Oxidative Stress in Assisted Reproductive Techniques, with a Focus on an Underestimated Risk Factor.

Based on current findings, the presence of oxidative stress has a significant impact on the quality of gametes and embryos when performing assisted reproductive techniques (ART). Unfortunately, in vitro manipulation of these cells exposes them to a higher level of reactive oxygen species (ROS). The primary goal of this review is to provide a comprehensive overview of the development of oxidative stress in female and male reproductive systems, as well as in the case of the pre-implantation embryo and its environment. This review also focuses on the origins of ROS and the mechanisms of oxidative stress-induced damage during ART procedures. A well-known but underestimated hazard, light exposure-related photo-oxidation, is particularly concerning. The effect of oxidative stress on ART outcomes, as well as the various strategies for preventing it, are also discussed. We emphasize the role and significance of antioxidants and light protection including forms, functions, and mechanisms in the development of gametes and embryos in vivo and in vitro.

Disrupted Balance of the Oxidant-Antioxidant System in the Pathophysiology of Female Reproduction: Oxidative Stress and Adverse Pregnancy Outcomes.

The significance of oxidative stress in the pathophysiology of male reproductive processes has been closely studied in the last two decades. Recently, it has become clear that oxidative stress can lead to numerous pathological conditions during female reproductive processes as well, contributing to the development of endometriosis, polycystic ovary syndrome and various forms of infertility. During pregnancy, physiological generation of reactive oxygen species (ROS) occurs in association with several developmental processes including oocyte maturation and implantation. An overproduction of ROS can lead to disturbances in fetal development and increases the risk for missed abortion, intrauterine growth restriction, pre-eclampsia, premature delivery and gestational diabetes. Our review focuses on the etiological role of the disrupted oxidant-antioxidant system during human gestation as it relates to adverse pregnancy outcomes.

Thrombocytes and Platelet-Rich Plasma as Modulators of Reproduction and Fertility.

Thrombocytes play an essential role in hemostasis and thrombosis. Moreover, the controlled activation of thrombocytes is required in reproduction and fertility. The platelet-activating factor and the controlled activation of platelets have important roles in folliculogenesis, ovulation, placental development, implantation and embryo development. Activated platelets accumulate in the follicular vessels surrounding the follicle and, due to its released soluble molecules (factors, mediators, chemokines, cytokines, neurotransmitters), locally increase oocyte maturation and hormone secretion. Furthermore, activated platelets are involved in the pathogenesis of ovarian hyperstimulation syndrome (OHSS) and preeclampsia. Low-dose aspirin can prevent OHSS during ovulation induction, while intrauterine or intraovarian administration of platelet-rich plasma (PRP) increases the endometrium thickness and receptivity as well as oocyte maturation. Activated thrombocytes rapidly release the contents of intracellular granules and have multiple adhesion molecules and receptors on their surface. Considering the numerous homeostatic endocrine functions of thrombocytes, it is reasonable to suppose a platelet-associated regulatory system (PARS) in reproduction. Although we are far from a complete understanding of the regulatory processes, the results of PARS research and the therapeutic application of aspirin and PRP during in vitro fertilization are promising.

Cardiometabolic Effects of Irisin in Patients with End-Stage Renal Disease on Regular Hemo- or Peritoneal Dialysis.

INTRODUCTION: Data on the role of irisin in vascular calcification in patients with end-stage renal diseases on regular dialysis are inconsistent, and the underlying mechanisms are not clearly defined. The present study was designed to explore the association of serum irisin with vascular stiffness and with the impact of well-established risk factors. METHODS: The clinical study enrolled 52 hemodialysis (HD) and 15 continuous ambulatory peritoneal dialysis (PD) patients with an age of >18 years receiving dialysis therapy for >3 months. Patients who had major pathologies affecting carbohydrate, lipid, and bone metabolism and those who had acute cardiovascular events were excluded. Thirty-seven healthy subjects matched for age and sex served as controls. Routine biochemical parameters were measured in fasting serum samples by standard methods. Serum irisin was determined using the commercial ELISA kit (BioVendor Laboratory Medicine Inc., Brno, Czech Republic). Arterial stiffness parameters - carotid-femoral pulse wave velocity (cf PWV) and augmentation index (Aix) - were measured using applanation tonometry (SphygmoCor System; AtCor Medical, Sydney, Australia). Body composition was assessed by segmental bioelectric impedance (InBody 2.0; Biospace Co. Ltd., Seoul, Korea). RESULTS: It was demonstrated that serum irisin levels were markedly depressed (p < 0.05), while the cf PWV significantly increased (p < 0.05) in HD/PD patients as compared to controls. Serum irisin proved to be independent of serum insulin, glucose, and HOMA-IR. However, it was inversely related to HbA1c (ß = -0.544, p = 0.035), iPTH (ß = -0.260, p = 0.035), and alkaline phosphatase (r = -0.325, p = 0.007). Furthermore, significant negative relationships were found of irisin to serum triglyceride and indices of body fat mass. Retrospective analysis at a follow-up period of 40 months revealed a direct relationship of irisin to all-cause mortality (p = 0.039). CONCLUSIONS: Our study demonstrated that serum irisin levels are reduced in uremic patients on regular HD/PD but failed to establish significant associations of irisin deficiency with vascular stiffness. However, the significant negative relationship of irisin to HbA1c, iPTH, and alkaline phosphatase suggests that it improves insulin sensitivity, inhibits bone resorption, mitigates bone-vascular interaction, and protects vascular function.

The Role of L-Arginine-NO System in Female Reproduction: A Narrative Review.

Accumulating evidence are available on the involvement of l-arginine-nitric oxide (NO) system in complex biological processes and numerous clinical conditions. Particular attention was made to reveal the association of l-arginine and methylarginines to outcome measures of women undergoing in vitro fertilization (IVF). This review attempts to summarize the expression and function of the essential elements of this system with particular reference to the different stages of female reproduction. A literature search was performed on the PubMed and Google Scholar systems. Publications were selected for evaluation according to the results presented in the Abstract. The regulatory role of NO during the period of folliculogenesis, oocyte maturation, fertilization, embryogenesis, implantation, placentation, pregnancy, and delivery was surveyed. The major aspects of cellular l-arginine uptake via cationic amino acid transporters (CATs), arginine catabolism by nitric oxide synthases (NOSs) to NO and l-citrulline and by arginase to ornithine, and polyamines are presented. The importance of NOS inhibition by methylated arginines and the redox-sensitive elements of the process of NO generation are also shown. The l-arginine-NO system plays a crucial role in all stages of female reproduction. Insufficiently low or excessively high rates of NO generation may have adverse influences on IVF outcome.

Expression of mRNAs for pro-and anti-apoptotic factors in granulosa cells and follicular fluid of women undergoing in vitro fertilization. A pilot study.

BACKGROUND: This observational clinical study evaluated the expression levels and predictive values of some apoptosis-related genes in granulosa cells (GCs) and follicular fluid (FF) of women undergoing in vitro fertilization (IVF). METHODS: GCs and FF were obtained at oocyte retrieval from 31 consecutive patients with heterogeneous infertility diagnosis (age: 34.3 ± 5.8 years, body mass index: 24.02 ± 3.12 kg/m2, duration of infertility: 4.2 ± 2.1 years). mRNA expression of pro-apoptotic (BAX, CASP3, CASP8) and anti-apoptotic (BCL2, AMH, AMHR, FSHR, LHR, CYP19A1) factors was determined by quantitative RT-PCR using ROCHE LightCycler 480. RESULTS: No significant difference in GC or FF mRNA expression of pro- and anti-apoptotic factors could be demonstrated between IVF patients with (9 patients) or without (22 patients) clinical pregnancy. Each transcript investigated was detected in FF, but their levels were markedly reduced and independent of those in GCs. The number of retrieved oocytes was positively associated with GC AMHR (r = 0.393, p = 0.029), but the day of embryo transfer was negatively associated with GC LHR (r = - 0.414, p = 0.020) and GC FSHR transcripts (r = - 0.535, p = 0.002). When pregnancy positive group was analysed separately the impact of apoptosis- related gene expressions on some selected measures of IVF success could be observed. Strong positive relationship was found between gene expression levels of pro- and anti-apoptotic factors in GCs. CONCLUSION: Our study provides only marginal evidences for the apoptosis dependence of IVF outcome and suggests that the apoptosis process induces adaptive increases of the anti-apoptotic gene expression to attenuate apoptosis and to protect cell survival.

Key to Life: Physiological Role and Clinical Implications of Progesterone.

The most recent studies of progesterone research provide remarkable insights into the physiological role and clinical importance of this hormone. Although the name progesterone itself means "promoting gestation", this steroid hormone is far more than a gestational agent. Progesterone is recognized as a key physiological component of not only the menstrual cycle and pregnancy but also as an essential steroidogenic precursor of other gonadal and non-gonadal hormones such as aldosterone, cortisol, estradiol, and testosterone. Based on current findings, progesterone and novel progesterone-based drugs have many important functions, including contraception, treatment of dysfunctional uterine bleeding, immune response, and prevention of cancer. Considering the above, reproduction and life are not possible without progesterone; thus, a better understanding of this essential molecule could enable safe and effective use of this hormone in many clinical conditions.

The Impact of Osteocalcin, Osteoprotegerin and Osteopontin on Arterial Stiffness in Chronic Renal Failure Patients on Hemodialysis.

BACKGROUND/AIMS: This cross-sectional study was designed to assess the relationship between vascular stiffness (VS) and bone-related proteins involved in the development of arteriosclerosis in patients on regular hemodialysis (HD). METHODS: 68 consecutive patients in stable clinical condition who received regular HD in the FMC Dialysis Center, Pécs were included. VS parameters (carotid-femoral pulse wave velocity - PWV, aortic augmentation index - AIx) were determined by applanation tonometry (SphygmoCor, AtCor Medical, Sidney) and the routine latoratory test were completed with measurements of osteocalcin (OC), osteopontin (OP) and osteoprotegerin (OPG) by using commercially available ELISA kits. 35 heathcare workers served as controls. RESULTS: In patients on regular HD PWV markedly increased and there was several-fold elevation in the interrelated bone-specific proteins (OC, OP, OPG). PWV was found to be independently associated only with OC (ß:-0.25, p<0.029) and age (r=0.411,p<0.000), but risk factors for arterial calcification had significant impact on OC (systolic blood pressure, hsCRP, BMI), OPG (age, BMI) and OP (LDL-cholesterol). CONCLUSION: Except for OC, our results failed to document direct association of vascular lesion with OP and OPG, therefore their high circulating levels may be an epiphenomenon or they may have counter-regulatory role to attenuate the uremic calcification process.

[Asymmetric dimethylarginine: predictor of cardiovascular diseases?]. / Aszimmetrikus dimetilarginin: a cardiovascularis betegségek prediktora?

Cardiovascular diseases are the most common diseases worldwide. They are responsible for one third of global deaths and they are the leading cause of disability, too. The usage of different levels of prevention in combination with effective risk assessment improved these statistical data. Risk assessment based on classic risk factors has recently been supported with several new markers, such as asymmetric dimethylarginine, which is an endogenous competitive inhibitor of nitric oxide synthase. Elevated levels of asymmetric dimethylarginine have been reported in obese, smoker, hypercholesterolemic, hypertensive and diabetic patients. According to previous studies, asymmetric dimethylarginine is a suitable indicator of endothelial dysfunction, which is held to be the preceding condition before atherosclerosis. Several researches found positive correlation between higher levels of asymmetric dimethylarginine and coronary artery disease onset, or progression of existing coronary disease. According to a study involving 3000 patients, asymmetric dimethylarginine is an independent risk factor of cardiovascular mortality in patients with coronary artery disease. This article summarizes the role of asymmetric dimethylarginine in prediction of cardiovascular diseases, and underlines its importance in cardiovascular prevention.

Serum and follicular fluid fetuin-A in women undergoing in vitro fertilization.

BACKGROUNDS: This case-control study was designed to assess the possible role of fetuin-A, a multifunctional protein, in reproductive processes of women undergoing in vitro fertilization (IVF). METHODS: Paired serum and follicular fluid (FF) samples were obtained from 35 unselected patients who received IVF treatment. Their main clinical chartacteristics: age 35.2±5.4 years, BMI 22.9±2.8, duration of infertility 3.2±2.0 years, gonadotropin administered 1199.4±202.3 IU, and estradiol level on day 6 of stimulation 1827±1342 pmol/L. In total 25 healthy women of similar age admitted for minor elective surgery served as controls for serum analysis. Fetuin-A and high-sensitivity C-reactive protein (hsCRP) were measured in serum and FF by using commercially available ELISA kits and turbidimetric immunoassay, respectively. RESULTS: Serum fetuin-A levels of patients participating IVF are markedly elevated when compared to those of healthy women (1.30±0.58 g/L vs. 0.55±0.09 g/L, p<0.000). Fetuin-A in FF proved to be comparable to its serum levels (1.17±0.45 g/L) and no relationship could be detected between the respective individual values. Moreover, markers of reproductive potential (number of oocytes and embryos) appeared to be independent of serum and FF fetuin-A. hsCRP in serum and FF was not related to fetuin-A and did not influence the number of oocytes and embryos. CONCLUSIONS: Fetuin-A concentration is high in FF of patients undergoing IVF, however, it can not be used as an estimate of fertilization success.

Acylcarnitine esters profiling of serum and follicular fluid in patients undergoing in vitro fertilization.

BACKGROUND: L-carnitine-mediated beta-oxidation of fatty acids has a well established role in energy supply of oocytes and embryos. Disturbed carnitine metabolism may impair the reproductive potential in IVF and can serve as a biomarker of pregnancy outcome. METHODS: Our study was performed between March 24, 2011 and May 9, 2011. We performed 44 unselected IVF cycles, (aged 23-40 years (mean: 32.3+/-5.1 years) and had BMI of 17.3-34.7 (mean: 23.80+/-4.9). Samples were also obtained from 18 healthy women of similar age admitted for minor elective surgery to serve as control for plasma carnitine profile. Serum and follicular fluid (FF) free carnitine (FC) and 20 major acylcarnitines (ACs) were measured by ESI/MS/MS method. RESULTS: Serum FC and AC levels in IVF patients were comparable to those in healthy control women. In FF FC and short-chain AC concentrations were similar to those in maternal serum, however, the levels of medium-chain, and long-chain AC esters were markedly reduced (p<0.05). The serum to FF ratio of individual carnitine compounds increased progressively with increasing carbon chain length of AC esters (p<0.05). There was a marked reduction in total carnitine, FC and AC levels of serum and FF in patients with oocyte number of >9 and/or with embryo number of >6 as compared to the respective values of <9 and/or <6 (p<0.05). CONCLUSIONS: In IVF patients with better reproductive potential the carnitine/AC pathway appears to be upregulated that may result in excess carintine consumption and relative depletion of carnitine pool. Consequently, IVF patients may benefit from carnitine supplementation.

Aquaporin-4 distribution in control and stressed astrocytes in culture and in the cerebrospinal fluid of patients with traumatic brain injuries.

Distribution of aquaporin-4 (AQP4) was studied by western analysis and immunofluorescence in rat astrocytes exposed to either hypothermic (30 °C) or hyperosmolar (0.45 M sucrose) stress, and in the cerebrospinal fluid (CSF) of patients who suffered traumatic brain injury (TBI). CSF was obtained from 5 healthy subjects and from 20 patients suffering from severe TBI. CSF samples were taken at admission and on days 3 and 5-7. Here we report that, in response to both hypothermia and hyperosmolar stress, AQP4 was markedly reduced in cultured astrocytes. We also found that AQP4 significantly increased in patients with severe brain injury in respect to healthy subjects (P < 0.002). AQP4 in CSF remained unchanged in patients with elevated intracranial pressure (ICP), whereas there was a clear tendency to further increase in those patients whose ICP could be controlled within the normal range. We conclude that AQP4 levels in CSF are elevated after TBI and it might serve as a useful biochemical marker to assess brain water metabolism in clinical settings.

L-arginine metabolism in early-onset and late-onset pre-eclamptic pregnancies.

OBJECTIVE: The present case-control study was undertaken to investigate l-arginine metabolism in pregnant women with early-onset and late-onset pre-eclampsia. Attempts were made to differentiate these two distinct diseases entities by using measured and derived parameters of l-arginine metabolism. STUDY DESIGN: Thirty-six patients with early-onset, 17 patients with late-onset pre-eclampsia and 15 healthy pregnant women at term were studied. Patients were categorized according to the weeks of gestation (< 34 vs. ≥ 34) at the appearance of clinical symptoms (hypertension + proteinuria). Venous samples were taken at gestational age of 29.8 ± 2.5, 36.1 ± 2.2 and 39.2 ± 1.2 weeks, respectively. L-arginine, asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), monomethylarginine (MMA) and l-ornithine were measured by LC-MS/MS method. L-arginine/ADMA, l-ornithine/l-arginine, ADMA/SDMA ratios and the arginine methylation index (arg-MI) were calculated. RESULTS: Plasma levels of ADMA and MMA were significantly higher (p < 0.002) in pre-eclamptic patients than in healthy women. No significant differences could be detected between patients with early-onset and late-onset pre-eclampsia in either parameter studied. L-ornithine correlated positively with ADMA (r = 0.526, p < 0.001) and MMA (r = 0.533, p < 0.001) in the whole study population, and inversely with l-arginine (r = - 0.277, p < 0.044) in the pre-eclamptic group. When compared with maternal plasma in venous cord blood l-arginine was markedly reduced (p < 0.05) and there was a significant elevation in ADMA, SDMA, MMA and l-ornithine (p < 0.001, for each) without discernible differences between the study groups. CONCLUSIONS: Parameters of l-arginine metabolism do not discriminate the early-onset from late-onset pre-eclampsia. Our study provided indirect evidences for the redirection of l-arginine-NOS to the l-arginine-arginase pathway.

Metabolic hormones in follicular fluid in women undergoing in vitro fertilization.

OBJECTIVE: To determine the concentrations of metabolic hormones in follicular fluid (FF) and to find clinical correlates of these biochemical parameters. STUDY DESIGN: FF was obtained from 108 women by ultrasonography-guided transvaginal puncture following controlled ovarian hyperstimulation. FF insulin, leptin, adiponectin and resistin levels were measured by enzyme-linked immunosorbent assay, and ghrelin was analyzed with radioimmunoassay. RESULTS: It was demonstrated that oocyte number correlated negatively with FF leptin (r = -0.190, p < 0.050) and insulin (r = -0.209, p < 0.031) and positively with resistin (r = 0.236, p < 0.014). After adjustments for confounding hormone parameters, resistin remained a positive (p < 0.000) predictor and insulin (p < 0.039) and adiponectin (p < 0.033), negative predictors of oocyte number. When the embryo number was considered, FF leptin proved to be a strong negative (p < 0.012) whereas resistin proved to be a positive outcome predictor (p < 0.004). CONCLUSION: In women undergoing in vitro fertilization (IVF), FF metabolic hormones may be involved in regulating ovarian function and in determining fertilization outcome. Resistin appears to have beneficial effects on the outcome of IVF, while leptin, insulin, adiponectin and ghrelin appear to have adverse or no effects.

[Some clinical aspects of sodium homeostasis disorders]. / A nátriumháztartás zavarainak néhány klinikai vonatkozása.

In this review three major issues of sodium homeostasis are addressed. Specifically, volume-dependent (salt-sensitive) hypertension, sodium chloride content of maintenance fluid and clinical evaluation of hyponatremia are discussed. Regarding volume-dependent hypertension the endocrine/paracrine systems mediating renal sodium retention, the relationship between salt intake, plasma sodium levels and blood pressure, as well as data on the dissociation of sodium and volume regulation are presented. The concept of perinatal programming of salt-preference is also mentioned. Some theoretical and practical aspects of fluid therapy are summarized with particular reference to using hypotonic sodium chloride solution for maintenance fluid as opposed to the currently proposed isotonic sodium chloride solution. Furthermore, the incidence, the aetiological classification and central nervous system complications of hyponatremia are presented, too. In addition, clinical and pathophysical features of hyponatremic encephalophathy and osmotic demyelinisation are given. The adaptive reactions of the brain to hypotonic stress are also described with particular emphasis on the role of brain-specific water channel proteins (aquaporin-4) and the benzamil-inhibitable sodium channels. In view of the outmost clinical significance of hyponatremia, the principles of efficient and safe therapeutic approaches are outlined.

Pathomechanisms of Prenatally Programmed Adult Diseases.

Based on epidemiological observations Barker et al. put forward the hypothesis/concept that an adverse intrauterine environment (involving an insufficient nutrient supply, chronic hypoxia, stress, and toxic substances) is an important risk factor for the development of chronic diseases later in life. The fetus responds to the unfavorable environment with adaptive reactions, which ensure survival in the short run, but at the expense of initiating pathological processes leading to adult diseases. In this review, the major mechanisms (including telomere dysfunction, epigenetic modifications, and cardiovascular-renal-endocrine-metabolic reactions) will be outlined, with a particular emphasis on the role of oxidative stress in the fetal origin of adult diseases.

Acute Vascular Response to Hemodialysis as Measured by Serum Syndecan-1 and Endothelin-1 Levels as Well as Vascular Stiffness.

BACKGROUND: Chronic hemodialysis (HD) patients have a very high cardiovascular risk. Acute vascular changes during dialysis mediated by factors of the endothelium may have a crucial role in this. The aim of this article is to study the acute vascular changes during HD. METHODS: In 29 consecutive chronic HD patients (age: 65.6 ± 10.4 years), their pre-, mid-, and post-HD plasma syndecan-1 (SDC-1) and endothelin-1 (ET-1) levels were measured. Applanation tonometry was performed before HD. RESULTS: Their SDC-1 levels increased during HD (p = 0.004). Males had higher ET-1 levels. The patients were divided into two groups based on their pre-HD pulse wave velocity (PWV): PWV ≥ 12 m/s and PWV < 12 m/s. The pre-HD and mid-HD SDC-1 levels were higher in the group with a PWV ≥ 12 m/s (10.174 ± 2.568 vs. 7.928 ± 1.794 ng/mL, p = 0.013, and 10.319 ± 3.482 vs. 8.248 ± 1.793 ng/mL, p = 0.044, respectively). The post-HD ET-1 levels were higher in the patient group with a PWV ≥ 12 m/s (10.88 ± 3.00 vs. 8.05 ± 3.48 pg/l, p = 0.027). Patients with a PWV ≥ 12 m/s had higher pre-HD peripheral and aortic systolic blood pressures (p < 0.05). The total cholesterol correlated with the SDC-1 decrease during HD (r = 0.539; p = 0.008). The pre-, mid-, and post-HD SDC-1 correlated with ultrafiltration (r = 0.432, p = 0.019; r = 0.377, p = 0.044; and r = 0.401, p = 0.012, respectively). CONCLUSION: SDC-1 and ET-1 contribute to the vascular changes observed during HD, and they have correlations with some cardiovascular risk factors.

Telomere Length and Telomerase Activity of Granulosa Cells and Follicular Fluid in Women Undergoing In Vitro Fertilization.

