults. The altered function of neonatal lymphocyte potassium channels may contribute to this phenomenon.

Gender differences in antidepressant use-related seasonality change in suicide mortality in Hungary, 1998-2006.

OBJECTIVES: Studies show that the seasonality of suicide (spring/early summer peak, winter low) is mainly the consequence of the seasonal incidence of depression-related suicides. The aim of the present study was to analyse the relationship between increasing antidepressant utilization and national suicide rate of Hungary between 1998 and 2006, with particular regard to seasonal patterns and gender differences. METHODS: Time trend analysis (ARIMA) had been applied to investigate the correlation between the trend of antidepressant prescription and both of suicide rates and seasonality index. RESULTS: During the 9 years of the study period there was a significant (P<0.001) correlation between the steadily increasing antidepressant prescription (113%) and continuous decline in total national suicide rate (23%) as well as both in females and males (21 and 23%, respectively), but this relationship was 8-fold stronger in males. Increasing antidepressant utilization was associated with significantly decreased seasonality of suicides only among males. CONCLUSIONS: The results suggest that decreasing seasonality of suicides could be a good marker of lowering rate of depression-related suicides in the population particularly among males.