Publications by authors named "Ulrike Subotic"

24 Publications

  • Page 1 of 1

Lack of Mucosal Cholinergic Innervation Is Associated With Increased Risk of Enterocolitis in Hirschsprung's Disease.

Cell Mol Gastroenterol Hepatol 2021 Mar 16. Epub 2021 Mar 16.

Department of Pediatric Surgery, University Children's Hospital Basel (UKBB) and University of Basel, Basel, Switzerland.

Background & Aims: Hirschsprung's disease (HSCR) is a congenital intestinal motility disorder defined by the absence of enteric neuronal cells (ganglia) in the distal gut. The development of HSCR-associated enterocolitis remains a life-threatening complication. Absence of enteric ganglia implicates innervation of acetylcholine-secreting (cholinergic) nerve fibers. Cholinergic signals have been reported to control excessive inflammation, but the impact on HSCR-associated enterocolitis is unknown.

Methods: We enrolled 44 HSCR patients in a prospective multicenter study and grouped them according to their degree of colonic mucosal acetylcholinesterase-positive innervation into low-fiber and high-fiber patient groups. The fiber phenotype was correlated with the tissue cytokine profile as well as immune cell frequencies using Luminex analysis and fluorescence-activated cell sorting analysis of colonic tissue and immune cells. Using confocal immunofluorescence microscopy, macrophages were identified in close proximity to nerve fibers and characterized by RNA-seq analysis. Microbial dysbiosis was analyzed in colonic tissue using 16S-rDNA gene sequencing. Finally, the fiber phenotype was correlated with postoperative enterocolitis manifestation.

Results: The presence of mucosal nerve fiber innervation correlated with reduced T-helper 17 cytokines and cell frequencies. In high-fiber tissue, macrophages co-localized with nerve fibers and expressed significantly less interleukin 23 than macrophages from low-fiber tissue. HSCR patients lacking mucosal nerve fibers showed microbial dysbiosis and had a higher incidence of postoperative enterocolitis.

Conclusions: The mucosal fiber phenotype might serve as a prognostic marker for enterocolitis development in HSCR patients and may offer an approach to personalized patient care and new therapeutic options.
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http://dx.doi.org/10.1016/j.jcmgh.2021.03.004DOI Listing
March 2021

A german-language competency-based multisource feedback instrument for residents: development and validity evidence.

BMC Med Educ 2020 Oct 12;20(1):357. Epub 2020 Oct 12.

Department for Assessment and Evaluation (AAE), Institute for Medical Education, University of Bern, Mittelstrasse 43, 3012, Bern, Switzerland.

Background: In medical settings, multisource feedback (MSF) is a recognised method of formative assessment. It collects feedback on a doctor's performance from several perspectives in the form of questionnaires. Yet, no validated MSF questionnaire has been publicly available in German. Thus, we aimed to develop a German MSF questionnaire based on the CanMEDS roles and to investigate the evidence of its validity.

Methods: We developed a competency-based MSF questionnaire in German, informed by the literature and expert input. Four sources of validity evidence were investigated: (i) Content was examined based on MSF literature, blueprints of competency, and expert-team discussions. (ii) The response process was supported by analysis of a think-aloud study, narrative comments, "unable to comment" ratings and evaluation data. (iii) The internal structure was assessed by exploratory factor analysis, and inter-rater reliability by generalisability analysis. Data were collected during two runs of MSF, in which 47 residents were evaluated once (first run) or several times (second and third run) on 81 occasions of MSF. (iv) To investigate consequences, we analysed the residents' learning goals and the progress as reported via MSF.

Results: Our resulting MSF questionnaire (MSF-RG) consists of 15 items and one global rating, which are each rated on a scale and accompanied by a field for narrative comments and cover a construct of a physician's competence. Additionally, there are five open questions for further suggestions. Investigation of validity evidence revealed that: (i) The expert group agreed that the content comprehensively addresses clinical competence; (ii) The response processes indicated that the questions are understood as intended and supported the acceptance and usability; (iii) For the second run, factor analysis showed a one-factor solution, a Cronbach's alpha of 0.951 and an inter-rater reliability of 0.797 with 12 raters; (iv) There are indications that residents benefitted, considering their individual learning goals and based on their ratings reported via MSF itself.

Conclusions: To support residency training with multisource feedback, we developed a German MSF questionnaire (MSF-RG), which is supported by four sources of validity evidence. This MSF questionnaire may be useful to implement MSF in residency training in German-speaking regions.
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http://dx.doi.org/10.1186/s12909-020-02259-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7552497PMC
October 2020

Correction to: Compartment pressures in children with normal and fractured lower extremities.

Eur J Trauma Emerg Surg 2019 06;45(3):567

Department of Pediatric Surgery, General and Thoracic Surgery, University Children's Hospital Zurich, Steinwiessstrasse 75, 8032, Zurich, Switzerland.

The original version of this article unfortunately contained a mistake in the author name Sasha Job Tharakan. The corrected name is given above.
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http://dx.doi.org/10.1007/s00068-019-01094-5DOI Listing
June 2019

Compartment pressures in children with normal and fractured lower extremities.

Eur J Trauma Emerg Surg 2019 06 4;45(3):493-497. Epub 2019 Feb 4.

Department of Pediatric Surgery, General and Thoracic Surgery, University Children's Hospital Zurich, Steinwiessstrasse 75, 8032, Zurich, Switzerland.

Purpose: Needle manometry is a tool to confirm suspected acute compartment syndrome (ACS). There is scarce evidence of normal pressure values of the lower extremities in children. The aim of this study is to assess the normal compartment pressures in non-injured lower extremities of children.

Methods: This prospective study included children up to the age of 16 years with lower extremity fractures that needed reduction. Between June 2009 and August 2015, 20 children were included. We used needle manometry to measure the pressures in the superficial (SPC), deep posterior (DPC) and in the anterior compartments (AC) on both the lower legs.

Results: On the healthy leg, the mean compartment pressure was 15.15 mmHg in the AC (range 7-30 mmHg), 14.32 mmHg in the SPC (range 8-24 mmHg) and 13.00 mmHg in the DPC (range 4-21 mmHg). On the injured leg, the mean compartment pressure was 24.07 mmHg in the AC (range 5-40 mmHg), 17.21 mmHg in the SPC (range 7-29 mmHg) and 17.13 mmHg in the DPC (range 6-37 mmHg). We found a perfusion gradient (diastolic blood pressure-compartment pressure) < 30 mmHg in at least one compartment of the fractured and healthy leg in 13 patients. Five patients underwent fasciotomy for suspected ACS and their data was excluded for the injured leg.

Conclusion: We could show that children have higher normal compartment pressures than adults in the lower leg. They seem to be able to tolerate higher absolute compartment pressures and lower pressure gradients before ACS occurs. More studies are needed to make a final statement on tolerable compartment pressures in children.
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http://dx.doi.org/10.1007/s00068-019-01082-9DOI Listing
June 2019

Buddy taping versus splint immobilization for paediatric finger fractures: a randomized controlled trial.

J Hand Surg Eur Vol 2019 Jul 31;44(6):640-647. Epub 2019 Jan 31.

1 Division of Hand Surgery, University Children's Hospital, Zurich, Switzerland.

The purpose of this single-centre randomized controlled trial was to assess the non-inferiority of buddy taping versus splint immobilization of extra-articular paediatric finger fractures. Secondary fracture displacement was the primary outcome; patient comfort, cost and range of finger motion were secondary outcomes. Ninety-nine children were randomly assigned to taping or splinting. Sixty-nine fractures were undisplaced; 31 were displaced and required reduction before taping or splinting. Secondary displacement occurred in one patient in the taping and three in the splinting group. The risk difference was below the predefined non-inferiority level of 5%. All secondary displacements occurred in the 31 displaced fractures after reduction and were in little fingers. Patient comfort was significantly higher and cost lower in the taping group. We conclude from this study the non-inferiority of buddy taping versus splint immobilization of extra-articular paediatric finger fractures in general. We advise treatment may need to be individualized for patients with displaced fractures because we cannot make any absolute conclusions for these fractures. I.
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http://dx.doi.org/10.1177/1753193418822692DOI Listing
July 2019

Di (2-Ethylhexyl) Phthalate and Its Role in Developing Cholestasis: An In Vitro Study on Different Liver Cell Types.

J Pediatr Gastroenterol Nutr 2018 02;66(2):e28-e35

Department of Pediatric Surgery, University Children's Hospital Basel, Basel, Switzerland.

Objectives: Di(2-ethylhexyl) phthalate (DEHP) is a plasticizer used in many polyvinylchloride medical devices and is washed out easily. Thereby critically ill infants can become exposed to DEHP concentrations significantly exceeding the recommended threshold. We suspect DEHP to play an important role in the development of intestinal failure-associated liver disease. The aim of this study was therefore to determine the direct influence of DEHP on different liver cell types.

Methods: HepG2, human upcyte hepatocytes, primary murine hepatocytes, LX-2, human upcyte hepatic stellate cells, and liver organoids were cultured with DEHP (0.5-500 μmol/L) and parameters including cytotoxicity, cell-cell interactions, and expression of metabolizing enzymes were investigated.

Results: DEHP modulated the expression of xenobiotic metabolizing enzymes, reduced the formation of bile canaliculi and cell polarity, and inhibited Cyp-activity in hepatocytes. DEHP had a toxic effect on LX-2 and induced the fibrogenic activation of hepatic stellate cells. The mode of action of DEHP was different in monolayer cultures compared to 3D-liver organoids, which were more sensitive to DEHP.

Conclusions: This study suggests that DEHP modulates expression and activity of drug-detoxifying liver enzymes in humans at a clinically relevant concentration. Furthermore, it may contribute to the development of cholestasis and fibrosis. These findings strongly support the opinion, that there is a significant potential for serious adverse effects of DEHP derived from medical devices on human health, especially in very young infants with immature livers.
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http://dx.doi.org/10.1097/MPG.0000000000001813DOI Listing
February 2018

Prenatal and Postnatal Management of Gastroschisis in German-Speaking Countries: Is There a Standardized Management?

Eur J Pediatr Surg 2018 Apr 9;28(2):183-193. Epub 2017 Feb 9.

Department of Pediatric Surgery, University Children's Hospital, Zurich, Switzerland.

