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.

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.

[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.

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.

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.

[Legal aspects of ritual circumcision]. / Juristische Aspekte der rituellen Zirkumzision.

Female circumcision (genital mutilation) is a criminal violation of human rights under German law. Even with consent of the person to be circumcised and/or her legal representative this procedure must not be carried out since a consent to female circumcision is unethical and therefore void. As much consent as there is on female circumcision the legal situation with ritual male circumcision is very unclear. In practice and unnoticed by the public male circumcision is carried out - be it for medical or ritual reasons - without deeper-going reflexions on the clearness of the medical indication or the legal situation with ritual circumcision. From the medical aspect there are big differences between female and male circumcision but also certain parallels. Various reasons, partly founded in prejudice and misinformation, make people refrain from regarding circumcision of boys also as illegal. Contrary to the prevailing opinion male circumcision also represents a bodily harm which a doctor can only carry out after a preoperative interview and with the consent of the affected person. Since ritual male circumcision does not serve the wellbeing of a child it is not possible for the parents to give their consent to the circumcision in lieu of the child. Male circumcision is only permitted if the child has given his consent and is thus only legally permitted if the child has reached an age at which he is mature enough to understand the meaning and extent of such an action which is hardly the case before he has completed his 16 (th) year.

Syncytin-1 and glial cells missing a: hypoxia-induced deregulated gene expression along with disordered cell fusion in primary term human trophoblasts.

BACKGROUND/AIMS: Pre-eclampsia, a major cause of perinatal morbidity, is characterized by alterations in placental oxygen availability and trophoblast differentiation. We investigated how different levels of hypoxia alter the expression of syncytin-1, glial cells missing a (GCMa) and syncytin-1 receptor ASCT2 and affect syncytialization in primary term human trophoblasts. METHODS: Cells were incubated at 1, 3, 6 and 21% O(2) for 24, 48 and 72 h with or without cyclic adenosine monophosphate (cAMP). Gene expression was analyzed by real-time PCR. Syncytialization was assessed using beta-human chorionic gonadotropin measurement and desmoplakin immunostaining. RESULTS: Following incubation with cAMP at 21% O(2), peak gene expression of syncytin-1 and GCMa was found after 24 h along with syncytium formation at 72 h. Conversely, incubation at 1% O(2) led to a time-dependent reduction of GCMa and syncytin-1 at the transcriptional level. Cell fusion occurred at 21 and 6% O(2) and was suppressed at 1% O(2). ASCT2 mRNA levels were preserved at normoxia and downregulated at 1% O(2) after 48 h. CONCLUSION: Our data support the premise that the expression of GCMa and syncytin-1 precedes syncytialization of trophoblasts, e.g. at 6% O(2), which is assumed to resemble physiological conditions. Severe hypoxia is associated with reduced GCMa and syncytin-1 transcripts and altered fusion of primary trophoblasts.

Women encounter ADRs more often than do men.

BACKGROUND: Several publications indicate that the female gender experiences a higher incidence of adverse drug reactions (ADRs) than does the male gender. The reasons, however, remain unclear. Gender-specific differences in the pharmacokinetic and pharmacodynamic behaviour of drugs could not be identified as an explanation. The aim of this study was to analyse ADR risk with respect to gender, age and number of prescribed drugs. METHODS: A prospective multicenter study based on intensive pharmacovigilance was conducted. Information on patient characteristics and evaluated ADRs was stored in a pharmacovigilance database--KLASSE. RESULTS: In 2,371 patients (1,012 female subjects), 25,532 drugs were prescribed. In 782 patients, at least one ADR was found. A multivariate regression analysis adjusting for age, body mass index (BMI) and number of prescribed drugs showed a significant influence of female gender on the risk of encountering ADRs [odds ratio (OR) 1.596, confidence interval (CI) 1.31-1.94; p < 0.0001). Dose-related ADRs (51.8%) were the dominant type in female subjects. Comparing system organ classes of the World Health Organisation (SOC-WHO), cardiovascular (CV) ADRs were particularly frequent in female subjects (OR 1.92, CI 1.15-3.19; p = 0.012). CONCLUSION: Our data confirm the higher risk of ADRs among female subjects compared with a male cohort. Several explanations were investigated. No single risk factor could be identified.

Carnitine status in early-treated children, adolescents and young adults with phenylketonuria on low phenylalanine diets.

BACKGROUND: In patients with phenylketonuria (PKU), the carnitine status may be impaired for metabolic or dietary reasons, including low carnitine intake, a deficient synthesis and acylcarnitine production from phenylalanine (Phe) metabolites. METHODS: Free carnitine and acylcarnitine status was assessed in 30 PKU patients, aged 0.5-36 years, mean age 13.8 years. Our cohort was divided into 2 groups according to the preparations of Phe-free amino acids (AA) prescribed, with or without carnitine supplementation. Daily Phe intake, dosage of AA mixtures and body weight were recorded along with measurements of acylcarnitines in blood spots (by tandem mass spectrometry) and serum AA. Control data were obtained from 50 healthy volunteers (aged 0.2-39 years, mean age 14.2. years). Statistical analysis comprised the t test, ANOVA and Pearson's correlation. RESULTS: PKU patients had lower free carnitine (C0) concentrations than controls (25.82 +/- 7.38 vs. 31.28 +/- 6.17 micromol/l; p < 0.001) and lower octanoyl- and decanoylcarnitine. Mean C0 and acylcarnitine concentrations did not differ between PKU patients taking the various protein substitutes with or without carnitine; mean C0 levels in PKU patients receiving AA enriched with carnitine were still lower compared with controls (p < 0.05). CONCLUSIONS: Actual dietary regimens can not completely normalize the carnitine status; therefore, carnitine levels should be given careful consideration in subjects with PKU.

