Publications by authors named "Steffi Mayer"

26 Publications

  • Page 1 of 1

Effect of physical activity and BMI SDS on bone metabolism in children and adolescents.

Bone 2021 Jul 24;153:116131. Epub 2021 Jul 24.

Department of Pediatric Surgery, University of Leipzig, Leipzig, Germany. Electronic address:

Objective: Children with obesity are known to have reduced bone density and are at a higher risk for fractures. This may be caused by decreased physical activity or a metabolic phenomenon. In this study, we evaluated associations of physical activity with bone metabolism in children and adolescents with and without obesity.

Methods: Results from 574 visits of 397 subjects, 191 girls and 206 boys aged five to 18 years (mean: 11.7 ± 2.8) representing 180 children with (mean BMI SDS 2.5 ± 0.4) and 217 without obesity (mean BMI SDS 0.2 ± 1.0) from the LIFE Child study, a population-based cohort of children/adolescents with normal weight and with obesity were analyzed for the impact of their daily physical activity (MET/day, SenseWear Accelerometer) on serum SDS levels for bone formation (alkaline phosphatase, osteocalcin, procollagen type I N propeptide [P1NP]), bone resorption (beta-crosslaps), and calcium homeostasis (parathormone, OH-25-vitamin D) by a linear regression model adjusted for gender- and age-based differences.

Results: For male subjects, BMI SDS significantly influenced the association of physical activity to PTH, vitamin D, and beta-crosslaps SDS levels. A higher physical activity was accompanied by increased PTH but decreased vitamin D SDS levels in children with normal weight. In males with obesity, all levels remained unaltered. In females, BMI SDS significantly impacted the association of physical activity to PTH, vitamin D, P1NP, beta-crosslaps, and osteocalcin SDS levels. In females with obesity, higher physical activity was related to higher SDS levels of vitamin D, P1NP, and beta-crosslaps. In contrast, in normal weight females, only PTH SDS was higher.

Conclusions: The effect of daily physical activity on bone metabolic markers and calciotropic hormones depends significantly on gender and BMI SDS. However, higher levels of physical activity were associated with increased bone turnover for female subjects with obesity only. Thus, motivating especially girls with obesity to be physically active may help improve their bone health.
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http://dx.doi.org/10.1016/j.bone.2021.116131DOI Listing
July 2021

High resolution three-dimensional imaging and measurement of lung, heart, liver, and diaphragmatic development in the fetal rat based on micro-computed tomography (micro-CT).

J Anat 2020 Dec 2. Epub 2020 Dec 2.

Department of Pediatric Surgery, University of Leipzig, Leipzig, Germany.

Understanding of normal fetal organ development is crucial for the evaluation of the pathogenesis of congenital anomalies. Various techniques have been used to generate imaging of fetal rat organogenesis, such as histological dissection with 3-dimensional reconstruction and scanning electron microscopy. However, these techniques did not imply quantitative measurements of developing organs (volumes, surface areas of organs). Furthermore, a partial or total destruction of the embryos prior to analysis was inevitable. Recently, micro-computed tomography (micro-CT) has been established as a novel tool to investigate embryonic development in non-dissected embryos of rodents. In this study, we used the micro-CT technique to generate 4D datasets of rat embryos aged between embryonic day 15-22 and newborns. Lungs, hearts, diaphragms, and livers were digitally segmented in order to measure organ volumes and analyze organ development as well as generate high-resolution 3D images. These data provide objective values compiling a 4D atlas of pulmonary, cardiac, diaphragmatic, and hepatic development in the fetal rat.
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http://dx.doi.org/10.1111/joa.13355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930770PMC
December 2020

Health-Related Quality of Life and Psychosocial Morbidity in Anorectal Malformation and Hirschsprung's Disease.

Eur J Pediatr Surg 2020 Jun 26;30(3):279-286. Epub 2020 Jun 26.

Department of Pediatric Surgery, Leipzig University, Leipzig, Sachsen, Germany.

Anorectal malformation (ARM) and Hirschsprung's disease (HD) are the most common congenital colorectal anomalies. Despite advances in surgical techniques and improvements in postoperative clinical care, short- and long-term physical and psychosocial morbidity of these patients remains high. This review outlines the current literature on the physical and psychosocial aspects of health-related quality of life (HrQoL) and its confounders in patients with ARM/HD. Moreover, important coping strategies are summarized to further improve HrQoL of ARM/HD patients and their families.
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http://dx.doi.org/10.1055/s-0040-1713597DOI Listing
June 2020

[Current Treatment of Esophageal Atresia with Tracheoesophageal Fistula - Updated Guidelines of the German Society of Pediatric Surgery].

Klin Padiatr 2020 Jul 26;232(4):178-186. Epub 2020 Jun 26.

Department of Pediatric Surgery, University Hospital Leipzig, Leipzig.

Esophageal atresia (EA) is a congenital anomaly that entails an interrupted esophagus with or without tracheoesophageal fistula (TEF). Depending on the distance of the two esophageal pouches a "short-gap" is distinguished from a "long-gap" variant. Up to 50% of newborns have additional anomalies. EA is prenatally diagnosed in 32-63% of cases. Recently, the interdisciplinary care in these children underwent substantial changes. Therefore, we summarize the current guideline of the German society of pediatric surgery for the treatment of patients with EA and distal TEF (Gross Type C). Controversies regarding the perioperative management include surgical-technical aspects, such as the thoracoscopic approach to EA, as well as general anesthesia (preoperative tracheobronchoscopy, intraoperative hypercapnia and acidosis). Moreover, postoperative complications and their management like anastomotic stricture are outlined. Despite significant improvements in the treatment of EA, there is still a relevant amount of long-term morbidity after surgical correction. This includes dysmotility of the esophagus, gastroesophageal reflux disease, recurrent respiratory infections, tracheomalacia, failure to thrive, and orthopedic complications following thoracotomy in the neonatal age. Therefore, close follow-up is mandatory to attain optimal quality of life.
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http://dx.doi.org/10.1055/a-1149-9483DOI Listing
July 2020

Thoracoscopic Repair of Congenital Diaphragmatic Hernia.