Introduction:  Evidence-based guidelines or protocols regarding the perinatal management of babies born with gastroschisis are lacking. The aim of this work is to evaluate the different current treatment modalities for newborns with gastroschisis during the perinatal period in the German-speaking countries Germany, Austria, and Switzerland. These data could serve as a starting point for the development of a multicenter randomized controlled trial.

Materials And Methods:  A questionnaire was developed with 30 questions divided into five sections: (1) prenatal diagnosis, (2) fetal therapy, (3) mode and timing of delivery, (4) operative management, and (5) postoperative management. All pediatric surgery institutions that treat newborns with gastroschisis were identified and asked to participate. Data were categorized by country and analyzed using descriptive statistics (frequency and percentage).

Results:  The return rate of the questionnaire was 95% (89 hospitals). A standard procedure was identified regarding prenatal ultrasound monitoring, interdisciplinary team approach, planned delivery through cesarean section, postnatal coverage of the intestine with a silastic bag, first intervention within the first 6 hours after birth, attempt of primary abdominal wall closure, and perioperative antibiotic treatment. For many crucial parameters, management was not standardized.

Conclusions:  There is no gold standard in German-speaking countries on how to manage fetuses and babies with gastroschisis. Moreover, this report unveils some questionable elements of daily practice for which there is no evidence at all and which can jeopardize outcome and even prove fatal (fetal therapy, preterm delivery, lack of abdominal pressure monitoring). Prospective randomized-controlled multicenter studies are needed to set a standard.
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http://dx.doi.org/10.1055/s-0037-1598103DOI Listing
April 2018

Leaching of plasticizers from polyvinylchloride perfusion lines by different lipid emulsions for premature infants under clinical conditions.

Int J Pharm 2017 Mar 23;520(1-2):119-125. Epub 2017 Jan 23.

Division of Visceral, Neonatal, and Fetal Surgery, Department of Pediatric Surgery, University Children's Hospital Zurich, Switzerland. Electronic address:

Plasticizers migrate from polyvinylchloride (PVC) infusion systems into lipid emulsions. The aim of this study was to investigate the leaching of different plasticizers from PVC perfusion lines by a selection of lipid emulsions under clinical conditions. Seven PVC perfusion lines with an equal length of 150cm and three internal diameters were perfused with three lipid emulsions: Intralipid 20%, ClinOleic 20% and SMOFlipid 20%, mimicking clinical conditions. The concentrations of the plasticizers were measured directly in the emulsions by gas chromatography - mass spectrometry. Of the four plasticizers examined in this study, di (2-ethylhexyl) phthalate (DEHP) leached the most and was found, on average, at 46.5μg/ml in the emulsions - around one order of magnitude higher than the other plasticizers. This study demonstrates that the leaching of DEHP by lipid emulsions in conditions of total parenteral nutrition is many times higher than should be accepted and higher when compared to the other plasticizers. There was no significant difference in leaching of plasticizers in relation to the type of lipid emulsion. The influence of tube diameter on the leaching rate of plasticizers should be taken into account especially in particular exposed patients.
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http://dx.doi.org/10.1016/j.ijpharm.2017.01.046DOI Listing
March 2017

Compartment Pressures in Children With Normal and Fractured Forearms: A Preliminary Report.

J Pediatr Orthop 2016 Jun;36(4):410-5

*Pediatric Hand Surgery, University Children's Hospital Zurich †Seminar for Statistics, ETH Zurich ‡Department of Emergency Medicine, University Children's Hospital Zurich, Zurich, Switzerland.

Introduction: Acute compartment syndrome (ACS) can lead to irreversible damage if fasciotomy is not performed in a timely manner. Needle manometry is a tool to confirm suspected ACS. The threshold for compartment pressures that can be tolerated has been debated. The aim of this study is to assess the normal compartment pressures in noninjured forearms of children. Further, we sought to quantify the maximum tolerable compartment pressures in fractured forearms of children, thus establishing a baseline and providing guidance in evidence-based decision making to evaluate children with suspected ACS.

Methods: This prospective study included children up to the age of 16 years with forearm fractures that needed reduction with or without osteosynthesis. Between June 2009 and March 2013, 41 children were included. Mean age was 9.25 years (range, 4 to 15.4 y). We used needle manometry to measure the pressures in the superficial and deep volar as well as in the dorsal compartments (DCs) on both the forearms. The mean pressures between compartments in healthy versus injured arms were analyzed using a 1-sided, paired t test.

Results: On the injured side, the mean compartment pressure was 19.12 mm Hg (range, 3 to 49 mm Hg) in the deep volar compartment, 15.56 mm Hg (range, 5 to 37 mmHg) in the DC, and 14.8 mm Hg (range, 2 to 35 mm Hg) in the superficial volar compartment. On the noninjured side, the mean compartment pressure was 12.9 mm Hg (range, 6 to 31 mm Hg) in the DC, 10.22 mm Hg (range, 3 to 22 mm Hg) in the deep volar compartment, and 9.66 mm Hg (range, 3 to 21 mm Hg) in the superficial volar compartment. We measured an absolute compartment pressure of >30 mm Hg in 15 patients on the fractured side. Three of them had an absolute compartment pressure of >45 mm Hg. Only 1 had ACS. This patient underwent fasciotomy and was excluded for further analysis. On follow-up (mean, 24.84 mo), no patient was found to have any sequelae of ACS.

Discussion: This is the first study to report normal compartment pressure measurements in noninjured forearms and in fractured forearms without clinical suspicion of ACS in children.The mean compartment pressure measured in the deep volar compartment (DVC) in healthy children was 10.22 mm Hg (range, 3 to 22 mm Hg) and therefore slightly higher than in adults. Some children with fractures tolerated absolute compartment pressures >30 mm Hg without clinical signs of ACS. Fasciotomy in children under close observation could eventually be delayed despite surpassing the accepted pressure limits for adults.

Level Of Evidence: Level I-prognostic.
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http://dx.doi.org/10.1097/BPO.0000000000000471DOI Listing
June 2016

In utero and postnatal imaging findings of parasitic conjoined twins (ischiopagus parasiticus tetrapus).

Pediatr Radiol 2015 Apr 7;45(5):767-70. Epub 2014 Oct 7.

Department of Diagnostic Imaging, University Children's Hospital Zurich, Steinwisstrasse 75, 8032, Zurich, Switzerland,

Conjoined twins are a rare developmental anomaly with a reported prevalence of 1.47 per 100,000 births. We present an uncommon case of a parasitic ischiopagus tetrapus with a parasitic ischiopagus partial twin joined to the complete fetus at the level of the ischium diagnosed in utero by fetal MRI. The correct prenatal diagnosis led to birth by caesarean section. Prenatal MRI findings are presented and corroborated by postnatal imaging delineating the full extent and associated anomalies of this rare malformation. Differential diagnosis of duplicated lower extremities is discussed.
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http://dx.doi.org/10.1007/s00247-014-3172-0DOI Listing
April 2015

Dermatofibrosarcoma protuberans in childhood treated with slow Mohs micrographic surgery.

Pediatr Dermatol 2013 Jul-Aug;30(4):462-8. Epub 2013 Feb 22.

Department of Plastic and Reconstructive Surgery, University Children's Hospital Zurich, Zurich, Switzerland.

Dermatofibrosarcoma protuberans (DFSP) in childhood is a rare tumor with high recurrence rates. Wide local excision can result in disfiguring mutilation, whereas Mohs micrographic surgery (MMS) reduces surgical margins. MMS in children is not performed routinely, as the required infrastructures such as a histopathology lab in close proximity to the operating room is often lacking. We retrospectively reviewed children diagnosed with DFSP treated at our hospital over 2 years. We recorded surgical treatment details, including margins, duration of inpatient stay, outcome, follow-up, and molecular genetic tumor tissue analysis. Four children with a median age of 6.8 years (range 6.0-8.8 years) were identified who had a diagnostic delay of a median of 2.5 years (range 0.5-4.0 years); all underwent complete tumor excision using the slow MMS technique using vacuum-assisted closure systems between repeated excisions and before wound closure. The median maximal safety margins were 1.5 cm (range 1.0-3.0 cm). By using vacuum-assisted closure systems, no dressing changes were needed, pain was limited, and full mobility was maintained in all children. The median total time in the hospital was 11 days (range 10-14 days). No relapses occurred during a median follow-up of 25.8 months (range 11.3-32.6 months). Collagen 1A1/platelet-derived growth factor B (COL1A1/PDGFB) translocation on chromosomes 17 and 22 was detected in all three analyzable specimens. Lesions suspected of being DFSP warrant prompt histologic evaluation; interdisciplinary management is mandatory in particular for children. Micrographic surgery allows smaller surgical margins than wide excision and should be considered as the treatment of choice in children with DFSP. The interim usage of vacuum-assisted closure systems increases patient comfort. Translocations in the COL1A1/PDGFB gene imply susceptibility to targeted treatment modalities for therapy-resistant cases.
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http://dx.doi.org/10.1111/pde.12039DOI Listing
February 2014

Manufactured volvulus.

Eur J Pediatr Surg 2013 Jun 21;23(3):234-7. Epub 2012 Nov 21.

Division of Visceral, Neonatal, and Fetal Surgery, Department of Pediatric Surgery, Children's University Hospital, Zurich, Switzerland.

Background/purpose: Malrotation with a common mesentery is the classical pathology allowing midgut volvulus to occur. There are only a few reports of small bowel volvulus without malrotation or other pathology triggering volvulation. We describe three cases of small bowel volvulus in very premature newborns with a perfectly normal intra-abdominal anatomy and focus on the question, what might have set off volvulation.

Methods: In 2005 to 2008, three patients developed small bowel volvulus without any underlying pathology. Retrospective patient chart review was performed with special focus on clinical presentation, preoperative management, intraoperative findings, and potential causative explanations. Mean follow-up period was 46 months.

Results: All patients were born between 27 and 31 weeks (mean 28 weeks) with a birth weight between 800 and 1,000 g (mean 887 g). They presented with an almost identical pattern of symptoms including sudden abdominal distension, abdominal tenderness, erythema of the abdominal wall, high gastric residuals, and radiographic signs of ileus. All of them were treated with intensive abdominal massage or pelvic rotation to improve bowel movement before becoming symptomatic.

