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author:("dtsch, Jörg")
1.  CNN3 Regulates Trophoblast Invasion and Is Upregulated by Hypoxia in BeWo Cells 
PLoS ONE  2014;9(7):e103216.
CNN3 is an ubiquitously expressed F-actin binding protein, shown to regulate trophoblast fusion and hence seems to play a role in the placentation process. In this study we demonstrate that CNN3 levels are upregulated under low oxygen conditions in the trophoblast cell line BeWo. Since hypoxia is discussed to be a pro-migratory stimulus for placental cells, we examined if CNN3 is involved in trophoblast invasion. Indeed, when performing a matrigel invasion assay we were able to show that CNN3 promotes BeWo cell invasion. Moreover, CNN3 activates the MAPKs ERK1/2 and p38 in trophoblast cells and interestingly, both kinases are involved in BeWo invasion. However, when we repeated the experiments under hypoxic conditions, CNN3 did neither promote cell invasion nor MAPK activation. These results indicate that CNN3 promotes invasive processes by the stimulation of ERK1/2 and/or p38 under normoxic conditions in BeWo cells, but seems to have different functions at low oxygen levels. We further speculated that CNN3 expression might be altered in human placentas derived from pregnancies complicated by IUGR and preeclampsia, since these placental disorders have been described to go along with impaired trophoblast invasion. Our studies show that, at least in our set of placenta samples, CNN3 expression is neither deregulated in IUGR nor in preeclampsia. In summary, we identified CNN3 as a new pro-invasive protein in trophoblast cells that is induced under low oxygen conditions.
PMCID: PMC4106885  PMID: 25050546
2.  Corticotropin-releasing hormone stimulates expression of leptin, 11beta-HSD2 and syncytin-1 in primary human trophoblasts 
The placental syncytiotrophoblast is the major source of maternal plasma corticotropin-releasing hormone (CRH) in the second half of pregnancy. Placental CRH exerts multiple functions in the maternal organism: It induces the adrenal secretion of cortisol via the stimulation of adrenocorticotropic hormone, regulates the timing of birth via its actions in the myometrium and inhibits the invasion of extravillous trophoblast cells in vitro. However, the auto- and paracrine actions of CRH on the syncytiotrophoblast itself are unknown. Intrauterine growth restriction (IUGR) is accompanied by an increase in placental CRH, which could be of pathophysiological relevance for the dysregulation in syncytialisation seen in IUGR placentas.
We aimed to determine the effect of CRH on isolated primary trophoblastic cells in vitro. After CRH stimulation the trophoblast syncytialisation rate was monitored via syncytin-1 gene expression and beta-hCG (beta-human chorionic gonadotropine) ELISA in culture supernatant. The expression of the IUGR marker genes leptin and 11beta-hydroxysteroid dehydrogenase 2 (11beta-HSD2) was measured continuously over a period of 72 h. We hypothesized that CRH might attenuate syncytialisation, induce leptin, and reduce 11beta-HSD2 expression in primary villous trophoblasts, which are known features of IUGR.
CRH did not influence the differentiation of isolated trophoblasts into functional syncytium as determined by beta-hCG secretion, albeit inducing syncytin-1 expression. Following syncytialisation, CRH treatment significantly increased leptin and 11beta-HSD2 expression, as well as leptin secretion into culture supernatant after 48 h.
The relevance of CRH for placental physiology is underlined by the present in vitro study. The induction of leptin and 11beta-HSD2 in the syncytiotrophoblast by CRH might promote fetal nutrient supply and placental corticosteroid metabolism in the phase before labour induction.
PMCID: PMC3492048  PMID: 22971074
CRH; leptin; 11beta-HSD2; Syncytin-1; Trophoblast; Syncytiotrophoblast; Placenta
3.  Unexpected recovery from longterm renal failure in severe diffuse proliferative lupus nephritis 
BMC Nephrology  2012;13:81.
Severe renal manifestation of systemic lupus erythematosus (SLE) is not uncommon and is associated with an indeterminate prognosis. Complete remission can be obtained, however, at least in the young when chronic lesions are absent and adequate anti-inflammatory therapy is immediately initiated.