Eur J Pediatr Surg 2020 Apr 8;30(2):137-141. Epub 2020 Mar 8.

Department of Pediatric Surgery, Universitätsklinikum Leipzig, Leipzig, Germany.

The surgical management of patients with congenital diaphragmatic hernia (CDH) is challenging and ever changing. It requires the highest expertise not only on the surgical level but also of neonatologists and anesthesiologists. In selected patients traditional open surgery is increasingly replaced by thoracoscopic CDH repair in many centers worldwide. Despite obvious and well-described advantages of the minimally invasive approach like a shorter ventilatory time, less pain, a shorter hospital length of stay, and a better cosmesis, important controversies remain. This review discusses hot topics of minimally invasive CDH repair, such as extracorporeal membrane oxygenation, hypercapnia/acidosis, patch repair, surgical training, and recurrence.
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http://dx.doi.org/10.1055/s-0040-1702222DOI Listing
April 2020

Publication Trends and Global Collaborations on Esophageal Atresia Research: A Bibliometric Study.

Eur J Pediatr Surg 2021 Apr 8;31(2):164-171. Epub 2020 Mar 8.

Department of Pediatric Surgery, Leipzig University, Leipzig, Sachsen, Germany.

Introduction:  Research on esophageal atresia (EA) has been heavily published over the past decades. Herein, we aimed to study the quantity and quality as well as key topics in EA research with regards to global collaborations among countries and authors.

Materials And Methods:  Publications on EA from 1945 to 2018 were extracted from the Web of Science core collection database. Productivity () was assessed by the number of publications. was estimated from the number of citations, citation rate per item and year, -index, and impact index. Collaborative networks were evaluated using VOSviewer. All measures were analyzed for countries, authors, and journals. The 10 most cited original articles between 1969 and 2018 in 5-year intervals ( = 100) were manually screened to assess the key points of EA research.

Results:  A total of 2,170 publications from 85 countries published in 388 journals were identified yielding 26,755 citations, both significantly increasing over time ( < 0.001). The most productive countries and authors also accounted for high-quality publications and benefited from an active global network. The most productive journals derived from the field of pediatric surgery but accounted only for one-third of EA papers. The best cited journals were unspecific for pediatric surgery. Long-term outcome remained the most important topic in EA research, followed by surgical techniques, epidemiology, associated anomalies, perioperative complications, and postnatal management. In contrast, basic science was underrepresented.

Conclusion:  Over the past seven decades, EA publications increased tremendously. Productiveness and quality benefited from global networking. Long-term outcome remains the key interest of EA research.
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http://dx.doi.org/10.1055/s-0040-1702223DOI Listing
April 2021

CHL1 and NrCAM are Primarily Expressed in Low Grade Pediatric Neuroblastoma.

Open Med (Wars) 2019 31;14:920-927. Epub 2019 Dec 31.

Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg Eppendorf, Hamburg, 20246, Germany.

Background: Neural cell adhesion molecules like close homolog of L1 protein (CHL1) and neuronal glia related cell adhesion molecule (NrCAM) play an important role in development and regeneration of the central nervous system. However, they are also associated with cancerogenesis and progression in adult malignancies, thus gain increasing importance in cancer research. We therefore studied the expression of CHL1 and NrCAM according to the course of disease in children with neuroblastoma.

Methods: CHL1 and NrCAM expression levels were histologically assessed by tissue microarrays from surgically resected neuroblastoma specimens of 56 children. Expression of both markers was correlated to demographics as well as clinical data including metastatic dissemination and survival.

Results: CHL1 was expressed in 9% and NrCAM in 51% of neuroblastoma tissue samples. Expression of CHL1 was higher in patients with low Hughes grade 1a/b (p=0.01). NrCAM was more often detected in patients with a low International Staging System (INSS) score 1/2 (p=0.04).

Conclusion: CHL1 and NrCAM expression was associated with low-grade pediatric neuroblastoma. These adhesion molecules may play a role in early tumor development of neuroblastoma.
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http://dx.doi.org/10.1515/med-2019-0109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6972343PMC
December 2019

Smartphone-Related Accidents in Children and Adolescents: A Novel Mechanism of Injury.

Pediatr Emerg Care 2021 Sep;37(9):e547-e550

From the Departments of Pediatric Surgery.

Objectives: Smartphones have become an integral part of daily life, often grabbing full attention of its user. We hypothesized that smartphone-associated trauma in children and adolescents has increased in the last decade. The objective of this study was to analyze smartphone-related injuries in children at two German centers for pediatric emergency care.

Methods: Smartphone-related injuries were recorded between January 2008 and March 2018 at two centers of pediatric surgery in Germany. Data were assessed for patient demography, cause of accident, type of injury, treatment, and outcome.