[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.

Contribution of androgens to the gender difference in leptin production in obese children and adolescents.

Recent studies demonstrated significantly higher serum leptin concentrations in females as compared with males, even after correction for differences in body fat mass. The aim of our study was to measure serum leptin concentrations in a large group of obese children and adolescents to determine the possible role of sex steroid hormones on both leptin serum concentrations and production in human adipocytes. Obese girls were found to have significantly higher leptin concentrations than boys at the same degree of adiposity (25.2+/-14.1 vs. 17.2+/-12.6 ng/ml, P < 0.001). In a multiple regression analysis with age and body mass index (percent body fat) as fixed variables, it turned out that testosterone had a potent negative effect on serum leptin in boys, but not in girls. In vitro experiments using newly developed human adipocytes in primary culture showed that both testosterone and its biologically active metabolite dihydrotestosterone are able to reduce leptin secretion into the culture medium by up to 62%. Using a semiquantitative reverse transcriptase-PCR method, testosterone was found to suppress leptin mRNA to a similar extent. These results suggest that, apart from differences in body fat mass, the higher androgen concentrations in obese boys are responsible for the lower leptin serum concentrations compared with obese girls.

Blood levels and renal effects of atrial natriuretic peptide in normal man.

Since mammalian atria were recently found to contain vasoactive and natriuretic peptides, we investigated the following in normal humans: plasma human atrial natriuretic peptide concentrations, effective renal plasma flow (ERPF), glomerular filtration rate (GFR), urinary water and electrolyte excretion, blood pressure (BP), and catecholamine, antidiuretic hormone (ADH), angiotensin II, and aldosterone levels before, during, and after intravenous administration of the newly synthetized alpha-human atrial natriuretic peptide (alpha hANP). In 10 subjects alpha hANP given as an initial bolus of 50 micrograms followed by a 45-min maintenance infusion at 6.25 micrograms/min increased plasma alpha hANP from 58 +/- 12 to 625 +/- 87 (mean +/- SEM) pg/ml; caused an acute fall in diastolic BP (-12%, P less than 0.001) and a hemoconcentration (hematocrit +7%, P less than 0.01) not fully explained by a negative body fluid balance; increased GFR (+15%, P less than 0.05) despite unchanged or decreased ERPF (filtration fraction +37%, P less than 0.001); augmented (P less than 0.05- less than 0.001) urinary chloride (+317%), sodium (+224%), calcium (+158%), magnesium (+110%), phosphate excretion (+88%), and free water clearance (from -0.76 to +2.23 ml/min, P less than 0.001) with only little change in potassium excretion; and increased plasma norepinephrine (P less than 0.001) while plasma and urinary epinephrine and dopamine, and plasma ADH, angiotensin II, and aldosterone levels were unchanged. The magnitude and pattern of electrolyte and water excretion during alpha hANP infusion could not be accounted for by increased GFR alone. Therefore, in normal man, endogenous alpha hANP seems to circulate in blood. alpha hANP can cause a BP reduction and hemoconcentration which occur, at least in part, independently of diuresis and are accompanied by sympathetic activation. An increase in GFR that occurs in the presence of unchanged or even decreased total renal blood flow is an important but not sole mechanism of natriuresis and diuresis induced by alpha hANP in man.

Effects of various dietary amino acid preparations for phenylketonuric patients on the metabolic profiles along with postprandial insulin and ghrelin responses.

AIM: We investigated the metabolic profiles along with insulin and ghrelin responses following ingestion of various amino acid (AA) substitutes commonly used in the treatment of phenylketonuria to study the effects of added macronutrients. METHODS: Twenty healthy and 6 phenylketonuric adults ingested AA mixtures with or without carbohydrates and fat (Anamix, Easiphen, or p-am 3; 0.35 g AA/kg body weight); milk powder shakes were used for control purposes. Serum AA, glucose, urea, insulin, and ghrelin were measured over 5 h. RESULTS: Peak AA concentrations were achieved at around 60 min postprandially for supplemented AA powders and control shakes, significantly later than for pure AA. Of interest, the mean Phe/Tyr ratio declined by 40-50% in phenylketonuric patients following intake of Easiphen, Anamix, or p-am 3. The insulin peaks, up to 500% as compared with baseline, occurred at 30 min and were approximately 100% higher after intake of AA plus macronutrients. Glucose and urea remained constant. Ghrelin showed a nadir at 60 min, followed by a rise leading to a 30% increase of initial concentrations for pure AA as compared with more constant levels for preparations with macronutrients. CONCLUSION: An oral AA bolus together with macronutrients retards hyperaminoacidemia, displays a higher insulin secretion, normoglycemia, and more stable ghrelin concentrations, whereas the pure AA tested here exerted weaker anabolic effects.

[Urinary tract infections in infants and children -- a consensus on diagnostic, therapy and prophylaxis]. / Harnwegsinfektionen im Säuglings- und Kindesalter. Konsensusempfehlungen zu Diagnostik, Therapie und Prophylaxe.

Urinary tract infections (UTI) are among the most common bacterial infections in infants and children. The early diagnosis of a pyelonephritis and its rapid, calculated antibacterial therapy are decisive for the prognosis. Urogenital anomalies, renal damage and bladder dysfunction may influence the risk of recurrences of UTI and pyelonephritic scarring. Diagnostic strategies therefore should focus on their early recognition. Pediatricians, urologists and infectiologists are cooperating in diagnostic, therapy and prophylaxis of UTI. The aim of the interdisciplinary consensus presented was to work out a concept which may help to manage childhood UTI in daily practice.

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.

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).