Case presentation
We report the unusual case of a 12-year-old girl who presented with severe oliguric renal failure, macrohematuria and skin rash. Renal biopsy revealed the diagnosis of severe diffuse proliferative glomerulonephritis (GN) with cellular crescents in 15 out of 18 glomeruli and full-house pattern in immunofluorescence indicating lupus nephritis IVB according to WHO, IV-G(A) according to ISN/RPS classification. The serological parameters confirmed the diagnosis of SLE and the patient was immediately treated with methylprednisolone, cyclophosphamide and immunoadsorption. Initially, despite rapid amelioration of her general condition, no substantial improvement of renal function could be achieved and the patient needed hemodialysis treatment for 12 weeks. Unexpectedly, in the further follow-up at first diuresis increased and thereafter also creatinine levels substantially declined so that hemodialysis could be discontinued. Today, 6 years after the initial presentation, the patient has normal renal function and a SLEDAI score of 0 under a continuous immunosuppressive therapy with Mycophenolate mofetil (MMF) and low dose steroid.
Despite the severity of the initial renal injury and the unfavourable renal prognosis the kidney apparently has a tremendous capacity to recover in young patients when the damage is acute and adequate anti-inflammatory therapy is initiated without delay.
PMCID: PMC3459702  PMID: 22867270
Proliferative lupus nephritis; Acute renal failure; Immunosuppressive treatment; Mycophenolate mofetil; Remission
4.  Endothelial cells influence the sodium nitroprusside mediated inhibition of platelet aggregation by an as yet unkown pathway 
Thrombosis Journal  2012;10:6.
The clinical use of Sodium nitroprusside (SNP) may be associated with an alteration of platelet function. The main focus of this study was the effect of SNP on platelet aggregation in the absence or presence of endothelial cells.
Methods: Platelets were incubated with different concentrations of SNP with and without endothelial cells. Platelet aggregation was induced by ADP.
Results: Platelet aggregation was significantly inhibited by all concentrations of SNP. Endothelial cells significantly increased this inhibitory effect of SNP. Time course studies showed an inverse correlation of incubation time to platelet aggregation inhibition in the absence of endothelial cells, and a direct correlation in the presence of endothelial cells. Blocking platelet and endothelial cell guanylate cyclase with 1 H-(1,2,4)-oxadiazolo(4,3-a) quinoxalin-1-one (ODQ), or pretreatment of the endothelial cells with cyclooxygenase – inhibitors, had no influence on the increased inhibitory effect of the endothelial cells. Cyanide reversed the inhibitory effect of SNP completely.
Conclusion: Endothelial cells play an important role in the SNP mediated inhibition of platelet aggregation. The effect is reversible only by cyanide, not by blocking classical NO signal transduction.
PMCID: PMC3528661  PMID: 22564812
Nitric oxide (NO); Platelet aggregation; Sodium-nitro-prusside (SNP); Cyanide; Endothelial cells
5.  Inhibition of TGF-β Signaling and Decreased Apoptosis in IUGR-Associated Lung Disease in Rats 
PLoS ONE  2011;6(10):e26371.
Intrauterine growth restriction is associated with impaired lung function in adulthood. It is unknown whether such impairment of lung function is linked to the transforming growth factor (TGF)-β system in the lung. Therefore, we investigated the effects of IUGR on lung function, expression of extracellular matrix (ECM) components and TGF-β signaling in rats. IUGR was induced in rats by isocaloric protein restriction during gestation. Lung function was assessed with direct plethysmography at postnatal day (P) 70. Pulmonary activity of the TGF-β system was determined at P1 and P70. TGF-β signaling was blocked in vitro using adenovirus-delivered Smad7. At P70, respiratory airway compliance was significantly impaired after IUGR. These changes were accompanied by decreased expression of TGF-β1 at P1 and P70 and a consistently dampened phosphorylation of Smad2 and Smad3. Furthermore, the mRNA expression levels of inhibitors of TGF-β signaling (Smad7 and Smurf2) were reduced, and the expression of TGF-β-regulated ECM components (e.g. collagen I) was decreased in the lungs of IUGR animals at P1; whereas elastin and tenascin N expression was significantly upregulated. In vitro inhibition of TGF-β signaling in NIH/3T3, MLE 12 and endothelial cells by adenovirus-delivered Smad7 demonstrated a direct effect on the expression of ECM components. Taken together, these data demonstrate a significant impact of IUGR on lung development and function and suggest that attenuated TGF-β signaling may contribute to the pathological processes of IUGR-associated lung disease.
PMCID: PMC3197638  PMID: 22028866
6.  Low birth weight, bone metabolism and fracture risk 
Dermato-endocrinology  2011;3(4):240-242.
As for other diseases of higher age, low birth weight was expected to be a risk factor for an altered bone metabolism and osteoporosis.
On the first glance this expectation appears to be confirmed by animal data: rats with intrauterine growth restriction following maternal protein malnutrition show a reduction of bone mineral density going in line with a decrease in serum vitamin D concentrations.
However, the situation is less clear in newborns with low birth weight: Some studies show a relation of birth weight and bone mineral density whereas others don't. The older the former low birth weight patients the fainter the effect seems to be. In fact young adults with idiopathic short stature have a low bone mineral density than the low birth weight group irrespective of whether they have experienced catch-up growth or not. As a consequence low birth weight is can not be identified as a relevant risk factor for hip fractures in menopausal women. Postmenopausal women with low birth weight even show higher vitamin D concentrations than normal birth weight individuals.
In conclusion, there is no consistent long term effect of low birth weight on bone mineral density or hip fracture risk later in life. Whether methodological weaknesses in the studies performed so far are causal or whether postnatal factors such as physical activity and nutrition are of higher importance can only be speculated upon at present.
PMCID: PMC3256340  PMID: 22259651
intrauterine growth restriction; low birth weight; bone mineral density; bone mineral content; fracture risk
7.  Mutations in the Human Laminin β2 (LAMB2) Gene and the Associated Phenotypic Spectrum 
Human mutation  2010;31(9):992-1002.
Mutations of LAMB2 typically cause autosomal recessive Pierson syndrome, a disorder characterized by congenital nephrotic syndrome, ocular and neurologic abnormalities, but may occasionally be associated with milder or oligosymptomatic disease variants. LAMB2 encodes the basement membrane protein laminin β2 which is incorporated in specific heterotrimeric laminin isoforms and has an expression pattern corresponding to the pattern of organ manifestations in Pierson syndrome. Herein we review all previously reported and several novel LAMB2 mutations in relation to the associated phenotype in patients from 39 unrelated families. The majority of disease-causing LAMB2 mutations are truncating, consistent with the hypothesis that loss of laminin β2 function is the molecular basis of Pierson syndrome. While truncating mutations are distributed across the entire gene, missense mutations are clearly clustered in the N-terminal LN domain, which is important for intermolecular interactions. There is an association of missense mutations and small in frame deletions with a higher mean age at onset of renal disease and with absence of neurologic abnormalities, thus suggesting that at least some of these may represent hypomorphic alleles. Nevertheless, genotype alone does not appear to explain the full range of clinical variability, and therefore hitherto unidentified modifiers are likely to exist.
PMCID: PMC2978072  PMID: 20556798
LAMB2; Pierson syndrome; nephrotic syndrome; autosomal recessive; podocyte; laminin; ocular malformation
8.  An exceptional Albanian family with seven children presenting with dysmorphic features and mental retardation: maternal phenylketonuria 
BMC Pediatrics  2005;5:5.
Phenylketonuria is an inborn error of amino acid metabolism which can cause severe damage to the patient or, in the case of maternal phenylketonuria, to the foetus. The maternal phenylketonuria syndrome is caused by high blood phenylalanine concentrations during pregnancy and presents with serious foetal anomalies, especially congenital heart disease, microcephaly and mental retardation.
Case presentation
We report on an affected Albanian woman and her seven children. The mother is affected by phenylketonuria and is a compound heterozygote for two pathogenetic mutations, L48S and P281L. The diagnosis was only made in the context of her children, all of whom have at least one severe organic malformation. The first child, 17 years old, has a double-chambered right ventricle, vertebral malformations and epilepsy. She is also mentally retarded, microcephalic, exhibits facial dysmorphies and small stature. The second child, a girl 15 years of age, has severe mental retardation with microcephaly, small stature and various dysmorphic features. The next sibling, a boy, died of tetralogy of Fallot at the age of three months. He also had multiple vertebral and rib malformations. The subsequent girl, now eleven years old, has mental retardation, microcephaly and epilepsy along with facial dysmorphy, partial deafness and short stature. The eight-year-old child is slightly mentally retarded and microcephalic. A five-year-old boy was a premature, dystrophic baby and exhibits mental retardation, dysmorphic facial features, brachydactyly and clinodactyly of the fifth finger on both hands. Following a miscarriage, our index case, the youngest child at two years of age, is microcephalic and mentally retarded and shows minor facial anomalies. All children exhibit features of phenylalanine embryopathy caused by maternal phenylketonuria because the mother had not been diagnosed earlier and, therefore, never received any diet.
This is the largest family suffering from maternal phenylketonuria reported in the literature. Maternal phenylketonuria remains a challenge, especially in woman from countries without a neonatal screening program. Therefore, it is mandatory to be alert for the possibility of maternal phenylketonuria syndrome in case of a child with the clinical features described here to prevent foetal damage in subsequent siblings.
PMCID: PMC1079877  PMID: 15811181
Maternal phenylketonuria; phenylalanine; phenylketonuria; pregnancy outcome

Results 1-8 (8)