Results: Ten children (8 girls, 2 boys; mean ± SD age, 10.6 ± 6.0 years; range, 10 weeks to 17 years) were included. Two patients were injured in 2008 to 2015, eight in 2016 to 2018, of which three required hospital admissions. Six accidents happened in public spaces, and four within domestic environments. Eight children (mean ± SD age, 13.3 ± 2.4 years; 7 girls) were injured while using their smartphone, therefore being distracted. Two children (mean ± SD age, 6.5 ± 6.4 months) were involuntarily hurt by the smartphone of their caregivers. The causes of accident and related injuries were highly variable and ranged from minor trauma (mild head injury [n = 3], abrasions [n = 2], bruises of fingers [n = 2]/hand [n = 1]/ankle [n = 2]) to major injuries requiring intensive care treatment (pelvic [n = 1] or vertebral body fractures [n = 1]).

Conclusions: Smartphone-associated injuries mainly caused by distraction gain increasing importance in pediatric traumatology. The frequency is higher in females compared with their male counterparts. The prevention of these accidents should become part of educational programs for children and adolescents.
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http://dx.doi.org/10.1097/PEC.0000000000001781DOI Listing
September 2021

Increased L1CAM (CD171) levels are associated with glioblastoma and metastatic brain tumors.

Medicine (Baltimore) 2018 Sep;97(38):e12396

Department of Pediatric Surgery Department of Neurosurgery Department of Neuropathology, University Hospital Leipzig, Leipzig, Germany.

L1 cell adhesion molecule (L1CAM) is a member of the immunoglobulin-like cell-adhesion molecule family that was shown to be associated with a worse prognosis in several human cancers. L1 ectodomain shedding via vesicles or exosomes has been detected in extracellular fluids after cleavage from the cell surface by metalloproteases. We evaluated the presence of L1CAM in cyst fluid and tissue from glioblastomas or brain metastases.The amount of L1CAM in cyst fluid of 9 glioblastomas and 11 brain metastases was assessed using enzyme-linked immunosorbent assay (ELISA). Corresponding tumor tissue slices were stained immunohistochemically for L1CAM. Cerebrospinal fluid of 20 non-tumor patients served as controls.Mean levels of L1CAM in tumor cyst fluid were significantly higher in glioblastoma (6118 ± 4095 ng/mL) and metastasis patients (8001 ± 6535 ng/mL) than in CSF of control patients (714 ± 22 ng/mL). The immunohistochemical expression of L1CAM in corresponding tissue was significantly higher in metastases than in glioblastomas.The present study demonstrates high levels of L1CAM in cyst fluid of glioblastoma and metastatic brain tumors. Soluble L1CAM may represent a motility promoting molecule in cancer progression, a co-factor for development of tumor cysts and a target for new treatment strategies.
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http://dx.doi.org/10.1097/MD.0000000000012396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6160187PMC
September 2018

Physiologic Changes in a Small Animal Model for Neonatal Minimally Invasive Surgery.

J Laparoendosc Adv Surg Tech A 2018 Jul 21;28(7):912-917. Epub 2018 May 21.

Department of Pediatric Surgery, University of Leipzig , Leipzig, Germany .

Background: Minimally invasive surgery (MIS) has gained increasing importance in neonatal surgery but the effects on neonatal physiology remain unclear. We aimed to characterize the impact of capnoperitoneum on physiologic parameters in a small animal model for neonatal MIS.

Material And Methods: Twenty-four 10-day-old Sprague Dawley rats underwent inhalative anesthesia (1% isoflurane in 100% O 250 mL/minutes) and were allowed to breathe spontaneously. CO was insufflated into the abdominal cavity for 1 hour via a 24G cannula. Anesthetized litter mates without insufflation served as sham controls, those without any treatment as external controls. Continuous monitoring included O-saturation, heart and respiration rate, pulse and breath distension. After euthanasia, blood gas analysis was performed.

Results: All animals survived the experiment. Capnoperitoneum was best tolerated at a pressure of 2 mmHg and a flow of 0.5 L/minutes. A significant decrease in heart rate was observed within the first 30 minutes of insufflation comparing the CO and sham group (P < .05). In both, the CO and sham group, postmortem pH-levels were lower and pCO levels were higher compared to external controls (P < .05). Additionally, levels of pCO were higher but pH levels remained unchanged in the CO compared to sham group (P < .05).

Conclusion: We established a small animal model for neonatal laparoscopy. A pressure of 2 mmHg and flow of 0.5 L/minutes induced physiologic alterations but was well tolerated by the animals. These settings can be used in future studies on the impact of the capnoperitoneum in neonatal MIS.
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http://dx.doi.org/10.1089/lap.2018.0075DOI Listing
July 2018

The intra- and extraluminal appendiceal microbiome in pediatric patients: A comparative study.

Medicine (Baltimore) 2017 Dec;96(52):e9518

Department of Pediatric Surgery, University Hospital Leipzig Experimental Surgery/CardiOMICs Research Group, Department of Diagnostics and New Technologies, Fraunhofer Institute for Cell Therapy and Immunology Institute of Pathology, University Hospital Leipzig Institute for Microbiology und Epidemiology of Infectious Diseases, University Hospital Leipzig Systematic Botany and Functional Biodiversity, Institute for Biology, University of Leipzig, Leipzig, Germany.

Intestinal microbiota is involved in metabolic processes and the pathophysiology of various gastrointestinal disorders. We aimed to characterize the microbiome of the appendix in acute pediatric appendicitis comparing extraluminal and intraluminal samples.Between January and June 2015, 29 children (3-17 years, mean age 10.7 ± 3.4 years, sex M:F = 2.6:1) undergoing laparoscopic appendectomy for acute appendicitis were prospectively included in the study. Samples for bacterial cultures (n = 29) and 16S ribosomal desoxyribonucleic acid (rDNA) sequencing (randomly chosen n = 16/29) were taken intracorporeally from the appendiceal surface before preparation ("extraluminal") and from the appendiceal lumen after removal ("intraluminal"). The degree of inflammation was histologically classified into catarrhal, phlegmonous, and gangrenous appendicitis.Seventeen bacterial species were cultivated in 28 of 29 intraluminal samples and 4 species were cultivated in 2 of 29 extraluminal samples. Using 16S rDNA sequencing, 267 species were detected in intraluminal but none in extraluminal samples. Abundance and diversity of detected species differed significantly between histological groups of acute appendicitis in bacterial cultures (P = .001), but not after 16S rDNA sequencing.The appendiceal microbiome showed a high diversity in acute pediatric appendicitis. The intraluminal microbial composition differed significantly depending on the degree of inflammation. As bacteria were rarely found extraluminally by culture and not at all by sequencing, the inflammation in acute appendicitis may start inside the appendix and spread transmurally.
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http://dx.doi.org/10.1097/MD.0000000000009518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6393148PMC
December 2017

The oral microbiome-the relevant reservoir for acute pediatric appendicitis?

Int J Colorectal Dis 2018 Feb 22;33(2):209-218. Epub 2017 Dec 22.

Department of Pediatric Surgery, University of Leipzig, Liebigstr. 20A, 04103, Leipzig, Germany.

Purpose: The oral microbiome has been related to numerous extra oral diseases. Recent studies detected a high abundance of oral bacteria in inflamed appendices in pediatric patients. To elucidate the role of oral bacteria in acute pediatric appendicitis, we studied the oral and appendiceal microbiome of affected children compared to healthy controls.

Methods: Between January and June 2015, 21 children undergoing appendectomy for acute appendicitis and 28 healthy controls were prospectively enrolled in the study. All individuals underwent thorough dental examination and laboratory for inflammatory parameters. Samples of inflamed appendices and the gingival sulcus were taken for 16S rDNA sequencing. RT-qPCR of Fusobacterium nucleatum, Peptostreptococcus stomatis, and Eikenella corrodens was performed and their viability was tested under acidic conditions to mimic gastric transfer.

Results: In phlegmonous appendices, Bacteroidetes and Porphyromonas were discovered as dominant phylum and genus. In sulcus samples, Firmicutes and Streptococcus were detected predominantly. P. stomatis, E. corrodens, and F. nucleatum were identified in each group. Viable amounts of P. stomatis were increased in sulci of children with acute appendicitis compared to sulci of healthy controls. In inflamed appendices, viable amounts of E. corrodens and F. nucleatum were decreased compared to sulci of children with appendicitis. Postprandial viability could be demonstrated for all tested bacteria.

Conclusion: In children with acute appendicitis, we identified several oral bacterial pathogens. Based on postprandial viability of selected species, a viable migration from the oral cavity through the stomach to the appendix seems possible. Thus, the oral cavity could be a relevant reservoir for acute appendicitis.
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http://dx.doi.org/10.1007/s00384-017-2948-8DOI Listing
February 2018

Dextran sodium sulfate (DSS) induces necrotizing enterocolitis-like lesions in neonatal mice.

PLoS One 2017 17;12(8):e0182732. Epub 2017 Aug 17.

Department of Pediatric Surgery, University of Leipzig, Leipzig, Germany.

Background: Necrotizing enterocolitis (NEC) is an inflammatory bowel disease of preterm human newborns with yet unresolved etiology. An established neonatal murine model for NEC employs oral administration of lipopolysaccharides (LPS) combined with hypoxia/hypothermia. In adult mice, feeding dextran sodium sulfate (DSS) represents a well-established model for experimental inflammatory bowel disease. Here we investigated the effect of DSS administration on the neonatal murine intestine in comparison with the established NEC model.

Methods: 3-day-old C57BL/6J mice were either fed formula containing DSS or LPS. LPS treated animals were additionally stressed by hypoxia/hypothermia twice daily. After 72 h, mice were euthanized, their intestinal tissue harvested and analyzed by histology, qRT-PCR and flow cytometry. For comparison, adult C57BL/6J mice were fed with DSS for 8 days and examined likewise. Untreated, age matched animals served as controls.

Results: Adult mice treated with DSS exhibited colonic inflammation with significantly increased Cxcl2 mRNA expression. In contrast, tissue inflammation in neonatal mice treated with DSS or LPS plus hypoxia/hypothermia was present in colon and small intestine as well. Comparative analysis of neonatal mice revealed a significantly increased lesion size and intestinal Cxcl2 mRNA expression after DSS exposure. Whereas LPS administration mainly induced local neutrophil recruitment, DSS treated animals displayed increased monocytes/macrophages infiltration.

Conclusions: Our study demonstrates the potential of DSS to induce NEC-like lesions accompanied by a significant humoral and cellular immune response in the small and large intestine of neonatal mice. The new model therefore represents a good alternative to LPS plus hypoxia/hypothermia administration requiring no additional physical stress.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0182732PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5560643PMC
October 2017

Prognostic Impact of Activated Leucocyte Cell Adhesion Molecule (ALCAM/CD166) in Infantile Neuroblastoma.

Anticancer Res 2016 Aug;36(8):3991-5

Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg Eppendorf, Hamburg, Germany.

Background/aim: Activated leukocyte cell adhesion molecule (ALCAM/CD166) as a member of the 'immunoglobulin superfamily' is known to be involved in cancer cell proliferation and migration. The aim of this study was to investigate the expression of ALCAM in neuroblastoma tissues.

Materials And Methods: ALCAM expression was analyzed in primary neuroblastoma specimens by immunohistochemistry on microarray sections. Histopathological and clinical data were correlated with ALCAM expression and survival analysis was performed.