Conclusions: Properistaltic maneuvers including abdominal massage and pelvic rotation may cause what we term a "manufactured" volvulus in very premature newborns. Thus, this practice was stopped.
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http://dx.doi.org/10.1055/s-0032-1330843DOI Listing
June 2013

Primary reconstruction of fingernail injuries in children with split-thickness nail bed grafts.

Eur J Pediatr Surg 2012 Aug 30;22(4):283-8. Epub 2012 May 30.

Department of Pediatric Hand Surgery, University Children's Hospital Zurich, Zurich, Switzerland.

Introduction: Failure to detect and treat partial or complete avulsions of the nail bed may lead to severe nail deformity that predisposes to repeat injuries and is cosmetically inacceptable. Treatment of these injuries with split-thickness nail bed grafts (STNBGs) is controversial and no pediatric series has been published.

Methods: A retrospective, single center case series of nine fingers with complex nail bed injuries that were reconstructed primarily with STNBGs was performed. Surgical outcome and patient satisfaction were assessed.

Results: For six nail bed reconstructions, the nail bed graft was harvested from the injured finger, and for the remaining three from the great toe. Harvesting of the great toe's nail bed could be performed without removal of the nail plate by only lifting it up distally. Insufficient vascularization required primary flap coverage in six cases with three Moberg flaps, two palmar V-Y flaps, and one thenar flap. No flap was lost and all nail bed grafts had a 100% take. Only one patient required reoperation due to a hook- and split-nail deformity. All other patients were satisfied or very satisfied and the surgical outcome was least satisfactory in all but two patients.

Conclusions: Primary reconstruction of complex nail bed injuries with STNBGs usually gives good cosmetic and functional results in children and prevents secondary nail growth disturbances reliably.
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http://dx.doi.org/10.1055/s-0032-1313337DOI Listing
August 2012

The microenvironment in the Hirschsprung's disease gut supports myenteric plexus growth.

Int J Colorectal Dis 2012 Jun;27(6):817-29

Department of Pediatric Surgery, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany.

Introduction: The transplantation of neural crest derived stem cells (NCSC) is a potent alternative for the treatment of Hirschsprung's disease (HSCR). Cells to be transplanted should find an appropriate microenvironment to survive and differentiate. Influences of HSCR-smooth-muscle-protein extracts upon isolated myenteric plexus cells, dissociated dorsal root ganglia and NCSC were studied in vitro to investigate the quality of this microenvironment effects.

Methods: Postnatal human gut from children undergoing colonic resection due to HSCR was divided in segments. Smooth muscle was dissected and homogenized. Glial-cell-line-derived-neurotrophic-factor (GDNF) and transforming-growth-factor-β-1 (TGFβ-1) concentration were measured in the homogenates from the individual segment using ELISA. Myenteric plexus and dissociated dorsal root ganglia (DRG) cultures, as well as NCSCs were exposed to protein extracts derived from ganglionic and aganglionic HSCR segments, and their effect upon neurite outgrowth, survival, and branching was evaluated.

Results And Conclusions: The amount of the factors varied considerably between the individual segments and also from patient to patient. Four major expression patterns could be detected. While all extracts tested lead to a significant increase in neurite outgrowth compared to the control, extracts from proximal segments tended to have more prominent effects. In one experiment, extracts from all individual segments of a single patient were tested. Neurite outgrowth, neuronal survival, and branching pattern varied from segment to segment, but all HSCR-muscle-protein extracts increased neuronal survival and network formation. Smooth muscle protein from aganglionic bowel supports the survival and outgrowth of myenteric neurons and NCSCs and is so an appropriate target for neural stem cell treatment.
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http://dx.doi.org/10.1007/s00384-012-1411-0DOI Listing
June 2012

Smooth muscle proteins from Hirschsprung's disease facilitates stem cell differentiation.

Pediatr Surg Int 2012 Feb;28(2):135-42

Department of Pediatric Surgery, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany.

Background And Aims: The transplantation of neural crest derived stem cells (NCSC's) is a potent alternative for the treatment of Hirschsprung's disease (HSCR). Cells to be transplanted should find an appropriate microenvironment to survive and differentiate. To investigate the quality of this microenvironment, effects of HSCR-smooth-muscle-protein extracts upon NCSC's were studied in vitro.

Methods: Postnatal human gut from children undergoing colonic resection due to HSCR was divided in segments. Smooth muscle was dissected and homogenized. Glial-cell-line-derived-neurotrophic-factor (GDNF) concentration was measured in the homogenates from the individual segment using ELISA. NCSC's were exposed to protein extracts derived from ganglionic and aganglionic HSCR segments, and their effect upon neurite outgrowth, survival and branching was evaluated.

Results: The amount of the factors varied considerably between the proximal and distal segments, and also from patient to patient. While extracts from proximal segments tended to have more prominent effects, all HSCR-muscle-protein extracts increased neuronal survival and network formation.

Conclusion: Muscle protein from aganglionic bowel supports the survival and outgrowth of NCSC's and is so an appropriate target for neural stem cell treatment.
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http://dx.doi.org/10.1007/s00383-011-3010-5DOI Listing
February 2012

A minimal invasive surgical approach for children of all ages with ureteropelvic junction obstruction.

J Pediatr Urol 2012 Aug 29;8(4):354-8. Epub 2011 Jul 29.

Pediatric Surgery, Children's University Hospital Zurich, Steinwiesstrasse 75, 8032 Zurich, Switzerland.

Objective: Open dismembered pyeloplasty is considered the gold standard to treat ureteropelvic junction obstruction (UPJO) in children. Laparoscopic pyeloplasty (LP) and robot-assisted pyeloplasty (RAP) are increasingly popular. Our present protocol consists of using minimally invasive techniques for all children with UPJO. Here, we report our first 40 cases operated under this protocol.

Patients And Methods: Retrospective chart review of patients who underwent LP and RAP for UPJO between 2006 and 2010 was performed. Children younger than 4 years of age underwent LP and children aged 4 years and older with robot assistance. Results were assessed comparing pre- and postoperative imaging studies, operating time, hospital course and complications.

Results: Thirty-nine patients underwent 41 dismembered pyeloplasties (20 patients LP, 19 patients RAP). No conversions to open surgery were performed. The difference in operative time was statistically significant. The average hospital stay was 7 days (LP) and 6 days (RAP). All patients showed significant decrease of hydronephrosis and the overall success rate was 100%. The complication rate was 25% in the LP and 28% in the RAP group.

Conclusion: Our data show that RAP and LP are effective to correct UPJO with similar outcomes and complication rates. None of the patients in this series required re-intervention to correct obstruction and the results are comparable with open surgery.
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http://dx.doi.org/10.1016/j.jpurol.2011.07.004DOI Listing
August 2012

Community-associated methicillin-resistant Staphylococcus aureus-infected chronic scalp wound with exposed dura in a 10-year-old boy: vacuum-assisted closure is a feasible option: case report.

Neurosurgery 2011 May;68(5):E1481-3; discussion E1484

Pediatric Surgery, Children's Hospital, University Zurich, Zurich, Switzerland.

Background And Importance: Since the introduction of vacuum-assisted closure (VAC) in 1997, it has been used successfully in treating difficult wounds, including spinal wounds and wounds in pediatric patients. There are no reports on VAC therapy in pediatric patients on the scalp, especially with exposed dura. This report describes a 10-year-old boy with a chronic wound of the scalp with exposed dura after multiple neurosurgical interventions who was treated successfully with VAC.

Clinical Presentation: A 10-year-old mentally disabled boy with Apert syndrome suffered from a chronic wound with community-associated methicillin-resistant Staphylococcus aureus (MRSA) infection after multiple neurosurgeon operations. For wound closure, VAC therapy was initiated on the bony defect with exposed dura. The wound healed successfully, and the MRSA disappeared.

Conclusion: The aims of VAC therapy are formation of new granulation tissue, wound cleansing, and bacterial clearance. In this case, the VAC device was excellent for temporary coverage of the defect and for wound cleaning, and it allowed a thick bed of granulation tissue to form over the dura, even with minimal constant negative pressure. The application and management were feasible even in a mentally disabled child. With this experience, we are encouraged to use the VAC device in difficult wounds, even in the head and neck area in children, and to bring this treatment into the outpatient clinic.
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http://dx.doi.org/10.1227/NEU.0b013e318210c7fbDOI Listing
May 2011

Efficacy and safety of propranolol as first-line treatment for infantile hemangiomas.

Eur J Pediatr 2011 Apr 9;170(4):493-501. Epub 2010 Oct 9.

Division of Plastic Surgery, University Children's Hospital Zurich, Zurich, Switzerland.

Unlabelled: Beta-blockers are a highly promising treatment modality for complicated infantile hemangiomas (IH). However, data on propranolol as first-line treatment, objective outcome measures and impact on hemodynamics in young infants is limited. We retrospectively evaluated a homogenous group of infants with proliferating complicated IH treated with propranolol (2 mg/kg/day). Outcome was assessed by blinded evaluation of clinical photographs by visual analogue scale (VAS), ultrasound examination and ophthalmological review (if appropriate). Tolerance and hemodynamic variables were recorded over time, including a 2-day in-patient observation at the initiation of therapy. Twenty-five infants (median age 3.6 (1.5-9.1) months) were included in the study. The median follow-up-time was 14 (9-20) months and 14 patients completed treatment at a median age of 14.3 (11.4-22.1) months, after a duration of 10.5 (7.5-16) months. In all patients, there was significant fading of colour (with a VAS of -9 (-6 to -9) after 7 months) and significant decrease in size of the IH (with a VAS of -8 (-3 to -10) after 7 months). Median thickness of the lesions assessed by ultrasound at baseline and after 1 month was 14 (7-28) mm and 10 (5-23) mm, respectively (p < 0.01). In children with periocular involvement, astigmatism and amblyopia resolved rapidly within 8 weeks. The overall tolerance of propranolol was good, and no relevant hemodynamic changes were noted.

Conclusion: Our report supports the excellent effect and good tolerance of this novel therapy, and we propose the use of propranolol as first-line treatment for IH.
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http://dx.doi.org/10.1007/s00431-010-1324-2DOI Listing
April 2011

Use of di(2-ethylhexyl)phthalate-containing infusion systems increases the risk for cholestasis.

Pediatrics 2009 Aug 27;124(2):710-6. Epub 2009 Jul 27.

