Surgical management of urachal remnants in children: open versus laparoscopic approach: A STROBE-compliant retrospective study.

Urachal remnants (UR) represent a failure in the obliteration of the allantois, which connects the bladder to the umbilicus, at birth. Surgical management of UR in children is controversial. The traditional surgical approach involves a semicircular intraumbilical incision or a lower midline laparotomy. Recently, many reports have supported the laparoscopic approach (LA) for removing UR. However, there is a paucity of data comparing the benefits of LA those of the open approach (OA).We retrospectively reviewed all children (aged ≤16 years) with UR who underwent surgical procedures. Age at surgery, sex, operative time, intraoperative or postoperative complications, total wound length, and length of hospital stay length after operation were analyzed.Overall, 30 children aged between 9 months and 16 years (mean 9.0 years) underwent surgical procedures: 15 were treated by OA and 15 were treated by LA. The only statistically significant variable was the operative time. Furthermore, we reanalyzed the age distributions of the older children (aged ≥10 years). In this group, no significant difference in the operative time between OA and LA was observed; however, there was a statistically significant difference in the total wound length.Our review indicated that LA required longer operative time than OA without any cosmetic advantage. However, in older children (aged ≥10 years), the difference in the operative time was not significant; moreover, LA provided greater cosmetic advantage. LA is recommended for older children (aged ≥10 years) because of its cosmetic advantage.

Congenital prepubic sinus associated with a urachal remnant: report of a case.

Congenital prepubic sinus is a rare congenital anomaly situated in the midline of the lower abdomen. We report a case of congenital prepubic sinus, closely associated with a urachal remnant. Preoperative magnetic resonance imaging showed clearly that the sinus tracked the urachus caudally. This finding supports the theory that the anomaly is caused by abnormal remnant tissue originating from the cloacal membrane, which tracks the allantois duct caudally along with fetal longitudinal growth.

Tratamiento laparoscópico de los remanentes uracales / Laparoscopic Treatment of Urachal Remnants

Objetivos: El uraco es una estructura vestigial obliterada derivada de la alantoides. El fracaso de este proceso de involución origina remanentes uracales evidentes. La cirugía es el tratamiento a elegir, ya que previene tanto la reaparición de los síntomas como la transformación maligna. El propósito de este estudio es presentar nuestra experiencia en el manejo laparoscópico de esta patología. Material y métodos: Tres pacientes del sexo masculino (mediana de edad de 39 años) se sometieron a extirpación laparoscópica de los remanentes uracales. Dos pacientes fueron diagnosticados con un quiste asintomático y un paciente con un seno uracal con secreción umbilical. Se utilizó una técnica de tres puertos para eliminar todo el tracto del uraco desde el ombligo hasta la cúpula vesical, junto con una pequeña parte de la vejiga. Resultados: La mediana de tiempo operatorio fue de 94 minutos y la pérdida de sangre fue mínima. Un paciente sufrió una pequeña rotura vesical intraoperatoria que se solucionó exitosamente con un cierre adecuado. No se observaron complicaciones postoperatorias y todos los pacientes fueron dados de alta al segundo día después de la operación. Dos años después no hubo pruebas de reaparición. Conclusiones: Los remanentes uracales se pueden tratar con éxito con la cirugía laparoscópica, con ventajas en términos de morbilidad, recuperación y resultado estético. Todavía se necesitan muchos estudios comparativos para establecerla definitivamente como el tratamiento estándar por excelencia (AU)

Objectives: The urachus is a vestigial obliterated structure derived from the alantois. Failure of this involution process originates patent urachal remnants. Surgery is the treatment of choice as it prevents both recurrence of symptoms and malignant transformation. The purpose of this study is to present our experience in the laparoscopic management of this pathology. Material and methods: Three male patients (mean age 39 years) underwent laparoscopic excision of urachal remnants. Two patients were diagnosed with an asymptomatic cyst and one patient with urachal sinus presenting with umbilical discharge. A three-port technique was used to remove the whole urachus tract from the umbilicus to the bladder dome, together with a small bladder patch. Results: Mean operating time was 94 min and blood loss was minimal. One patient had small intra-operative bladder rupture, successfully managed with adequate closure. No postoperative complications were observed and all patients were discharged on the second postoperative day. Two years later there was no evidence of recurrence. Conclusions: Urachal remnants can be successfully treated by laparoscopic surgery, with advantages in terms of morbidity, recovery and cosmetic outcome. Large number, comparative studies are still needed to definitely establish it as the gold standard treatment (AU)

The Mrj co-chaperone mediates keratin turnover and prevents the formation of toxic inclusion bodies in trophoblast cells of the placenta.

