Nanette Sarioglu

Mutations in Multiple PKD Genes May Explain Early and Severe Polycystic Kidney Disease

Autosomal dominant polycystic kidney disease (ADPKD) is typically a late-onset disease caused by mutations in PKD1 or PKD2, but about 2% of patients with ADPKD show an early and severe phenotype that can be clinically indistinguishable from autosomal recessive polycystic kidney disease (ARPKD). The high recurrence risk in pedigrees with early and severe PKD strongly suggests a common familial modifying background, but the mechanisms underlying the extensive phenotypic variability observed among affected family members remain unknown. Here, we describe severely affected patients with PKD who carry, in addition to their expected familial germ-line defect, additional mutations in PKD genes, including HNF-1β, which likely aggravate the phenotype. Our findings are consistent with a common pathogenesis and dosage theory for PKD and may propose a general concept for the modification of disease expression in other so-called monogenic disorders.

Mirror Syndrome: A Systematic Review of Fetal Associated Conditions, Maternal Presentation and Perinatal Outcome

Introduction: Mirror syndrome, also referred to as Ballantyne’s syndrome, is normally defined as the development of maternal edema in association with fetal hydrops. The incidence of mirror syndrome is low and few cases have been published. We describe a case report in association with fetal Ebstein anomaly and provide a systematic review on the fetal associated conditions, maternal presentation and perinatal outcome reported for mirror syndrome. Data Sources: A PubMed database search was done until December 2008 (English, French or German) without any restriction of publication date or journal, using the following key words: Ballantyne syndrome, Mirror syndrome, Triple edema, Pseudotoxemia, Maternal hydrops syndrome, Pregnancy toxemia, Acute second trimester gestosis, and Early onset preeclampsia. Reported cases were considered eligible when fetal associated conditions, maternal symptoms and fetal outcome were clearly described. Results: Among 151 publications a total of 56 reported cases satisfying all inclusion criteria were identified. Mirror syndrome was associated with rhesus isoimmunization (29%), twin-twin transfusion syndrome (18%), viral infection (16%) and fetal malformations, fetal or placental tumors (37.5%). Gestational age at diagnosis ranged from 22.5 to 27.8 weeks of gestation. Maternal key signs were edema (80–100%), hypertension (57–78%) and proteinuria (20–56%). The overall rate of intrauterine death was 56%. Severe maternal complications including pulmonary edema occurred in 21.4%. Maternal symptoms disappeared 4.8–13.5 days after delivery. Discussion: Mirror syndrome is associated with a substantial increase in fetal mortality and maternal morbidity.

Abnormal vascular architecture at the placental-maternal interface in placenta increta

OBJECTIVE The objective of the study was to characterize the vascular architecture at the placental-maternal interface in pregnancies complicated by placenta increta and normal pregnancies. STUDY DESIGN Vessel numbers and cross-section area density and spatial and area distributions in 13 placenta-increta placental beds were compared with 9 normal placental beds using computer-assisted image analysis of whole-slide CD31 immunolabeled sections. RESULTS The total areas occupied by vessels in normal and placenta-increta placental beds were comparable, but vessels were significantly sparser and larger in the latter. Moreover, placenta-increta-vessel distributions (area and distance from the placental-myometrial junction) were more heterogeneous. CONCLUSION Size and spatial organization of the placenta-increta vascular architecture at the placental-maternal interface differed from normal and might partially explain the severe hemorrhage observed during placenta-increta deliveries.

Changing Expression of Cyclooxygenases and Prostaglandin Receptor EP4 During Development of the Human Ductus Arteriosus

Programmed proliferative degeneration of the human fetal ductus arteriosus (DA) in preparation for its definite postnatal closure has a large developmental variability and is controlled by several signaling pathways, most prominently by prostaglandin (PG) metabolism. Numerous studies in various mammalian species have shown interspecies and developmental differences in ductal protein expression of cyclooxygenase (COX) isoforms and PG E receptor subtypes (EP1-4). We examined COX1, COX2, and EP4 receptor protein expression immunohistochemically in 57 human fetal autopsy DA specimens of 11–38 wk of gestation. According to their histologic maturity, specimens were classified into four stages using a newly designed maturity score that showed that histologic maturity of the DA was not closely related to gestational age. COX1 expression was found in all DA regions and rose steadily during development. COX2 staining remained weak throughout gestation. EP4 receptor staining increased moderately during gestation and was limited to the intima and media. In conclusion, histologic maturity classification helps to address developmentally regulated processes in the fetal DA. Concerning prostaglandin metabolism our findings are in line with animal studies, which assigned COX1 the predominant role in the DA throughout gestation. EP4 receptor presumably plays a key role for active patency of the human DA in the third trimester.

Vasa praevia: risk-adapted modification of the conventional management--a retrospective study.

PURPOSE Undiagnosed vasa praevia carries an imminent risk of fetal death and increases with IVF. When diagnosed, the question arises as to whether the conventional prenatal management of routine steroid administration for fetal lung maturation and elective caesarean section in week 35 is generally justified in face of the risks involved. We present a retrospective study of a risk-adapted modification of the conventional management of vasa praevia. MATERIAL AND METHODS We analysed 11 years of records involving 18 cases of antenatally diagnosed vasa praevia at our perinatal centre. Each case was managed by a risk-adapted modification of the conventional treatment where both, the steroid administration and the timing of delivery, were dependent on the patient history and clinical signs for preterm birth. RESULTS There were no lethal fetal, neonatal, or maternal complications. The earliest caesarean section took place at 34 weeks 1 day, the latest at 37 weeks 1 day, and in more than half of the cases at ≥ 36 weeks. CONCLUSION Steroid application is generally recommended for pregnancies before 34 weeks carrying a risk for preterm birth. Thus, retrospectively, none of our cases required steroid administration. This supports our protocol of not obligatorily administering steroids. Delaying the caesarean section up to two weeks beyond the conventionally recommended date of 35 weeks in 78% of our cases resulted in no complications. This justifies the suitability of determining the timing of delivery based on our individual patient assessment. In conclusion, the following recommendations for a risk-adapted management of vasa praevia can be made: 1. weekly evaluation of risk factors for preterm delivery; 2. steroid administration only at risk for preterm birth; 3. admission to hospital with full obstetric and neonatal care facilities between 32 and 34 weeks; 4. elective caesarean section between 35 and 37 weeks, risk-adapted.

The Expression of VEGF and its Receptors in the Human Ductus Arteriosus

Programmed proliferative degeneration of the human fetal ductus arteriosus (DA) preceding definite postnatal closure has a large developmental variability and is controlled by several signaling pathways. Among these vascular endothelial growth factor (VEGF) and its receptors (VEGF-Rs) play an important role. Until now, gestational age dependent expression of VEGF and its receptors has not been investigated in a large number of human DA tissue specimens. We examined protein expression of VEGF and the three VEGF-Rs immunohistochemically in 63 human fetal autopsy DA specimens of 11–38 wk gestation. Specimens were classified into different maturity stages according to their histologic appearance. VEGF and VEGF-Rs-staining was detected in all maturity stages. VEGF-staining was localized perinuclearly in all vascular layers and did not change during development. VEGF-R1 and VEGF-R3 expression was marked in the endothelium in early maturity stages and decreased during development. In contrast, -R2 predominated in the media in later developmental stages. Our results emphasize the importance of VEGF as a mediator during programmed proliferative degeneration of fetal DA and support the hypothesis that VEGF-R1 and VEGF-R3 are required for normal blood vessel development during embryogenesis. In contrast, VEGF-R2 is the predominant receptor in later angiogenic signaling.

Detection of infectious colitis by 18F-fluorodeoxyglucose-positron emission tomography in a child receiving intensive care after cardiac surgery.

Pyrexia of unknown origin (PUO) and suspected focal infection/inflammation are challenging medical problems. Nuclear medicine methods using scintigraphy with 111In- or 99mTc-labelled antibodies or 67Ga-citrate have been validated for the diagnosis and detection of inflammatory processes. Recently, positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) has been described as a promising imaging method, especially for PUO. We report the use of FDG-PET in an 18-month-old boy that revealed unexpected infectious colitis after cardiac surgery. This case suggests that FDG-PET is a valuable tool for the detection of unknown inflammatory foci in childhood, especially when the time needed for examination and radiation exposure are to be considered.

The transcription factor Ets-1 is expressed in human amniochorionic membranes and is up-regulated in term and preterm premature rupture of membranes.

Abstract Objective: The major tensile strength of fetal membranes is provided by their extracellular matrix (ECM) components. The transcription factor Ets-1 is a critical mediator of ECM remodelling. The purpose of this study was to examine whether Ets-1 is expressed in human fetal membranes and whether it is implicated in premature membrane rupture. Study design: Amniochorionic membranes from 52 women in the following categories were analyzed for Ets-1 expression: preterm and term premature rupture of membranes, preterm and term labor and delivery, and preterm and term cesarean sections without previous onset of labor. Ets-1 protein was localized with the use of immunohistochemistry. Ets-1 levels were determined with a histoscore. Results: Ets-1 protein was localized to the trophoblast as well as to the stromal layers. Ets-1 protein expression was up-regulated in the stroma of term and preterm prematurely ruptured membranes. Conclusion: Ets-1 is expressed in human fetal membranes and its expression is up-regulated with premature rupture of membranes, suggesting a role for Ets-1 in ECM remodelling of the membranes.

First-Trimester Prenatal Diagnosis of Okihiro Syndrome

A case of Okihiro syndrome (OS) detected by 2- and confirmed by 3-dimensional ultrasound at 13+2 gestational weeks is reported. While the pregnant woman affected by the OS presented with limb anomalies, the fetus showed severe thoracoabdominal and skeletal anomalies. Termination of pregnancy was performed at 14+1 gestational weeks and confirmed the sonographically detected symptoms. The diagnosis was confirmed by autoptic, radiologic and molecular genetic analysis. To our knowledge, this is the first case of prenatal diagnosis of OS.

Reduction of postoperative adhesions by perfluorocarbons: an experimental study in a rat model.

Peritoneal adhesions are a well-known and frequently occurring postoperative complication. Many published studies have looked into the prophylaxis of adhesions following abdominal surgery, but only few clinically relevant agents have been reported. Most publications refer to adult patients and not to paediatric patient collectives. This experimental study in a rat model compares the effect of perfluorocarbons as adhesion prophylaxis with those of a well-known anti-adhesive agent Adept and with an untreated control group. We hypothesized that PFC might have a double effect: initially it could suppress the accumulation of monocytes and neutrophilic granulocytes, and subsequently it would work as a barrier to prevent contact between the visceral and parietal layers of the peritoneum. After a standardised operation, PFC was injected into the abdominal cavity of rats in the study group. Macroscopically, the PFC group did not fare significantly better, but nevertheless a clear tendency towards fewer adhesions after the application of PFC could be ascertained.