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

Introduction: Most polyvinylchloride infusion systems are plasticized with up to 60% of di(2-ethylhexyl)phthalate (DEHP). DEHP is easily extracted from the tubing by total parenteral nutrition (TPN) solutions and has been shown to have toxic effects on various organ systems including the liver in animals and humans. A role was postulated for DEHP in the development of hepatobiliary dysfunction in premature and newborn infants receiving parenteral nutrition, and the incidence of cholestasis was investigated after changing from polyvinylchloride infusion systems to polyvinylchloride-free infusion systems.

Materials And Methods: Two 3-year periods from 1998 to 2004 were investigated retrospectively before and after changing from polyvinylchloride to polyvinylchloride-free infusion systems in our department. This resulted in 1 group of 30 patients treated with polyvinylchloride lines and a second group of 46 patients treated with polyvinylchloride-free lines. The 2 groups were examined for the incidence of cholestasis and other possible contributing factors. Statistics were performed by using SAS software (SAS Institute, Cary, NC).

Results: After changing infusion systems, the incidence of cholestasis dropped from 50% to 13%. Using DEHP-plasticized polyvinylchloride infusion systems for TPN increased the risk for cholestasis by a factor of 5.6. The use of polyvinylchloride lines correlated strongly with the development of TPN-associated cholestasis (P = .0004).

Conclusions: Using DEHP-containing polyvinylchloride infusions systems contributes to the development of cholestasis. Therefore, the use of DEHP-free infusion systems for TPN is recommended, especially in premature and newborn infants.
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http://dx.doi.org/10.1542/peds.2008-1765DOI Listing
August 2009

Early elective cesarean delivery before 36 weeks vs late spontaneous delivery in infants with gastroschisis.

J Pediatr Surg 2008 Jul;43(7):1342-6

Pediatric Surgery Department, Mannheim-Heidelberg University, Mannheim, Germany.

Purpose: The aim of this study is to assess the value of early elective cesarean delivery for patients with gastroschisis in comparison with late spontaneous delivery.

Methods: Analysis of infants with gastroschisis admitted between 1986 and 2006 at a tertiary care center was performed. The findings were analyzed statistically.

Results: Eighty-six patients were involved in the study. This included 15 patients who underwent emergency cesarean delivery (EM CD group) because of fetal distress and/or bowel ischemia. The remaining 71 patients born electively were stratified into 4 groups. The early elective cesarean delivery (ECD) group included 23 patients born by ECD before 36 weeks; late vaginal delivery (LVD) group included 23 patients who had LVD after 36 weeks; 24 patients had LCD after 36 weeks because of delayed diagnosis that resulted in late referral; and 1 patient had early spontaneous vaginal delivery (EVD group) before 36 weeks. The mean time to start oral feeding, incidence of complications, and primary closure were significantly better in the ECD group than in the LVD group. The duration of ventilation and the length of stay were shorter in ECD group, but the difference was not statistically significant.

Conclusion: Elective cesarean delivery before 36 weeks allows earlier enteral feeding and is associated with less complications and higher incidence of primary closure (statistically significant).
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http://dx.doi.org/10.1016/j.jpedsurg.2007.12.050DOI Listing
July 2008

Extraction of diethylhexylphthalate by home total parenteral nutrition from polyvinyl chloride infusion lines commonly used in the home.

J Pediatr Gastroenterol Nutr 2008 Jul;47(1):81-6

University Clinic of Pediatric Surgery, University of Marburg, Marburg, Germany.

Objectives: Recently, our group detected that polyvinyl chloride (PVC) perfusion lines leach large amounts of the toxic plasticizer diethylhexylphthalate (DEHP) under conditions typical of intensive care units. In the present study, we investigated the extraction of DEHP from PVC connecting tubes that are commonly used for total parenteral nutrition (TPN) solutions. The aim of the study was to estimate the amount of DEHP to which children receiving home TPN are exposed for months and years.

Materials And Methods: 1000 mL of TPN, identical in constitution and amount to the home TPN of 1 of our patients, were perfused through 5 different connecting tube systems and collected in hexane-rinsed glass bottles. The concentration of DEHP in the TPN was analyzed before and after perfusion.

Results: Before perfusion of the lines, the solution had a DEHP concentration of 0.05 to 0.69 microg/mL (baseline value). After perfusion of the lines, the load of DEHP in the solution varied between 1.41 and 2.07 microg/mL. This TPN was established for children weighing 20 kg. The daily dosage is between 71 and 104 microg x kg(-1) x day(-1). TPN is administered at home for many months and years. The monthly charge of DEHP is between 42.3 and 62.1 mg. Children weighing 20 kg therefore receive a dosage between 2.1 and 3.1 mg x kg(-1) x month(-1).

Conclusions: Diethylhexylphthalate and its metabolite monoethylhexylphthalate have been demonstrated to be carcinogenic, embryotoxic, hepatotoxic, pneumotoxic, and cardiotoxic and are known to disrupt endocrine pathways and liver detoxifying capacity in animals. They are suspected of having multiple effects in humans as well. The doses presented above should therefore be avoided in children receiving home TPN by the use of tubing systems that are completely free of DEHP. Such systems are available.
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http://dx.doi.org/10.1097/MPG.0b013e318164d933DOI Listing
July 2008

Diethylhexylphthalate extracted by typical newborn lipid emulsions from polyvinylchloride infusion systems causes significant changes in histology of rabbit liver.