Defects in protein-folding and -degradation machinery have been identified as a major cause of intracellular protein aggregation and of aggregation-associated diseases. In general, it remains unclear how these aggregates are harmful to normal cellular function. We demonstrate here that, in the developing placenta of the mouse, the absence of the Mrj (Dnajb6) co-chaperone prevents proteasome degradation of keratin 18 (K18; Krt18) intermediate filaments, resulting in the formation of keratin inclusion bodies. These inclusions in chorionic trophoblast cells prevent chorioallantoic attachment during placental development. We show further that keratin-deficient embryos undergo chorioallantoic attachment and that, by genetically reducing keratin expression in Mrj(-/-) conceptuses, chorioallantoic attachment was rescued. Therefore, the chorioallantoic attachment phenotype in Mrj mutants is not due to a deficiency of the normal keratin cytoskeleton, but rather is cytotoxicity caused by keratin aggregates that disrupt chorion trophoblast cell organization and function.

Allantoic cyst: a prenatal clue to patent urachus.

A patent urachus, which is typically diagnosed as leakage from the umbilicus postnatally, can present as an allantoic cyst in the umbilical cord antenatally. We report a case of a patent urachus with an allantoic cyst diagnosed via fetal MR imaging at 24 weeks' gestation. Early detection allowed for appropriate counseling and prompt corrective surgery after birth.

Edd, the murine hyperplastic disc gene, is essential for yolk sac vascularization and chorioallantoic fusion.

EDD is the mammalian ortholog of the Drosophila melanogaster hyperplastic disc gene (hyd), which is critical for cell proliferation and differentiation in flies through regulation of hedgehog and decapentaplegic signaling. Amplification and overexpression of EDD occurs frequently in several cancers, including those of the breast and ovary, and truncating mutations of EDD are also observed in gastric and colon cancer with microsatellite instability. EDD has E3 ubiquitin ligase activity, is involved in regulation of the DNA damage response, and may control hedgehog signaling, but a definitive biological role has yet to be established. To investigate the role of Edd in vivo, gene targeting was used to generate Edd knockout (Edd(Delta/Delta)) mice. While heterozygous mice had normal development and fertility, no viable Edd-deficient embryos were observed beyond E10.5, with delayed growth and development evident from E8.5 onward. Failed yolk sac and allantoic vascular development, along with defective chorioallantoic fusion, were the primary effects of Edd deficiency. These extraembryonic defects presumably compromised fetal-maternal circulation and hence efficient exchange of nutrients and oxygen between the embryo and maternal environment, leading to a general failure of embryonic cell proliferation and widespread apoptosis. Hence, Edd has an essential role in extraembryonic development.

Effects of VLA-4 antagonists in rat whole embryo culture.

BACKGROUND: Pharmacological antagonism of VLA-4 (Very Late Antigen 4, alpha(4)beta(1) integrin) has become an attractive target for the treatment of predominantly eosinophil mediated disease states such as asthma, allergic rhinitis, multiple sclerosis, rheumatoid arthritis, diabetes, and inflammatory bowel disease. Gene knockouts of the alpha(4)-integrin subunit of VLA-4 or its cell surface ligand, VCAM-1, however, have been shown to result in embryo-lethality in homozygous null mice due to defects in chorio-allantoic or epi-myocardial fusion. Although gene knockout phenotypes are not always manifested by pharmacological antagonism, those studies suggested that VLA-4 antagonists might cause embryo-lethality or drug-induced malformations. METHODS: To test these concepts, early neurulating rat embryos were cultured by the methods of New ('78) after intra-coelomic microinjection of a VLA-4 blocking antibody or in the presence of small molecule VLA-4 antagonists. RESULTS: Defects in chorio-allantoic fusion were induced after microinjection of VLA4 blocking antibody and after continuous exposure to small molecule antagonists. In a minority of affected embryos chorio-allantoic fusion was completely blocked whereas the majority of affected embryos had only superficial chorio-allantoic fusion and the allantois was enlarged and edematous. Although the allantoic mesoderm covered the trophoblasts of the chorionic plate and contained blood vessels there was only minimal invasion of the trophoblasts by the allantoic mesoderm. The lowest observed effect level generally correlated with the IC(approximately 95), as determined in 90% plasma. DISCUSSION: Based on these data, VLA-4 antagonism might represent a significant risk to the developing embryo/fetus. In vitro exposure, however, is "constant" and does not take into account the elimination phase of these xenobiotics in vivo. Given the high concentrations required to elicit an effect, therapeutic blood levels in vivo may be several fold lower than those that affect the conceptus, depending on the tissue penetration of the compound and the route of administration. VLA-4 also exists in a range of conformations and activation states in vivo and the gene KOs and present studies do not define whether these developmental processes are dependent upon a particular activation state of VLA-4. Therefore, state-selective antagonists may have an improved embryonic safety profile. Additional studies will be required to determine potential effects of VLA-4 antagonists on embryo/fetal development in vivo.

Bone morphogenetic protein 4 in the extraembryonic mesoderm is required for allantois development and the localization and survival of primordial germ cells in the mouse.

Evidence suggests that the specification of primordial germ cells (PGCs) in the mammalian embryo does not depend on maternal determinants. Rather, previous genetic analysis in the mouse has shown that bone morphogenetic protein 4 (Bmp4) is required for the formation of both PGCs and allantois. Bmp4 is expressed in both the trophoblast-derived extraembryonic ectoderm (ExE) and in the epiblast-derived extraembryonic mesoderm (ExM), in which the PGCs, allantois primordium, and angioblasts are first detected. We have shown that Bmp4 made in the ExE functions to induce precursors of PGCs and allantois in the adjacent epiblast, resulting in complete lack of both cell types in homozygous null mutants. However, the function of Bmp4 in the ExM is totally unknown. To address this question, we generated tetraploid (4N) chimeras by aggregating Bmp4 null ES cells with wild-type tetraploid embryos. In this combination, wild-type tetraploid cells contribute to the extraembryonic trophoblast and primitive endoderm lineages but are excluded from the epiblast and its derivatives, including the ExM. Our results clearly demonstrate that Bmp4 made in the ExM does not affect the establishment of either PGC or allantois lineages, but is required for PGC localization and survival and for the differentiation of the allantois. These findings suggest that Bmp4 expressed in epiblast-derived tissues plays vital roles in reproduction by regulating both the development of the germ line and the vascular connection between the embryo and the placenta.

Cooperation of endoderm-derived BMP2 and extraembryonic ectoderm-derived BMP4 in primordial germ cell generation in the mouse.

The primordial germ cells (PGCs) of the mouse are derived from proximal epiblast cells that are adjacent to the extraembryonic ectoderm during gastrulation. Previous studies have demonstrated that extraembryonic ectoderm-derived BMP4 and BMP8B are both required for PGC generation. Here we show that Bmp2, a member of the Dpp class of the Bmp superfamily, also plays a role in PGC generation. PGC number is significantly reduced in Bmp2 heterozygous and homozygous embryos at the N2 generation onto C57BL/6 background. Bmp2 homozygous embryos also have a short allantois and about 50% of them do not undergo normal chorioallantoic fusion. Using whole-mount in situ hybridization, we show that Bmp2 is primarily expressed in the endoderm of mouse pregastrula and gastrula embryos. Using a genetic approach, we further show that Bmp2 and Bmp4, but not Bmp2 and Bmp8b, have an additive effect on PGC generation. These results suggest that PGC generation in the mouse embryo is regulated not only by extraembryonic ectoderm-derived BMP4 and BMP8B, but also by endoderm-derived BMP2.

Mrj encodes a DnaJ-related co-chaperone that is essential for murine placental development.

We have identified a novel gene in a gene trap screen that encodes a protein related to the DnaJ co-chaperone in E. coli. The gene, named Mrj (mammalian relative of DnaJ) was expressed throughout development in both the embryo and placenta. Within the placenta, expression was particularly high in trophoblast giant cells but moderate levels were also observed in trophoblast cells of the chorion at embryonic day 8.5, and later in the labyrinth which arises from the attachment of the chorion to the allantois (a process called chorioallantoic fusion). Insertion of the ROSAbetageo gene trap vector into the Mrj gene created a null allele. Homozygous Mrj mutants died at mid-gestation due to a failure of chorioallantoic fusion at embryonic day 8.5, which precluded formation of the mature placenta. At embryonic day 8.5, the chorion in mutants was morphologically normal and expressed the cell adhesion molecule beta4 integrin that is known to be required for chorioallantoic fusion. However, expression of the chorionic trophoblast-specific transcription factor genes Err2 and Gcm1 was significantly reduced. The mutants showed no abnormal phenotypes in other trophoblast cell types or in the embryo proper. This study indicates a previously unsuspected role for chaperone proteins in placental development and represents the first genetic analysis of DnaJ-related protein function in higher eukaryotes. Based on a survey of EST databases representing different mouse tissues and embryonic stages, there are 40 or more DnaJ-related genes in mammals. In addition to Mrj, at least two of these genes are also expressed in the developing mouse placenta. The specificity of the developmental defect in Mrj mutants suggests that each of these genes may have unique tissue and cellular activities.

Defects of the chorioallantoic placenta in mouse RXRalpha null fetuses.

The active derivatives of vitamin A (the retinoids) play important and multiple roles in mammalian development and homeostasis. We have previously shown that specific retinoic acid receptors are expressed in the chorioallantoic placenta of the mouse and that among these, RXRalpha is strongly expressed in the developing labyrinthine zone (Sapin, V., Ward, S. J., Bronner, S., Chambon, P., Dollé, P., Dev. Dyn. 208, 199-210, 1997). Here, we show that mouse fetuses with a targeted disruption of the RXRalpha gene develop defects of the chorioallantoic placenta. Both morphological abnormalities and alterations in the expression of molecular markers were found, mostly confined to the labyrinthine zone of placentas from mid-late gestation mutants. This region exhibited edema, abnormal stasis of maternal blood, and signs of disruption of the endothelial layer of fetal vessels. We also detected a reduction in the number of lipid droplets in the trophoblastic layer and abnormal fibrin deposits in the junctional zone of the mutant placentas. These abnormalities most probably result in an impairment of the functional capacities of exchange between the maternal and fetal circulations in the mutant placentas. Thus, placental defects could represent an extraembryonic cause of lethality for RXRalpha null mutant fetuses, in addition to the previously described embryonic cardiac defects.

Minimally united ischiopagus twins: infraumbilical union with cloacal anomalies.

In researching the embryology and pathological anatomy of conjoined twins, more than 1,200 cases were reviewed from the literature of the past 100 years; a few additional cases were obtained by personal communications. One hundred twenty-eight were classified as ischiopagus, the typical cases having union in the perineum, the pelvis, and the lower abdominal wall. Eighteen atypical ischiopagus cases, however, were conjoined only in the infraumbilical abdominal wall, none with union in the perineum or the bony pelvis but all with anomalies of the cloaca. Twelve infants survived surgery in nine of the ten cases separated since 1964. The malformations of the cloaca were not immediately life-threatening, but the death of one twin or an associated gastroschisis or ruptured omphalocele in some cases required prompt attention. The invariable involvement of the urachus and/or bladder and the shared distal ileum and colon led to the conclusion that the anomalies in these twins arose from union of the allantois and the caudal portion of the yolk sac.

Rescue of the tail defect of Brachyury mice.

The mouse Brachyury (T) gene is required for normal development of axial structures. Embryos homozygous for the T mutation show severe deficiencies in mesoderm formation. They lack the notochord and allantois, have abnormal somites, and die at approximately 10 days postcoitum probably as a result of the allantois defect. Mice heterozygous for the T mutation exhibit a variable short-tailed phenotype. The T gene has been cloned and shown to be expressed in the tissues most strongly affected by the mutation. In this paper, we show that a single-copy transgene representing the wild-type T allele is able to rescue the T-associated tail phenotype. In addition, we show that increasing dosage of the T gene in Tc/+ mice causes an increased extension of the axis. These data show the correlation of the level of T product with the extension of the anteroposterior axis, directly demonstrating the involvement of the T product in this process.

Allantois as the bursa-equivalent in man.

This article proposes the hypothesis that allantois is the anatomical homologue of bursa of Fabricius in mammalia. This hypothesis is based on immunohistochemical study of sections from hematopoietic organs of three fetuses with cloacal exstrophy. In the complex maldevelopment of cloacal exstrophy the common features are absence of distal midgut and exstrophy of cloaca with an exstropic intervening intestinal band. It has been suggested that gut is of dual origin and in addition to the yolk sac, allantois, absent in this maldevelopment, is involved in the embryogenesis of intestines by developing into distal midgut. There was absence of B-lymphocyte in two of three fetuses with rudimentary midgut and aplastic allantois. Meanwhile, B-cells were identified in the hematopoietic tissues and the prominent Peyer's patches of the more developed exstrophic allantois in the third case presented here. Therefore, it is concluded that allantois as the origin of distal midgut and lymphatic-rich ileocecal portion of digestive system is directly involved in the B-cell formation and represents the bursa of Fabricius in man.