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1. Does Breastmilk Influence the Development of Bronchopulmonary Dysplasia?

Author

Bendiks, Meike, Berghäuser, Martin A., Böckenholt, Kai, Bohnhorst, Bettina, Böttger, Ralf, Brune, Thomas, Dawczynski, Kristin, Dördelmann, Michael, Ehlers, Silke, Eichhorn, Joachim G., Felderhoff-Müser, Ursula, Franz, Axel, Gebauer, Corinna, Gerleve, Hubert, Göpel, Wolfgang, Gortner, Ludwig, Haase, Roland, Heitmann, Friedhelm, Hentschel, Roland, Hepping, Nico, Hillebrand, Georg, Höhn, Thomas, Hörnig-Franz, Isabelle, Hubert, Mechthild, Jenke, Andreas, Jensen, Rainer, Kannt, Olaf, Körner, Hans T., Kribs, Angela, Küster, Helmut, Linnemann, Knud, Möller, Jens, Müller, Andreas, Müller, Dirk, Olbertz, Dirk M., Orlikowsky, Thorsten, Reese, Jochen, Roll, Claudia, Rossi, Rainer, Rüdiger, Mario, Schaible, Thomas, Schiffmann, Jan-Holger, Schmidkte, Susanne, