Tryptophan catabolism to serotonin and kynurenine in women undergoing in-vitro fertilization.

This cross-sectional clinical study was designed to explore the impact of tryptophan-kynurenine and tryptophan-serotonin (5 HT) pathways on reproductive performance during in vitro fertilization (IVF). Paired serum and follicular fluid (FF) samples were obtained from 64 consecutive IVF patients. The analysis was done by using LC-MS/MS. Ovarian hyperstimulation resulted in decreased serum tryptophan (p<0.004), 5-HT (p<0.049) and kynurenine (p<0.001). FF levels of tryptophan (R=0.245, p<0.051), kynurenine (R=0.556, p<0.001) and 5-HT (R=0.523, p<0.001) were positively related to their respective serum levels. Clinical pregnancy was associated with higher serum 5-HT (p<0.045) and FF 5-HT (p<0.020) and lower kynurenine to 5-HT ratio (p<0.024). Chemical pregnancy was also positively related to FF 5-HT (R=0.362, p<0.024). Moreover, there was a direct relationship of the number of mature oocytes to the FF 5-HT (R=0.363, p<0.020) but it was inversely related to FF tryptophan to 5-HT and FF kynurenine to 5-HT ratios (R=-0.389, p<0.016 and R=-0.337, p<0.036, respectively). Multivariate logistic regression revealed that the number of mature oocytes was significantly influenced by FF 5-HT (?=0.473, p<0.001). In IVF patients ovarian hyperstimulation results in a reduction of the availability of tryptophan to catabolic pathways to kynurenine and 5-HT. Outcome measures improved significantly when 5-HT predominated over kynurenine.

Closing the gap - detection of clinically relevant von Willebrand disease in emergency settings through an improved algorithm based on rotational Thromboelastometry.

BACKGROUND: Hemorrhage and blood loss are still among the main causes of preventable death. Global hemostatic assays are useful point-of-care test (POCT) devices to rapidly detect cumulative effects of plasma factors and platelets on coagulation. Thromboelastography (TEG) and Thromboelastometry (ROTEM) are established methods in many anesthesiological departments for guided hemostatic treatment. However, von Willebrand disease remains undetected by standard ROTEM, especially during emergency care, despite being the most prevalent congenital hemostatic disorder. METHODS: In our monocentric cohort pilot study we focused on hemostatic challenges associated with von Willebrand disease. Twenty-seven patients with suspected von Willebrand disease were included. We modified the routine ROTEM assay by adding a preincubation with ristocetin and commercially available plasma-derived von Willebrand factor to identify clinically relevant von Willebrand disease (VWD). RESULTS: Addition of von Willebrand factor to the ristocetin assay of a VWD type 3 patient restored the reaction of the whole blood probe to match the response of a healthy person. Our modified ROTEM assay with ristocetin (Ricotem) showed that all high responders (n = 7) had VWD. In the low responder group (n = 16) - 10 of 16 had VWD and in the normal responder group (n = 5), 2 of 5 had mild type 1 VWD. CONCLUSIONS: This new modification of the standard ROTEM assay enables the detection of otherwise unnoticed critical von Willebrand disease based on alterations in clot formation and might serve as a novel approach to reliably assess severe VWD patients by platelet-mediated blood clotting in an emergency setting. We recommend incorporating this new VWD-focused screening tool into the current ROTEM-based management algorithm of acute microvascular bleeding.

[Renal transplantation: Opportunities and risks for medical refugees]. / Nierentransplantation: Chancen und Risiken bei medizinischen Flüchtlingen.

BACKGROUND: Families with children and adolescents with end-stage renal disease came to Germany from the former Eastern Bloc countries before the wave of refugees in 2015, in order to enable their children to survive with adequate kidney replacement therapy and in the best case a kidney transplant. METHODS: In a case study, medical records of 4 childen and adolescents were retrospectively analyzed. These patients who fled to Germany for the treatment of terminal renal failure applied for asylum and were successfully transplanted after the usual waiting period. RESULTS: Four of the eight children and adolescents who came to Erlangen for treatment of terminal renal failure between 2003 and 2013 received a functioning kidney transplant (deceased donor kidney) after dialysis therapy was difficult due to lack of compliance to drug and dietary recommendations such as fluid restriction. Since children and adolescents are treated with chronic dialysis only with the aim of kidney transplantation, a living donation was discussed but was not possible for medical reasons. 3 recipients are symptom-free with a functional graft. DISCUSSION: The case study demonstrates that children and adolescents fleeing to Germany due to their end stage renal disease are better integrated after kidney transplantation, have better chances of obtaining a good education and can be expected to live independently with their own income in the future.

Hypermethylation and loss of retinoic acid receptor responder 1 expression in human choriocarcinoma.

BACKGROUND: Human placental development resembles tumorigenesis, due to the invasive and fusogenic potential of trophoblasts. However, these features are tightly controlled in trophoblasts. Disturbance of this spatial and temporal regulation is thought to contribute to the rare formation of choriocarcinomas. Promoter hypermethylation and loss of the tumor suppressor Retinoic acid receptor responder 1 (RARRES1) were shown to contribute to cancer progression. Our study investigated the epigenetic and transcriptional regulation of RARRES1 in healthy human placenta in comparison to choriocarcinoma cell lines and cases. METHODS: Three choriocarcinoma cell lines (Jeg-3, JAR and BeWo) were treated with three different retinoic acid derivates (Am580, Tazarotene and all-trans retinoic acid) and 5-aza-2'-deoxycytidine. We analyzed RARRES1 promoter methylation by pyrosequencing and performed realtime-PCR quantification to determine RARRES1 expression in placental tissue and trophoblastic cell lines. Additionally, RARRES1 was stained in healthy placentas and in biopsies of choriocarcinoma cases (n = 10) as well as the first trimester trophoblast cell line Swan71 by immunofluorescence and immunohistochemistry. RESULTS: In the choriocarcinoma cell lines, RARRES1 expression could not be induced by sole retinoic acid treatment. Stimulation with 5-aza-2'-deoxycytidine significantly induced RARRES1 expression, which then could be further increased with Am580, Tazarotene and all-trans retinoic acid. In comparison to healthy placenta, choriocarcinoma cell lines showed a hypermethylation of the RARRES1 promoter, which correlated with a reduced RARRES1 expression. In concordance, RARRES1 protein expression was lost in choriocarcinoma tissue. Additionally, in the trophoblastic cell line Swan71, we found a significant induction of RARRES1 expression with increased cell density, during mitosis and in syncytial knots. CONCLUSIONS: Our findings showed that RARRES1 expression is absent in choriocarcinoma due to promoter methylation. Based on our analysis, we hypothesize that RARRES1 might exert tumor suppressive functions in multiple cellular processes (e.g. cell cycle regulation, adhesion, invasion and apoptosis).

Searching the web: a survey on the quality of advice on postnatal sequelae of intrauterine growth restriction and the implication of developmental origins of health and disease.

Intrauterine growth restriction (IUGR) and fetal growth restriction (FGR) are pregnancy complications associated with morbidity in later life. Despite a growing body of evidence from current research on developmental origins of health and disease (DOHaD), little information is currently provided to parents on long-term metabolic, cardiovascular and neurologic consequences. As parents strongly rely on internet-based health-related information, we examined the quality of information on IUGR/FGR sequelae and DOHaD in webpages used by laypersons. Simulating non-clinicians experience, we entered the terms 'IUGR consequences' and 'FGR consequences' into Google and Yahoo search engines. The quality of the top search-hits was analyzed with regard to the certification through the Health On the Net Foundation (HON), currentness of cited references, while reliability of information and DOHaD-related consequences were assessed via the DISCERN Plus score (DPS). Overall the citation status was not up-to-date and only a few websites were HON-certified. The results of our analysis showed a dichotomy between the growing body of evidence regarding IUGR/FGR-related sequelae and lack of current guidelines, leaving parents without clear directions. Furthermore, detailed information on the concept of DOHaD is not provided. These findings emphasize the responsibility of the individual physician for providing advice on IUGR/FGR-related sequelae, monitoring and follow-up.

Spectrum, Applicability and Diagnostic Capacity of Contrast-Enhanced Ultrasound in Pediatric Patients and Young Adults after Intravenous Application - A Retrospective Trial.

Purpose: To investigate the spectrum, applicability and diagnostic capacity of intravenous contrast-enhanced ultrasound imaging (CEUS) in a pediatric population. Materials and Methods: From 08/2005 to 11/2015, n = 40 pediatric patients and young adults from 0 - 26 years (Ø 11.4 ±â€Š7.5) and 3.0 - 85.3 kg (Ø 40.8 ± 25.6) with n = 55 investigations received n = 79 IV applications of ultrasound contrast agent (UCA). UCA dose and side effects were documented. Scanned organs were the liver (n = 42), spleen (n = 9), kidney (n = 3), and testis (n = 1). Histology, surgery or reference imaging was compared to CEUS and clinical follow-up. Results: The UCA dose < 20 kg was 0.4 ±â€Š0.3 ml, (0.05 ±â€Š0.02 ml/kg) and > 20 kg was 1.0 ±â€Š0.4 ml (p< 0.0001) (0.02 ±â€Š0.01 ml/kg, p< 0.0001). Adverse effects occurred in 2/79 applications (2.5 %). Agreement CEUS/gold standard resulted in 32/34 investigations. For liver diagnostics (gold standard: MRI, CT, histology, serology), n = 11 malignant and n = 15 benign focal liver lesions were included. The specificity was 100 % (95 % CI: 0.77 - 1.00), the sensitivity was 82 % (95 % CI: 0.48 - 0.98), the positive predictive value was 100 % (95 % CI: 0.69 - 1.00) and the negative predictive value was 88 % (95 % CI: 0.62 - 0.98, p< 0.0001). In n = 2 reference imaging misdiagnosed and CEUS was in accordance with clinical follow-up. All splenic/renal lesions were diagnosed correctly. In n = 1 an insufficient testicular perfusion was ruled out. The observation time was 30.4 ±â€Š30.5 months. Conclusion: CEUS is a well-tolerated and diagnostically equivalent modality in pediatric care, providing fundamental advantages compared to currently approved imaging modalities for these age groups.

[Phosphate Intoxication after Application of Enema--a Life-threatening Iatrogenic Complication]. / Phosphatintoxikation nach Klysmagabe--eine lebensgefährliche iatrogene Komplikation.

INTRODUCTION: Enemas are used in pediatric patients with constipation. Retention of phosphate containing enemas with prolonged resorption or reduced renal elimination of phosphate can result in life-threatening hyperphosphatemia with subsequent lethal hypocalcemia and acidosis. CASE PRESENTATION: We report the case of a 6-month-old child who received phosphate-containing enema to treat acute aggravation of constipation. The used enema here was not licensed for this age group. Phosphate intoxication resulted (phosphate 19.87 mmol/l) and presented like a sepsis. Hyperphosphatemia was treated by hemodialysis. A non-diagnosed Hirschsprung disease had led to prolonged resorption of phosphate containing enema and to an ileus and toxic megacolon that had to be operated. CONCLUSION: Insufficient elimination of phosphate containing enema can result in lethal or life threatening hyperphosphatemia, hypocalcemia and metabolic acidosis. These can be treated efficaciously by hemodialysis. Because of the high risk of intoxication in using enemas containing phosphate in infants or in patients with gastrointestinal or renal comorbidities, physicians treating constipation should choose enemas without phosphate but with ingredients with lower risk like glycerol or sorbitol in this age group.

The placental mTOR-pathway: correlation with early growth trajectories following intrauterine growth restriction?

Idiopathic intrauterine growth restriction (IUGR) is a result of impaired placental nutrient supply. Newborns with IUGR exhibiting postnatal catch-up growth are of higher risk for cardiovascular and metabolic co-morbidities in adult life. Mammalian target of rapamycin (mTOR) was recently shown to function as a placental nutrient sensor. Thus, we determined possible correlations of members of the placental mTOR signaling cascade with auxologic parameters of postnatal growth. The protein expression and activity of mTOR-pathway signaling components, Akt, AMP-activated protein kinase α, mTOR, p70S6kinase1 and insulin receptor substrate-1 were analysed via western blotting in IUGR v. matched appropriate-for-gestational age (AGA) placentas. Moreover, mTOR was immunohistochemically stained in placental sections. Data from western blot analyses were correlated with retrospective auxological follow-up data at 1 year of age. We found significant catch-up growth in the 1st year of life in the IUGR group. MTOR and its activated form are immunohistochemically detected in multiple placental compartments. We identified correlations of placental mTOR-pathway signaling components to auxological data at birth and at 1 year of life in IUGR. Analysis of the protein expression and phosphorylation level of mTOR-pathway components in IUGR and AGA placentas postpartum, however, did not reveal pathognomonic changes. Our findings suggest that the level of activated mTOR correlates with early catch-up growth following IUGR. However, the complexity of signals converging at the mTOR nexus and its cellular distribution pattern seem to limit its potential as biomarker in this setting.

Memorandum on the use of information technology to improve medication safety.

BACKGROUND: Information technology in health care has a clear potential to improve the quality and efficiency of health care, especially in the area of medication processes. On the other hand, existing studies show possible adverse effects on patient safety when IT for medication-related processes is developed, introduced or used inappropriately. OBJECTIVES: To summarize definitions and observations on IT usage in pharmacotherapy and to derive recommendations and future research priorities for decision makers and domain experts. METHODS: This memorandum was developed in a consensus-based iterative process that included workshops and e-mail discussions among 21 experts coordinated by the Drug Information Systems Working Group of the German Society for Medical Informatics, Biometry and Epidemiology (GMDS). RESULTS: The recommendations address, among other things, a stepwise and comprehensive strategy for IT usage in medication processes, the integration of contextual information for alert generation, the involvement of patients, the semantic integration of information resources, usability and adaptability of IT solutions, and the need for their continuous evaluation. CONCLUSION: Information technology can help to improve medication safety. However, challenges remain regarding access to information, quality of information, and measurable benefits.

The tumor suppressor gastrokine-1 is expressed in placenta and contributes to the regulation of trophoblast migration.

INTRODUCTION: Gastrokine-1 (GKN1) is a secreted auto-/paracrine protein, described to be expressed in the gastric mucosa. In gastric cancers GKN1 expression is commonly down-regulated. While current research focusses on the exploration of tumor-suppressive properties of GKN1 with regard to its potential clinical use in the treatment of gastroenterologic tumor disease, nothing is known about GKN1 expression and function in other organ systems. We investigated GKN1 expression in placental tissue and cells. MATERIALS AND METHODS: GKN1 was localized using immunohistochemistry in first and third trimester placental tissue, hydatidiform moles and various gestational trophoblastic neoplasias. We determined the expression of GKN1 in immunomagnetic bead-separated term placental cells and in choriocarcinoma cell lines. The role of GKN1 for JEG-3 migration was studied using live cell imaging. E-cadherin, MMP-2 and -9, TIMP-1 and -2, as well as urokinase (uPA) expression levels were determined. RESULTS: GKN1 is expressed in healthy third trimester placentas. Its expression is specifically limited to the extravillous trophoblast (EVT). GKN1 expression is significantly reduced in choriocarcinoma cell lines and gestational trophoblastic neoplasias. GKN1 attenuates the migration of JEG-3 choriocarcinoma cells in vitro, possibly via AKT-mediated induction of E-cadherin. GKN1 treatment reduced MMP-9 expression in JEG-3. DISCUSSION: Besides its role in gastric physiology our results clearly indicate regulatory functions of GKN1 in the EVT at the feto-maternal interface during pregnancy. Based on our findings in the JEG-3 choriocarcinoma cell line, an auto-/paracrine role of GKN1 for EVT motility and villous anchorage at the basal plate is conceivable. Thus, the tumor suppressor GKN1 is expressed in placental EVT and might contribute to the regulation of EVT migration/invasion.

[Venous thromboembolism in adolescents associated with fourth-generation oral contraceptives]. / Venöse Thromboembolien bei Jugendlichen mit Kontrazeptiva der vierten Generation.

Venous thromboembolism (VTE) is a rare, but feared adverse drug reaction of combined oral contraceptives. Modern oral contraceptives contain novel progestins, which are suspected of causing thrombotic events more frequently than well-known progestins. Drospirenone is one of those new fourth-generation progestins with antiandrogenic and antimineralocorticoid effects. Especially girls and young women do not only wish for contraception, but also for positive effects on skin and body weight. In the last decade, however, the safety of this progestin was often under discussion.A detailed literature search was conducted to obtain an overview of currently available data on the risk of VTE among girls and young women using drospirenone-containing contraceptives. It appears that drospirenone-containing contraceptives have a similar increase in risk as third-generation oral contraceptives and antiandrogens. Compared to second-generation contraceptives containing the progestin levonorgestrel there is an approximate 2-fold risk increase (1.0 to 2.8-fold) in women aged 10-55 years. Accurate data regarding the risk in the age group under 18 years are lacking. Nevertheless, the risk of VTE appears to be higher in young -women during the first months of treatment. Until more data for nov-el progestins are available and the safety profile is well defined well-studied second-generation oral contraceptives with low dose estrogen and better risk-benefit ratio should be preferred in young women. In any case, all patients should be comprehensively informed regarding the benefits and risks of each contraceptive method.

[High blood pressure in obese children and adolescents]. / Bluthochdruck bei Adipositas im Kindes- und Jugendalter.

Obesity is also an important risk factor in children and adolescents for "essential" arterial hypertension, and contrary to what was assumed earlier, high blood pressure does cause damage to the cardiovascular system. As known from adults, elevated blood pressure induces cardiac hypertrophy, calcifications and atherosclerosis at the coronary vessels and thickens the small blood vessels. These early vascular alterations are particularly pronounced, when increased blood pressure is accompanied by other risk factors, such as dyslipidemia, hyperinsulinemia or smoking. As in any child with elevated blood pressure, the diagnostic evaluation should focus on confirmation of hypertension, determine if an underlying cause can be identified and whether hypertensive target organ damage is present. New reference office blood pressure values were recently published by a large representative community-based study in Germany. Therapy should begin with lifestyle modifications; however, antihypertensive medications will often be needed. Hypertension in obese adolescents occurs frequently and must be diagnosed and treated adequately.

Contribution of different placental cells to the expression and stimulation of antimicrobial proteins (AMPs).

The placenta is a major barrier that prevents potentially infectious agents from causing fetal diseases or related complications during pregnancy. Therefore, we postulated that the placenta might express a broad repertoire of antimicrobial proteins as well as inflammatory chemokines and cytokines to combat invading microorganisms. Here we demonstrate that placental cells indeed express a wide range of AMPs (antimicrobial peptides and proteins) including bactericidal/permeability-increasing protein (BPI), secretory leukocyte protease inhibitor (SLPI), human ß-defensin 2 (hBD2), acyloxyacyl hydrolase (AOAH), and cathelicidin (CAP18). In addition, these cells also secrete pro-inflammatory cytokines and chemokines upon stimulation with bacterial ligands. Notably, we show that BPI expression by placental cells could be completely attributed to granulocytes while highly purified placental trophoblasts expressed only a subset of the AMPs like SLPI. Unexpectedly, trophoblast AMPs did not exhibit inducible secretion in response to various TLR ligands and further investigations showed that the unresponsiveness of trophoblasts to lipopolysaccharide (LPS) was due to a lack of TLR4 expression. In summary, we have shown that the expression of different AMPs can be allocated to various cells in the placenta and the repertoire of the AMPs expressed by placental cells is a result of a cooperation of leukocytes as well as cells from embryonic origin.

Evaluation of a modified thromboelastography assay for the screening of von Willebrand disease.

Thromboelastography (TEG) has been shown to be a valuable point-of-care device for the rapid diagnosis of various bleeding disorders. However, TEG has thus far not been used for the screening for von Willebrand disease (VWD). We evaluated the performance of a modified TEG assay for the laboratory screening of VWD. Three hundred twenty-eight patients (148 male, 180 female, median age 8.4 years, range 0.1 - 72.7 years) were included in the study. The diagnosis and classification of patients was based on personal and familial case history, von Willebrand factor antigen, ristocetin cofactor levels, collagen binding assay, factor VIII coagulant activity and multimer analysis. The ratio of clot strength after preincubation with ristocetin, and without ristocetin, represents the component of clot strength that is formed by cross-linked fibrin fibres and is dependent on the agglutinated platelet fraction. The decrease of the maximum amplitude is a function of the ristocetin concentration and provides a diagnostic parameter able to differentiate between healthy individuals and patients having VWD. Based on a preliminary cut-off value of 25% for the area under the curve (AUC) ratio, the sensitivity varied from 53% to 100% for the different VWD patient groups. The test is suitable for use as a screening test using whole blood and has the additional benefit of being suitable as a point of care test. It appears also useful for monitoring responses to desmopressin (DDAVP) and infusion therapy.

The effect of valproate therapy on thrombin generation determined by calibrated automated thrombography.

BACKGROUND: There is some evidence for coagulation disorders, e.g. decreased coagulation factor activity or thrombocytopenia, related to the use of antiepileptic drugs, mainly associated with valproate. The aim of our study was to evaluate the influence of valproate on thrombin generation. METHOD: Patients with epilepsy receiving multiple anticonvulsant medications either with, or without, valproate were compared. The study group included 90 samples from patients with epilepsy, aged 1.3-20.1 years. Antiepileptic combination therapy without valproate was administered in 50 cases and therapy including valproate in 40 cases. The reference group consisted of 50 non-epileptic patients. Thrombin generation in platelet poor plasma was measured by calibrated automated thrombography. RESULTS: No differences were measured for thrombin generation parameters between controls and patients without valproate therapy. In epileptic patients with valproate therapy, peak height and lag time were significantly lower in comparison to non-epileptic patients. In comparison to epileptic patients without valproate therapy, significant differences were found for lag time and peak time. Patients with valproate therapy had a significantly lower fibrinogen concentration. Platelet counts were decreased in a dose dependent manner. CONCLUSION: No major differences in thrombin generation were found between children on antiepileptic therapy with and without valproate. The decreased fibrinogen levels result in shorter lag time and peak time.

L-carnitine supplementation and adipokines in patients with end-stage renal disease on regular hemodialysis.

Chronic hemodialysis (HD) patients frequently encounter carnitine depletion, elevated adipose tissue-derived hormones/cytokines, that may contribute to accelerated arteriosclerosis. 10 non-diabetic HD patients were studied over 28 weeks. In the 12 weeks treatment period 1 g L-carnitine was given iv after each HD session. Measurements of plasma free- and acylcarnitines, insulin, leptin, adiponectin, resistin and ghrelin were performed at baseline, at weeks 2, 4, 8, 12 (treatment period) and at weeks 24-28 (post-treatment period). L-carnitine supplementation resulted in progressive increase of free- and acylcarnitine levels. Plasma levels of insulin, resistin, leptin and ghrelin remained at the already elevated baseline values. L-carnitine therapy induced a significant increase in plasma adiponectin from 20.2 ± 12.7 µg/ml (baseline) to 32.7 ± 20.2 µg/ml in week 2 (p<0.05) and 35.4 ± 19.6 µg/ml in week 12 (p < 0.03), which remained unchanged in the post-carnitine period. Plasma insulin levels correlated positively with leptin (r = 0.525, p<0.0001) and resistin (r = 0.284, p<0.005); adiponectin levels correlated inversely with leptin (r = -0.255, p<0.02) and resistin (r = -0.213, p<0.04) irrespective of carnitine status. Plasma levels of adipokines and related hormones are greatly elevated in patients on regular HD. L-carnitine administration further augmented the plasma levels of protective adiponectin, therefore it may have a role in preventing cardiovascular complications of uremia.

[Management of high blood pressure in children and adolescents: Recommendations of the European Society of hypertension]. / Manejo de la hipertensión arterial en niños y adolescentes: recomendaciones de la Sociedad Europea de Hipertensión.

Hypertension in children and adolescents has been gaining ground in cardiovascular medicine, mainly due to the advances made in several areas of pathophysiological and clinical research. These guidelines arose from the consensus reached by specialists in the detection and control of hypertension in children and adolescents. Furthermore, these guidelines are a compendium of scientific data and the extensive clinical experience it contains represents the most complete information that doctors, nurses and families should take into account when making decisions. These guidelines, which stress the importance of hypertension in children and adolescents, and its contribution to the current epidemic of cardiovascular disease, should act as a stimulus for governments to develop a global effort for the early detection and suitable treatment of high pressure in children and adolescents. J Hypertens 27:1719-1742 Q 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins.