Payam Saadai

Human induced pluripotent stem cell-derived neural crest stem cells integrate into the injured spinal cord in the fetal lamb model of myelomeningocele

BACKGROUND/PURPOSE Neurological function in patients with myelomeningocele (MMC) is limited even after prenatal repair. Neural crest stem cells (NCSCs) can improve neurological function in models of spinal cord injury. We aimed to evaluate the survival, integration, and differentiation of human NCSCs derived from induced pluripotent stem cells (iPSC-NCSCs) in the fetal lamb model of MMC. METHODS Human iPSCs derived from skin fibroblasts were differentiated into NCSCs in vitro, mixed with hydrogel, and seeded on nanofibrous scaffolds for surgical transplantation. Fetal lambs (n=2) underwent surgical MMC creation and repair with iPSC-NCSC seeded scaffolds. Gross necropsy and immunohistochemistry were performed at term. RESULTS IPSC-NCSCs expressed NCSC markers, maintained > 95% viability, and demonstrated neuronal differentiation in vitro. Immunohistochemical analysis of repaired spinal cords thirty days after transplantation demonstrated the co-localization of human nuclear mitotic apparatus protein (NuMA) and Neurofilament M subunit (NFM) in the area of spinal cord injury. No gross tumors were identified. CONCLUSIONS Human iPSC-NCSCs survived, integrated, and differentiated into neuronal lineage in the fetal lamb model of MMC. This is the first description of human stem cell engraftment in a model of fetal MMC and supports the concept of using NCSCs to address spinal cord damage in MMC.

Long-term outcomes after fetal therapy for congenital high airway obstructive syndrome

BACKGROUND/PURPOSE Congenital high airway obstructive syndrome (CHAOS) is a rare and devastating condition that is uniformly fatal without fetal intervention. We sought to describe fetal treatment and long-term outcomes of CHAOS at a single referral center. METHODS The medical records of patients with fetal CHAOS evaluated at our center between 1993 and 2011 were reviewed. Maternal history, radiographic findings, antenatal management, and postnatal outcomes were compared. RESULTS Twelve fetuses with CHAOS were identified. Eleven had concomitant hydrops at diagnosis. Six were electively terminated, and 2 had intra- or peripartum demise. Four patients underwent fetal intervention. Two underwent delivery via ex utero intrapartum treatment (EXIT) procedure with tracheostomy placement only, and 2 underwent fetal bronchoscopy with attempted wire tracheoplasty followed by EXIT with tracheostomy at delivery. All 4 patients who underwent EXIT were alive at last follow-up. One patient was ventilator and tracheostomy free and feeding by mouth. CONCLUSION Long-term and tracheostomy-free survival is possible with appropriate fetal intervention even in the presence of hydrops. Fetal intervention earlier in pregnancy may improve long-term outcomes, but patient selection for intervention remains challenging. Magnetic resonance imaging may help select those patients for whom fetal intervention before EXIT delivery may be beneficial.

Fetal surgery for myelomeningocele.

Myelomeningocele is a devastating birth defect affecting a significant number of live births worldwide. Prenatal repair of myelomeningocele has been performed in the United States for 5 years with mixed results. The initial intent was to preserve distal neurological function by covering the exposed spinal cord. Although there has been relatively little effect on distal sensorimotor function, prenatal repair serendipitously led to an apparent reduction in hindbrain herniation and a possible decreased need for ventriculoperitoneal shunting. The long-term clinical consequences of these findings are not clear. What is clear, however, is that further study in the form of a prospective, randomized trial is mandatory.

In utero repair of myelomeningocele with autologous amniotic membrane in the fetal lamb model

BACKGROUND Despite advances in prenatal repair, myelomeningocele (MMC) still produces devastating neurologic deficits. The amniotic membranes (AM) are a biologically active tissue that has been used anecdotally for human fetal MMC repair. This study evaluated the use of autologous AM compared to skin closure in an established fetal MMC model. METHODS Seven fetal lambs underwent surgical creation of MMC at gestational age of 75days followed by in utero repair at gestational age of 100days. Lambs were repaired with an autologous AM patch followed by skin closure (n=4) or skin closure alone (n=3). Gross necropsy and histopathology of the spinal cords were performed at term to assess neuronal preservation at the lesion. RESULTS An increase in preserved motor neurons and a larger area of spinal cord tissue were seen in AM-repaired lambs, as was decreased wound healing of the overlying skin. Loss of nearly all spinal cord tissue with limited motor neuron preservation was seen in skin only-repaired lambs. CONCLUSIONS AM-repaired lambs showed increased protection of spinal cord tissue compared to skin only-repaired lambs, but the overlying skin failed to close in AM-repaired lambs. These results suggest a potential role for AM in fetal MMC repair that warrants further study.

Prenatal repair of myelomeningocele with aligned nanofibrous scaffolds-a pilot study in sheep.

BACKGROUND/PURPOSE Spinal cord damage in myelomeningocele (MMC) results from abnormal cord development and subsequent local trauma. Prenatal surgery prevents additional neural injury. However, existing damage is not reversed. Biodegradable nanofibrous scaffolds (NSs) promote regeneration of neural tissues. They mimic the microtopography of the extracellular matrix and guide tissue formation and organization. The purpose of this pilot study was to evaluate the practicality and safety of using biodegradable NS as a regenerative device in prenatal MMC repair. METHODS Two fetal lambs underwent a surgically induced MMC defect followed by open fetal repair using aligned biodegradable NS. Lambs were killed at day 138. Spinal cords were examined for inflammation or fibrosis and stained for spinal cord architecture, myelin, and neuron cell bodies. RESULTS Prenatal repair with NS demonstrated technical feasibility. There was no evidence of a surrounding inflammatory response or foreign-body reaction to the scaffold. CONCLUSION Biodegradable NS can be used surgically for the prenatal repair of MMC in a large animal model and does not appear to elicit an inflammatory or fibrotic reaction in fetal tissue. Further studies will determine their potential for neural cell infiltration, delivery of growth factors, drugs or stem cells, and functional recovery greater than standard repair.

Alterations in maternal-fetal cellular trafficking after fetal surgery

BACKGROUND/PURPOSE Bidirectional trafficking of cells between the mother and the fetus is routine in pregnancy and a component of maternal-fetal tolerance. Changes in fetal-to-maternal cellular trafficking have been reported in prenatal complications, but maternal-to-fetal trafficking has never been studied in the context of fetal intervention. We hypothesized that patients undergoing open fetal surgery would have altered maternal-fetal cellular trafficking. METHODS Cellular trafficking was analyzed in patients with myelomeningocele (MMC) who underwent open fetal surgical repair (n = 5), patients with MMC who had routine postnatal repair (n = 6), and healthy control healthy patients (n = 9). As an additional control for the fetal operation, trafficking was also analyzed in patients who were delivered by an ex utero intrapartum treatment procedure (n = 6). Microchimerism in maternal and cord blood was determined using quantitative real-time polymerase chain reaction for nonshared alleles. RESULTS Maternal-to-fetal trafficking was significantly increased in patients who underwent open fetal surgery for MMC compared with healthy controls, patients who underwent postnatal MMC repair, and patients who underwent ex utero intrapartum treatment. There were no differences in fetal-to-maternal cell trafficking among groups. CONCLUSION Patients undergoing open fetal surgery for MMC have elevated levels of maternal microchimerism. These results suggest altered trafficking and/or increased proliferation of maternal cells in fetal blood and may have important implications for preterm labor.

Congenital high airway obstruction sequence (CHAOS): a new case and a review of phenotypic features.

Congenital high airway obstruction sequence (CHAOS) has traditionally been defined as airway obstruction with ultrasound evidence of distal airway dilatation, expanded lungs, ascites, and hydrops. It can result from aplasia or intrinsic obstruction to the formation of the upper airway (larynx and trachea) during development. CHAOS is commonly sporadic and there is no known causative gene. In this comprehensive review on CHAOS, we examined 117 reported cases of this sequence and describe a new case. Malformations in addition to high airway obstruction were present in 64/118 (54.2%) of patients. The most frequent anomalies affected the digits and musculoskeletal system, but there was no distinct phenotype or characteristic dysmorphic appearance associated with CHAOS. The ex utero intrapartum therapy (EXIT) procedure has greatly improved survival for these patients and 36/118 (30.5%) were alive at the time of reporting. Only 2 patients out of 12 who underwent laryngotracheoplasty were tracheostomy‐free at the time of their reporting. Six out of 13 were able to produce some speech. Our review provides valuable information on associated anomalies and survival in this complex sequence. The phenotypic variability seen in this review of patients makes it likely that the causes of CHAOS are genetically heterogeneous.

The fetal urinoma revisited.

The fetal urinoma is a rare but important diagnosis, as it indicates substantial underlying obstruction with implications for the functionality of the affected kidney. This case series describes a single centers experience with the diagnosis and management of fetal urinomas. All 25 cases were diagnosed or referred to our medical center over an 11‐year period. Most cases were secondary to either posterior urethral valves or ureteropelvic junction obstruction. Fetal interventions, including percutaneous drainage of the urinoma and cystoscopic alleviation of bladder outlet obstruction, were performed in 4 cases.

Hepatic portocholecystostomy for biliary atresia: A 25-year follow-up and review

We report the successful salvage of a patients native liver 25 years after hepatic portocholecystostomy for biliary atresia. Our case demonstrates the effectiveness of biliary specific, high-resolution CT imaging in the diagnosis of, and operative planning for complex cases of biliary obstruction. We also report the longest-term pathologic follow-up of biliary atresia after hepatic portocholecystostomy. Life-long follow-up of patients with biliary atresia is important to prevent life-threatening complications of biliary stasis/obstruction.

Incidence of Gastroschisis in California

pants as patient information is more likely derived from the presentation when the electronic medical record becomes less accessible. The increased ability to hear patient presentations was likely because of the concurrent reduction in simultaneous conversations, as well as a noticeable change with the arrangement of the rounding group becoming more compact. The association of these changes with efficiency or clinical outcomes was not monitored. Limitations include the potential for a Hawthorne effect4 and a change in the residents during the study period. Alternative technologies should be identified that optimize human-computer interactions and facilitate effective communication.