Results: Sixty-six children were included in the study. Strong expression of ALCAM was detected in 52 (79%) of the samples. Weak expression was significantly correlated with the International Neuroblastoma Staging System (INSS) stage (p=0.024) and positive n-MYC amplification (p=0.019). Recurrence-free survival (RFS) and overall survival (OS) were significantly shorter if ALCAM was expressed weakly (p=0.032 and p=0.001).

Conclusion: Weak ALCAM expression was significantly correlated with established markers for poor prognosis, as well as shorter RFS and OS. ALCAM might be considered as a prognostic marker for infantile neuroblastoma.
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August 2016

Diaphragm Repair with a Novel Cross-Linked Collagen Biomaterial in a Growing Rabbit Model.

PLoS One 2015 6;10(7):e0132021. Epub 2015 Jul 6.

Center for Surgical Technologies and Organ Systems Cluster, Department of Development and Regeneration, Faculty of Medicine, KU Leuven, Leuven, Belgium; Department of Obstetrics and Gynecology, University Hospital Gasthuisberg, KU Leuven, Leuven, Belgium.

Background: Neonates with congenital diaphragmatic hernia and large defects often require patch closure. Acellular collagen matrices (ACM) have been suggested as an alternative to synthetic durable patches as they are remodeled by the host or could also be used for tissue engineering purposes.

Materials And Methods: 2.0x1.0 cm diaphragmatic defects were created in 6-weeks old New-Zealand white rabbits. We compared reconstruction with a purpose-designed cross-linked ACM (Matricel) to 4-layer non-cross-linked small intestinal submucosa (SIS) and a 1-layer synthetic Dual Mesh (Gore-Tex). Unoperated animals or animals undergoing primary closure (4/0 polyglecaprone) served as age-matched controls. 60 (n = 25) resp. 90 (n = 17) days later, animals underwent chest x-ray and obduction for gross examination of explants, scoring of adhesion and inflammatory response. Also, uniaxial tensiometry was done, comparing explants to contralateral native diaphragmatic tissue.

Results: Overall weight nearly doubled from 1,554±242 g at surgery to 2,837±265 g at obduction (+84%). X-rays did show rare elevation of the left diaphragm (SIS = 1, Gore-Tex = 1, unoperated control = 1), but no herniation of abdominal organs. 56% of SIS and 10% of Matricel patches degraded with visceral bulging in four (SIS = 3, Matricel = 1). Adhesion scores were limited: 0.5 (Matricel) to 1 (SIS, Gore-Tex) to the left lung (p = 0.008) and 2.5 (Gore-Tex), 3 (SIS) and 4 (Matricel) to the liver (p<0.0001). Tensiometry revealed a reduced bursting strength but normal compliance for SIS. Compliance was reduced in Matricel and Gore-Tex (p<0.01). Inflammatory response was characterized by a more polymorphonuclear cell (SIS) resp. macrophage (Matricel) type of infiltrate (p<0.05). Fibrosis was similar for all groups, except there was less mature collagen deposited to Gore-Tex implants (p<0.05).

Conclusions: Matricel induced a macrophage-dominated inflammatory response, more adhesions, had appropriate strength but a lesser compliance compared to native tissue. The herein investigated ACM is not a viable option for CDH repair.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0132021PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4493058PMC
April 2016

A novel surgical approach for intratracheal administration of bioactive agents in a fetal mouse model.

J Vis Exp 2012 Oct 31(68). Epub 2012 Oct 31.

Molecular Virology and Gene Therapy, KU Leuven.

Prenatal pulmonary delivery of cells, genes or pharmacologic agents could provide the basis for new therapeutic strategies for a variety of genetic and acquired diseases. Apart from congenital or inherited abnormalities with the requirement for long-term expression of the delivered gene, several non-inherited perinatal conditions, where short-term gene expression or pharmacological intervention is sufficient to achieve therapeutic effects, are considered as potential future indications for this kind of approach. Candidate diseases for the application of short-term prenatal therapy could be the transient neonatal deficiency of surfactant protein B causing neonatal respiratory distress syndrome(1,2) or hyperoxic injuries of the neonatal lung(3). Candidate diseases for permanent therapeutic correction are Cystic Fibrosis (CF)(4), genetic variants of surfactant deficiencies(5) and α1-antitrypsin deficiency(6). Generally, an important advantage of prenatal gene therapy is the ability to start therapeutic intervention early in development, at or even prior to clinical manifestations in the patient, thus preventing irreparable damage to the individual. In addition, fetal organs have an increased cell proliferation rate as compared to adult organs, which could allow a more efficient gene or stem cell transfer into the fetus. Furthermore, in utero gene delivery is performed when the individual's immune system is not completely mature. Therefore, transplantation of heterologous cells or supplementation of a non-functional or absent protein with a correct version should not cause immune sensitization to the cell, vector or transgene product, which has recently been proven to be the case with both cellular and genetic therapies(7). In the present study, we investigated the potential to directly target the fetal trachea in a mouse model. This procedure is in use in larger animal models such as rabbits and sheep(8), and even in a clinical setting(9), but has to date not been performed before in a mouse model. When studying the potential of fetal gene therapy for genetic diseases such as CF, the mouse model is very useful as a first proof-of-concept because of the wide availability of different transgenic mouse strains, the well documented embryogenesis and fetal development, less stringent ethical regulations, short gestation and the large litter size. Different access routes have been described to target the fetal rodent lung, including intra-amniotic injection(10-12), (ultrasound-guided) intrapulmonary injection(13,14) and intravenous administration into the yolk sac vessels(15,16) or umbilical vein(17). Our novel surgical procedure enables researchers to inject the agent of choice directly into the fetal mouse trachea which allows for a more efficient delivery to the airways than existing techniques(18).
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http://dx.doi.org/10.3791/4219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3499071PMC
October 2012

A longer tracheal occlusion period results in increased lung growth in the nitrofen rat model.

Prenat Diagn 2012 Jan 3;32(1):39-44. Epub 2011 Nov 3.

Department of Obstetrics and Gynaecology, Division Woman and Child, University Hospital Gasthuisberg, Herestraat 49, Leuven, Belgium.

Objective: Prenatal tracheal occlusion (TO) promotes lung growth and is applied clinically in fetuses with severe congenital diaphragmatic hernia. Limited data are available regarding the effect of duration of TO on lung development. Our objective was to evaluate the effects of long (2 and 2.5 days) versus short (1 day) TO on lung development in rats with nitrofen-induced diaphragmatic hernia.

Method: Nitrofen was administered on embryonic day (ED) 9 and fetal TO performed either on ED18.5, 19 or 20 (term = 22 days). Sham-operated and untouched littermates served as controls. On ED21, lungs were harvested and only fetuses with a left-sided diaphragmatic defect were included in further analyses.

Results: Lung-body-weight ratio incrementally increased with the duration of TO. Increased proliferation following long TO was confirmed by immunohistochemistry and qRT-PCR for the proliferation marker Ki-67. Irrespective of duration, TO induced more complex airway architecture. Medial wall thickness of pulmonary arteries was thinner after long rather than short TO.

Conclusion: In the nitrofen rat model of congenital diaphragmatic hernia, a longer period of TO leads to enhanced lung growth and less muscularized pulmonary arteries.
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http://dx.doi.org/10.1002/pd.2881DOI Listing
January 2012

The correlation between lung volume and liver herniation measurements by fetal MRI in isolated congenital diaphragmatic hernia: a systematic review and meta-analysis of observational studies.

Prenat Diagn 2011 Nov 14;31(11):1086-96. Epub 2011 Sep 14.

Centre for Surgical Technologies, Faculty of Medicine, Katholieke Universiteit Leuven, Leuven, Belgium.

Objective: We conducted a meta-analysis to assess the correlation of lung volume and liver position measured by magnetic resonance imaging (MRI) with survival until discharge in fetuses with isolated congenital diaphragmatic hernia (CDH).

Method: Systematic searches of MEDLINE and EMBASE from 1 January 1980 to 10 December 2010 were performed. Studies correlating total fetal lung volumes (TFLV, observed/expected (O/E) TFLV) and/or liver position by fetal MRI to survival in expectantly managed fetuses with CDH were included. Data on the side of the defect, position of the liver, TFLV, O/E TFLV, gestational age (GA) at MRI, GA and weight at birth were collected. Odds ratio (OR) for dichotomous data, mean differences (MD) or standardized mean differences (SMD) for continuous variables were determined using RevMan 5.0 software.

Results: Nineteen studies (n = 602 fetuses) were included. Survival was associated with left-sided defects (OR 2.52; p = 0.01), "liver down" (OR 0.18; p < 0.00001), a higher TFLV (MD 9.63; p < 0.00001) and O/E TFLV (SMD 0.98; p < 0.00001) as well as higher birth weight (MD 146.60; p = 0.04). GA at MRI (MD 0.70) and GA at birth (MD 0.33) were not correlated with survival.

Conclusions: MRI measurements of fetal lung volumes, liver position and side of the defect correlate well with neonatal survival in fetuses with isolated CDH.
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http://dx.doi.org/10.1002/pd.2839DOI Listing
November 2011

Single-incision multiport laparoscopy does not cause more pain than conventional laparoscopy: a prospective evaluation in children undergoing appendectomy.

J Laparoendosc Adv Surg Tech A 2011 Oct 21;21(8):753-6. Epub 2011 Jul 21.

Department of Pediatric Surgery, University Hospital Leipzig, Leipzig, Germany.

Background: The benefit of single-incision multiport laparoscopy (SIMPL) remains a matter of vivid discussion. For good reason it has been speculated that SIMPL causes more postoperative pain, because a minilaparotomy is required to place the multiport system. We prospectively evaluated postoperative pain scores and requirement of analgesic medication following conventional laparoscopic (CL) versus SIMPL appendectomy in children.

Methods: The access for laparoscopic appendectomy was decided upon the surgeon's preference. Between April and October 2010, individual abdominal pain scores at 8, 16, 24, 48, and 72 hours postoperatively as well as the incidence of umbilical or shoulder pain and the total amount of peri- and postoperative analgesics, operative time, length of hospital stay, and demographics were assessed. Analgesics (paracetamol and/or metamizole, 15 mg/kg body weight) were administered regularly or on inquiry of the patient. Data are presented as means±standard deviation tested at a significance level of P<.05.

Results: All operations were laparoscopically completed without conversion or addition of extra ports. Thirty-nine patients (8 SIMPL appendectomy) at a mean age of 12.3±2.4 years and a mean body mass index of 19.16±3.2 kg/m(2) were included. Equal operation times were observed (SIMPL: 68.5±19.9 minutes versus CL: 66.2±19.5 minutes). There were no significant differences for the individual pain scores or the incidence of umbilical and shoulder pain between study groups. The total amount of required analgesic medication was significantly lower after SIMPL appendectomy (SIMPL: 65.73±43.8 mg/kg versus CL: 106.39±46.4 mg/kg, P=.04).

Conclusion: In summary, the present study substantiates the evidence that SIMPL appendectomy in children and adolescents is not only feasible but also beneficial for the patient without translation into increased postoperative pain. Presently, we are conducting a randomized, blinded study to validate these findings.
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http://dx.doi.org/10.1089/lap.2011.0131DOI Listing
October 2011

The embryology of the diaphragm.

Semin Pediatr Surg 2011 Aug;20(3):161-9

Department of Pediatric Surgery, University of Leipzig, Leipzig, Germany.

Despite the progress in prenatal diagnosis and intervention as well as postnatal therapeutic strategies, congenital diaphragmatic hernia (CDH) is still associated with a meaningful mortality because of the induced pulmonary hypoplasia. An essential key in understanding the pathogenesis of CDH is the underlying embryology, which has been neglected during the last decades. Likewise, the development of the normal diaphragm is still poorly understood. Obsolescent perceptions, mainly formed from histologic sections, are still propagated. In this review we present an atlas of scanning electron microscopy images that depict the normal and defective development of the diaphragm in the nitrofen rat model for CDH. Our findings suggest that the normal diaphragm mainly develops from the posthepatic mesenchymal plate. If the development of the posthepatic mesenchymal plate is impaired, a diaphragmatic defect occurs.
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http://dx.doi.org/10.1053/j.sempedsurg.2011.03.006DOI Listing
August 2011

Congenital myelomeningocele - do we have to change our management?

Cerebrospinal Fluid Res 2010 Oct 14;7:17. Epub 2010 Oct 14.

Department of Pediatric Surgery, University Hospital Leipzig, Liebigstrasse 20a, 04103 Leipzig, Germany.

Background: Eagerly awaiting the results of the Management of Myelomeningocele Study (MOMS) and with an increasing interest in setting up intrauterine myelomeningocele repair (IUMR), the optimal management of patients suffering from congenital myelomeningocele (MMC) has become a matter of debate again. We performed a cross-sectional study at our referral-center for MMC to determine the outcome for our expectantly managed patients.

Materials And Methods: A computed chart review at our institution revealed 70 patients suffering from MMC. Forty-three patients were eligible for the study and analyzed further. A retrospective analysis was performed only in patients that underwent MMC repair within the first two days of life and were seen at our outpatient clinic between 2008 and 2009 for a regular multidisciplinary follow-up. Data were collected on: gestational age (GA) and weight at birth, age at shunt placement and shunt status after the first year of life, radiological evidence for Arnold-Chiari malformation (ACM) and tethered cord (TC), need for surgery for TC, bladder function, lower leg function and educational level. Data were compared to published results for IUMR and to studies of historical controls.

Results: Patients were born with MMC between 1979 and 2009 and are now 13.3 ± 8.9 (mean ± SD) years of age. At birth, mean GA was 37.8 ± 2.3 weeks and mean weight was 2921.3 ± 760.3 g, both significantly higher than in IUMR patients. Shunt placement in our cohort was required in 69.8% at a mean age of 16.0 ± 10.7 days, which was less frequent than for historical controls. Amongst our cohort, radiological observations showed 57.1% had ACM II and 41.9% had TC. Only two of our patients underwent a surgical correction for TC. Clean intermittent catheterization was performed in 69.7% of our patients, 56.4% were (assisted) walkers and 64.1% attended regular classes, both comparable to historical controls.

Conclusions: With a close and interdisciplinary management by pediatric surgeons, neurologists and urologists, the long-term outcome of patients suffering from MMC can currently be considered satisfactory. With respect to the known drawbacks of fetal interventions for mother and child, especially preterm delivery, the results of the MOMS trial should be awaited with caution before proceeding with a complex intervention like IUMR.
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http://dx.doi.org/10.1186/1743-8454-7-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2964623PMC
October 2010

EXIT procedure in a neonate with a prenatally diagnosed granular cell tumor.

Pediatr Surg Int 2010 Sep 3;26(9):935-7. Epub 2010 Aug 3.

Department of Pediatric Surgery, University Hospital Leipzig, Leipzig, Germany.

Congenital oral tumor masses might cause ventilation problems in the neonate. We report the first case of an EXIT procedure performed in a fetal granular cell tumor arising from the maxilla that was diagnosed prenatally followed by surgical correction on the 4th day of life. The EXIT procedure is an elegant approach to optimize perinatal airway management in such tumors.
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http://dx.doi.org/10.1007/s00383-010-2674-6DOI Listing
September 2010

Albumin as an adjunct to tracheal occlusion in fetal rats with congenital diaphragmatic hernia: a placebo-controlled study.

Am J Obstet Gynecol 2010 Feb 24;202(2):198.e1-9. Epub 2009 Dec 24.

Center for Surgical Technologies, Faculty of Medicine, Katholieke Universiteit Leuven, Leuven, Belgium.

Objective: We sought to investigate effects of intratracheal albumin injection prior to tracheal occlusion (TO) on lung proliferation in fetal rats with nitrofen-induced congenital diaphragmatic hernia.

Study Design: On embryonic day 19, nitrofen-exposed fetuses underwent TO, TO and 50 microL of either intratracheal albumin 20% or saline, or remained untouched. Main outcome at embryonic day 21.5 was expression of the proliferation marker Ki-67. Secondary outcomes were lung-to-bodyweight ratio (LBWR), tropoelastin expression, density and spatial distribution of elastin, pulmonary/alveolar morphometry, and fetal survival.

Results: TO increased Ki-67 messenger RNA and LBWR. Albumin further increased LBWR and density of Ki-67-positive cells but also fetal mortality. TO with or without adjuncts induced elastin deposits at the tips of arising secondary crests, increased air space size, and decreased septal thickness.

Conclusion: TO had effects on lung proliferation and advanced the morphologic appearance. Addition of albumin increased density of proliferating cells and LBWR, yet at the expense of additional fetal loss.
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http://dx.doi.org/10.1016/j.ajog.2009.10.877DOI Listing
February 2010

Maternal administration of betamethasone inhibits proliferation induced by fetal tracheal occlusion in the nitrofen rat model for congenital diaphragmatic hernia: a placebo-controlled study.

Pediatr Surg Int 2008 Dec;24(12):1287-95

Faculty of Medicine, Centre for Surgical Technologies, Katholieke Universiteit Leuven, Minderbroedersstraat 17, 3000, Leuven, Belgium.

Purpose: Fetal tracheal occlusion (TO) is offered to fetuses with severe pulmonary hypoplasia due to congenital diaphragmatic hernia (CDH). TO induces lung growth, but even when performed minimally invasive, there is a risk for iatrogenic preterm delivery. Whenever this is anticipated, maternal glucocorticoids (GC) may be given to enhance lung maturation. The pulmonary effects of GC in fetuses with CDH that underwent TO are yet poorly defined. Therefore, we conducted a placebo-controlled study in the nitrofen (NF) rat model for CDH.

Methods: Pregnant rats were gavage fed NF or olive oil (OO) on ED9.5. At ED19.0, fetuses were either assigned to TO or left untouched. Maternal betamethasone (BM) or saline (PLAC) was administered on ED20. Necropsy was done on ED21.5 to obtain lung-to-body-weight ratio (LBWR), and perform quantitative RT-PCR and fluorescent immunostaining for Ki-67 and proliferating cell nuclear antigen (PCNA) in fetal lungs.

Results: CDH fetuses had a lower LBWR than normal fetuses, but comparable pulmonary PCNA and Ki-67 expression levels. TO increased LBWR, irrespective of maternal BM or PLAC. However, BM but not PLAC inhibited proliferation in TO and unoperated fetuses.

Conclusion: Rats with NF-induced CDH have hypoplastic lungs with normal proliferation indices. TO triggers proliferation, an effect countered by BM.
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http://dx.doi.org/10.1007/s00383-008-2269-7DOI Listing
December 2008

Prenatal diagnosis, prediction of outcome and in utero therapy of isolated congenital diaphragmatic hernia.

Prenat Diagn 2008 Jul;28(7):581-91

Fetal Medicine Unit of University Hospitals Leuven, Leuven, Belgium.

Congenital diaphragmatic hernia (CDH) can be associated with genetic or structural anomalies with poor prognosis. In isolated cases, survival is dependent on the degree of lung hypoplasia and liver position. Cases should be referred in utero to tertiary care centers familiar with this condition both for prediction of outcome as well as timed delivery. The best validated prognostic indicator is the lung area to head circumference ratio. Ultrasound is used to measure the lung area of the index case, which is then expressed as a proportion of what is expected normally (observed/expected LHR). When O/E LHR is < 25% survival chances are < 15%. Prenatal intervention, aiming to stimulate lung growth, can be achieved by temporary fetal endoscopic tracheal occlusion (FETO). A balloon is percutaneously inserted into the trachea at 26-28 weeks, and reversal of occlusion is planned at 34 weeks. Growing experience has demonstrated the feasibility and safety of the technique with a survival rate of about 50%. The lung response to, and outcome after FETO, is dependent on pre-existing lung size as well gestational age at birth. Early data show that FETO does not increase morbidity in survivors, when compared to historical controls. Several trials are currently under design.
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http://dx.doi.org/10.1002/pd.2033DOI Listing
July 2008

Bradykinin-induced nociceptor sensitisation to heat depends on cox-1 and cox-2 in isolated rat skin.

Pain 2007 Jul 28;130(1-2):14-24. Epub 2006 Dec 28.

Department of Physiology and Pathophysiology, Friedrich-Alexander-University of Erlangen-Nuremberg, Universitaetsstr. 17, D-91054 Erlangen, Germany.

Bradykinin is an important inflammatory mediator that can either activate and/or sensitise nociceptors to heat stimuli applied to the skin. Several studies have suggested that prostaglandins and thus the cyclooxygenase (cox) enzymes are important in the sensitisation process but little is known about the relative involvement of the two cox isoforms, cox-1 and cox-2. Extracellular recordings were made from C-mechanoheat-sensitive fibres in isolated rat skin-saphenous nerve preparations. Bradykinin-mediated sensitisation of heat responses in these afferents was significantly attenuated by the selective cox-1 inhibitor, SC-560, and by the selective cox-2 inhibitor, NS-398. In the same experiments, bradykinin-mediated induction of ongoing activity was reduced by SC-560 but not NS-398. In a second series of experiments, bradykinin-stimulated synthesis and release of prostaglandin E2 (PGE2) was measured in isolated skin-nerve preparations. Although the basal release of PGE2 appeared unaffected by either drug, bradykinin-stimulated PGE2 release from the skin was inhibited by both SC-560 and NS-398. Immunocytochemical evaluation revealed cox-1 immunostaining was present in large cutaneous nerve branches, small intradermal nerve bundles as well as nerve endings within the skin. Cox-1 labelling was also present in non-neuronal cell types such as mast cells. Cox-2 immunoreactivity was weak but where present was located in small nerve bundles, smaller intradermal nerve bundles and nerve endings. This study shows that both cox isoforms are present in skin and that they have an important role in mediating bradykinin-evoked heat sensitisation of C-MH sensitive fibres through cox-1 and cox-2 dependent prostaglandin synthesis.
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http://dx.doi.org/10.1016/j.pain.2006.10.027DOI Listing
July 2007
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