JPEN J Parenter Enteral Nutr 2007 May-Jun;31(3):188-93

Clinic of Pediatric Surgery, University of Marburg, Germany.

Background: Looking for a candidate substance inducing hepatobiliary dysfunction under parenteral nutrition (PN) in newborns, we recently discovered that newborn infusions extract large amounts of the plasticizer diethylhexylphthalate (DEHP) from commonly used polyvinylchloride (PVC) infusion lines. This plasticizer is well known to be genotoxic and teratogenic in animals and to cause changes in various organs and enzyme systems even in humans. The aim of this study was to examine the effect of DEHP, extracted in the same way and in the same amount as in newborns, on livers of young rabbits.

Methods: Prepubertal rabbits received lipid emulsion through central IV lines continuously for 3 weeks either via PVC or polyethylene (PE) infusion systems. Livers were examined after 1 and 3 weeks by light and electron microscopy.

Results: By light microscopy, hydropic degeneration, single-cell necrosis, fibrosis, and bile duct proliferation were observed more in the PVC group. Electron microscopy revealed multiple nuclear changes, clusters and atypical forms of peroxisomes, proliferation of smooth endoplasmic reticulum, increased deposition of lipofuscin, and a mild perisinusoidal fibrosis only in the PVC group. These changes, which are generally regarded as reaction upon a toxic stimulus, could be exclusively attributed to DEHP.

Conclusions: This investigation proved that DEHP produces toxin-like changes in livers of young rabbits in the same dose, duration, and method of administration as in newborn infants. For this reason, it is likely that DEHP is the substance that causes hepatobiliary dysfunction in newborns under PN. Possible modes of action of DEHP are proposed.
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http://dx.doi.org/10.1177/0148607107031003188DOI Listing
June 2007

Extraction of the plasticizers diethylhexylphthalate and polyadipate from polyvinylchloride nasogastric tubes through gastric juice and feeding solution.

J Pediatr Gastroenterol Nutr 2007 Jan;44(1):71-6

University Clinic of Pediatric Surgery Mannheim, Germany.

Objectives: Except for polyadipate, which is used as an alternative in polyvinylchloride (PVC) feeding tubes, diethylhexylphthalate (DEHP) is the plasticizer used almost exclusively in PVC medical products. A clear response to the chronic intake of DEHP has been shown in several organ systems from different species. In the present study, we compared the extraction of DEHP and polyadipate from PVC gastric tubes.

Methods: An in vivo setting was simulated. We used 5 cm of PVC nasogastric tubes containing DEHP or polyadipate, which were incubated with gastric juice for 1 week and a feeding solution for 4 weeks. The leakage of these plasticizers was measured daily in the gastric juice group and weekly in the feeding solution group. The amount of plasticizer extracted was compared between groups and days.

Results: In the feeding solution group, the extraction of DEHP ranged from 200 to 542 microg after 1 week and from 660 to 1700 microg after 4 weeks. The extraction of polyadipate was 10 times lower than that of DEHP. In the gastric juice group, extracted DEHP ranged from 635 to 1043 microg, whereas the extraction of polyadipate was 100 times lower.

Conclusions: Within 1 week, the extraction of DEHP from a 5-cm PVC tube reaches up to 1 mg. Extrapolated, this represents an in vivo load of up to 4 mg. The load accumulated by a newborn in an intensive care unit can therefore easily reach several milligrams of DEHP per day. Polyadipate nasogastric tubes may therefore be an alternative and help to reduce the daily load of DEHP.
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http://dx.doi.org/10.1097/01.mpg.0000237939.50791.4bDOI Listing
January 2007

Kinetics of diethylhexyl-phthalate extraction From polyvinylchloride-infusion lines.

JPEN J Parenter Enteral Nutr 2002 Sep-Oct;26(5):305-9

Department of Pediatric Surgery, University Hospital Mannheim, University of Heidelberg, Germany.

Background: For infusion therapy, polyvinylchloride (PVC)-infusion lines are commonly used. In this study, we examined the temperature dependency and the dynamics of extraction in the time course of infusion.

Methods: PVC-infusion lines used on the newborn ICU were perfused with a typical 24-hour fat infusion. We collected the perfused solution and measured the concentration of DEHP. This procedure was carried out at 27 degrees C and 33 degrees C. In another experiment, we examined the extraction rate in the time course of a 24-hour infusion. The infusion was collected every 4 hours.

Results: We discovered that extraction of DEHP depends highly on the surrounding temperature. Whereas at 27 degrees C, the extraction of DEHP was 422.78 microg/mL, the leaching reached 540.78 microg/mL at 33 degrees C under otherwise identical conditions. This is important because the temperature on a newborn ICU is between 31 and 37 degrees C in an incubator. In the other experiment, we found out that the extraction rate rose from 25.44 microg/mL in the first 4 hours to 478.1 microg/mL after 24 hours.

Conclusions: The result of this study is that the actual daily load of DEHP for a 2-kg newborn is 30% higher than measured before. The rate of extraction is dependent on the time of contact between solution and tubing. If PVC-infusion systems are used, solutions should be as cold as possible, and infusion time should be as short as possible.
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http://dx.doi.org/10.1177/0148607102026005305DOI Listing
March 2003