This study aimed to evaluate the interrelationship between telomere length, telomerase activity and oxidative DNA damage in patients undergoing in vitro fertilization (IVF). This single-center, observational clinical study comprised 102 unselected, consecutive patients with various infertility diagnoses. Granulosa cells (GCs) and follicular fluid (FF) were analyzed simultaneously for telomere functions and for the marker of oxidative DNA damage, 8-hydroxy-2-deoxyguanosine (8-OHdG). An Absolute Human Telomere Lengths Quantification qPCR Assay kit and Telomerase Activity Quantification qPCR Assay kit (Nucleotestbio, Budapest, Hungary), as well as an 8-OHdG ELISA kit (Abbexa Ltd., Cambridge, United Kingdom) were used for analyses. Similar telomere lengths were found in GCs and FF, however telomerase activity was markedly depressed, while 8-OHdG levels were markedly elevated in FF compared with those in GCs (p < 0.01). Telomere lengths were independent of telomerase activity both in GCs and FF. However, GC 8-OHdG was inversely related to telomerase activity in GCs and FF (p < 0.05). Importantly, 8-OHdG levels both in GCs and FF had significant negative impact on the number of the retrieved and MII oocytes (p < 0.01), whereas FF 8-OHdG was negatively related further to the number of fertilized oocytes and blastocysts (p < 0.01). In conclusion, we could not confirm the direct association of telomere function and reproductive potential. However, oxidative DNA damage, as mainly reflected by 8-OHdG, adversely affected early markers of IVF outcome and clinical pregnancies.

Birth by cesarean section is associated with elevated neonatal plasma levels of dimethylarginines.

BACKGROUND: This study was undertaken to compare the effects of vaginal delivery and cesarean section on the L-arginine-nitric oxide system by measuring levels of L-arginine, an endogenous nitric oxide synthase antagonist asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA) in the cord blood and postnatally. METHODS: Plasma samples were obtained from the umbilical vein and artery at birth and from peripheral venous blood on the second postnatal day in 30 full-term newborn infants: 10 born vaginally and 20 born by cesarean section. RESULTS: After vaginal delivery, ADMA concentration was higher in the umbilical vein than in the umbilical artery (mean 1.06 vs 0.90 µmol/L [P = 0.027]); and ADMA level fell after birth to 0.66 µmol/L on the second postnatal day (P = 0.007 vs umbilical artery). Newborns born by cesarean section had similar ADMA levels in umbilical arterial and venous blood, 1.19 and 1.18 µmol/L, and the ADMA level fell to 0.84 µmol/L by the second postnatal day (P < 0.001). Vaginal birth induced neither significant umbilical venoarterial difference nor a postnatal fall in SDMA. After cesarean section, SDMA was essentially the same in umbilical vein, umbilical artery and postnatal peripheral vein samples. At 2 days of age, both ADMA and SDMA levels stayed higher in infants born by cesarean section than in vaginally born infants. CONCLUSIONS: ADMA level falls after both vaginal and cesarean birth, whereas SDMA level does not. The higher ADMA level after cesarean birth compared with vaginal birth may contribute to decreased nitric oxide production and bioavailability in neonatal vascular beds.

Dramatic decrease of carnitine esters after interruption of exogenous carnitine supply in hemodialysis patients.

L-carnitine supplementation is extensively used in patients on maintenance hemodialysis (HD) to improve dialysis-related clinical symptoms. In a series of studies, we investigated the dynamics of carnitine pool in carnitine-supplemented HD patients; here we report dramatic decrease with special changes of the ester profile due to interruption of the exogenous intake after the last HD session. Serum samples were collected from 18 L-carnitine-repleted end-stage renal disease (ESRD) patients before the L-carnitine supplementation, after completion of a carnitine supplementation period treatment (12 weeks, 1 g/IV/HD), right before the HD session, and 44 h after the dialysis. Levels of free carnitine (FC) and the individual esters were determined using electrospray MS/MS technique. Normally, L-carnitine supplementation causes significant elevation of all carnitine compounds to supraphysiological levels, which reaches a standard steady-state-like profile. In this study we found a dramatic decrease in the level of FC, and in short- and medium-chain acylcarnitines (ACs) 44 h after the last dialysis. At the end of this interdialytic period, FC levels increased to only 65% of the predialysis level, whereas the amounts of C2 and C3 esters recovered to only 50%. The level of C6 was 65% of the predialysis level, whereas the amount of C8 chain length ACs returned to 72% of the predialysis level. No significant change was seen in AC concentrations above C10 chain length. Omission of one single dosage of supplemental carnitine in long-term administration schemes results in dramatic decrease and reprofiling of carnitine esters even after the usual 44 h of interdialytic period.