Variant adiponutrin confers genetic protection against cholestatic itch.

Lysophosphatidic acid (LPA) mediates cholestatic pruritus. Recently the enzyme PNPLA3, expressed in liver and skin, was demonstrated to metabolise LPA. Here we assess the association of the PNPLA3 variant p.Ile148Met, known to be associated with (non-)alcoholic fatty liver disease (NAFLD) in genome-wide association studies, with cholestatic itch in 187 patients with primary biliary cirrhosis (PBC) and 250 PBC-free controls as well as 201 women with intrahepatic cholestasis of pregnancy (ICP) and 198 female controls without a history of ICP. Our hypothesis was that the intensity of cholestatic itch differs in carriers of distinct PNPLA3 p.Ile148Met genotypes. Patients with PBC carrying the allele p.148Met that confers an increased NAFLD risk reported less itching than carriers of the p.148Ile allele (ANOVA P = 0.048). The PNPLA3 p.148Ile allele increased the odds of requiring plasmapheresis for refractory pruritus (OR = 3.94, 95% CI = 0.91-17.00, P = 0.048). In line with these findings, the PNPLA3 p.148Met allele was underrepresented in the ICP cohort (OR = 0.66, 95% CI = 0.47-0.92, P = 0.013). Notwithstanding the need for further replication of these findings, we conclude that the PNPLA3 allele p.148Met might confer protection against cholestatic pruritus, possibly due to increased LPA-acyltransferase activity in liver and/or skin.

Longitudinal determination of serum placental protein 13 during development of preeclampsia.

OBJECTIVE: To determine maternal serum placental protein 13 (PP13) in normal pregnancy and preeclampsia. METHODS: A prospective, longitudinal study with 41 normal pregnant women, 18 cases with preterm delivery or cervix insufficiency and 4 with developing late-onset preeclampsia. Six hundred and sixty-six maternal blood samples were obtained every 2-4 weeks starting at 5-8 weeks gestation (10-12 samples/patient) and tested for serum PP13 by ELISA. RESULTS: In normal pregnant women delivering at term, median maternal serum PP13 levels were growing from 166 to 202 pg/ml and 382 pg/ml in the first, second and third trimester, respectively. Preeclamptic women had significantly reduced PP13 levels in the first trimester (multiples of median of 0.14 at 7-8 weeks; p = 0.005 compared to normal). PP13 in the third trimester was significantly higher compared to normal at 35-36 weeks with PP13 multiples of median of 1.79. CONCLUSION: This preliminary study indicates that low levels of PP13 in early pregnancy identify at-risk pregnancies, whereas high levels precede the syndrome in late pregnancy and suggest syncytiotrophoblast necrosis.

Transforming growth factor beta1 up-regulates interferon regulatory factor 8 during dendritic cell development.

Langerhans cells (LC) represent the cutaneous contingent of dendritic cells (DC). Their development critically depends on transforming growth factor beta1 (TGF-beta1) as demonstrated by analysis of TGF-beta1(-/-) mice, which lack LC. Here we used a two-step culture system and transcriptional profiling by DNA microarrays to search for TGF-beta1 target genes in DC. The study identified interferon regulatory factor 8 (IRF-8) as a novel target gene of TGF-beta1 signaling in DC. TGF-beta1 effectively induced Smad2/3 phosphorylation and IRF-8 RNA and protein expression. Blocking the TGF-beta1/Smad pathway by ectopic expression of inhibitory Smad7 and by SB431542 inhibitor abolished TGF-beta1 induced up-regulation of IRF-8. Furthermore, TGF-beta1-dependent induction of IRF-8 occurred in the absence of protein biosynthesis, suggesting a direct action of TGF-beta1/Smad signaling on IRF-8 gene activity. TGF-beta1 also induced expression of the chemokine receptor CCR7 and enhanced DC migration towards CCR7 ligand ELC. DC of IRF-8(-/-) mice show reduced CCR7 expression and migratory activity, thereby implicating the TGF-beta1/Smad/IRF-8 signaling pathway in CCR7 regulation. Thus, this study identified a novel TGF-beta1/Smad/IRF-8 signaling pathway with an impact on DC phenotype and function.

Three new cases of congenital agenesis of the trachea.

Congenital absence of the trachea is a rare anomaly that might confront the obstetrician or neonatologist with an unexpected emergency. These patients present with cyanosis, severe respiratory distress, insufficient gas exchange, absence of audible crying and difficult or impossible endotracheal intubation. In more than 90% it is associated with further congenital malformations. Adequate oxygenation depends on the existence of a tracheo- or bronchooesphageal fistula and the length of the proximal trachea. We present the cases of three neonates with tracheal agenesis with tracheooesophageal fistula. Two of the neonates died within the first hour of life because endotracheal intubation was impossible and oxygenation through an oesophageally placed tube was insufficient. The third infant could be oxygenated through a tracheooesophageal fistula. The ventilation was at least insufficient and no surgical intervention was made. The diagnosis of a congenital absence of the trachea usually is made after birth because of the clinical signs and the course within the first minutes of life. The only way that the diagnosis can be made prenatally is by magnetic resonance imaging (MRI). The knowledge of this clinical picture helps to make decisions in an unexpected emergency in the immediate postpartum period and also in patients whose ventilation is very difficult right from the start.

Expression of the actin stress fiber-associated protein CLP36 in the human placenta.

Differentiation processes in the trophoblast comprise polarization, cell fusion and migration. All these processes involve dramatic reorganizations of cytoskeletal proteins such as intermediate filaments or actin. Due to very restricted knowledge on cytoskeletal changes in trophoblast, we analyzed the protein expression of an actin stress fiber-associated protein, the carboxy-terminal LIM domain protein (CLP36). CLP36 belongs to the enigma family of proteins, binds to alpha-actinin and is involved in the cytoskeletal reorganization and signal transduction of a variety of cells. CLP36 protein was found to be exclusively expressed in the cytotrophoblast layer. Colocalization of CLP36 with Mib-1 revealed that CLP36 protein expression is restricted to proliferative and early post-proliferative trophoblast cells. Blockage of syncytial fusion by culture of villous explants in the presence of caspase 8 inhibitors further supported this notion since CLP36 was only found in the basal and proliferative layer of the multilayered cytotrophoblast. We present evidence for the exclusive protein expression of CLP36 in proliferative and early post-proliferative trophoblast cells. Pathological pregnancy syndromes such as preeclampsia are driven by alterations of trophoblast differentiation and turnover, where it needs to be elucidated whether CLP36 is involved in these alterations.

Trophoblast fusion: fusogenic proteins, syncytins and ADAMs, and other prerequisites for syncytial fusion.

Trophoblast fusion in the placenta is an event of major importance for the preservation of a healthy pregnancy. This process takes place throughout pregnancy and is crucial for the maintenance of the syncytiotrophoblast layer, the direct border between maternal blood and fetal tissues. Different regulatory proteins have been reported that are involved in trophoblast fusion. Syncytin-1 is a candidate regulator of fusion together with its receptors ASCT2 (RDR) and ASCT1. Little is known about the receptor properties and the interactions between receptor and ligand. Syncytin-2 or HERV-FRD is another strong candidate also of retroviral origin; while its actual function still remains to be explored. ADAM12 has been proposed to be a candidate regulator of trophoblast fusion since it is known to be involved in myoblast fusion, a process with a variety of similarities to trophoblast fusion. Beside these regulatory proteins, there is the necessity of a flip of phosphatidylserine from the inner to the outer leaflet of the plasma membranes of the fusing cells. Moreover, appropriate events of the early and still reversible stages of the apoptosis cascade are indispensable for trophoblast fusion. In this review, we present some details on the above events and proteins with their most important properties that could explain their roles in trophoblast fusion.

Antihypertensive therapy in patients with pre-eclampsia: A prospective randomised multicentre study comparing dihydralazine with urapidil.

BACKGROUND: Drug treatment is imperative for pregnant women with pregnancy-induced hypertension (PIH) and pre-eclampsia. For more than 40 years, dihydralazine has been the drug of choice for this indication. Another particularly effective and better tolerable antihypertensive is urapidil. Yet only a few studies on limited patient collectives have been published on the clinical experience with urapidil in PIH. METHODS: Urapidil was interindividually compared to dihydralazine in a total of 42 patients, at six participating clinical centres. Patients were randomly assigned to the treatment groups. Urapidil was administered at an initial dose of 12.5-25mg, dihydralazine was administered at a uniform initial dose of 5mg. Patients were closely monitored for the initial 24h of therapy. Until delivery and in the postpartal phase, mother and baby underwent four additional follow-up checks at regular intervals. RESULTS: Either drug was effective in lowering BP. Urapidil treatment proved to be better controllable. There were clear differences as to tolerability. In the urapidil group, one patient complained of headaches. In the dihydralazine group, six patients experienced adverse occurrences. Under dihydralazine treatment, some marked HR increases occurred, interpretable as reflectory tachycardia. CONCLUSIONS: Urapidil proved to be equally effective as dihydralazine in lowering BP in patients with pre-eclampsia, but showed a better controllability and tolerability. Urapidil can hence be recommended as a promising alternative for patients with PIH.

Adverse effects of lupus anticoagulant positive blood sera on placental viability can be prevented by heparin in vitro.

OBJECTIVE: Lupus anticoagulant poses a significant risk factor for obstetric complications, whereas heparin improves live birth rates in those pregnancies. Pathophysiology of antiphospholipid antibodies on placental function involves coagulopathies and thrombosis but also dysregulated trophoblast turnover. STUDY DESIGN: With the use of placental explant cultures, we assessed the effect of lupus anticoagulant positive sera (LA + sera) on apoptosis, mitosis, and invasion of trophoblast and determined the role of unfractionated heparin in regulating these functions. RESULTS: LA + sera were associated with increased placental apoptosis (TUNEL, M30 formation, DNA laddering). LA + sera decreased villous trophoblast proliferation and reduced extravillous trophoblast invasion through matrigel. Heparin attenuated LA + sera-induced apoptosis and facilitated trophoblast invasion. CONCLUSION: Lupus anticoagulant may impair placentation by increasing apoptosis, attenuating mitosis and reducing invasion of the trophoblast. The direct effects on trophoblast viability by heparin demonstrate an alternative biologic function for this anticoagulant and raise the possibility that anomalous trophoblast development may be therapeutically regulated.

HELLP syndrome, multifactorial thrombophilia and postpartum myocardial infarction.

A case of postpartum acute myocardial infarction with intraventricular thrombus occurred in a woman with HELLP syndrome. Since coronary artery disease was ruled out angiographically, the assumed pathophysiological mechanism for myocardial malperfusion was intermittend coronary vasospasm and thrombosis. There were several thrombophilic risk factors detectable (heterozygous factor V Leiden, low levels of antithrombin III, protein S deficiency), whose possible impact in this rare but severe clinical condition is discussed.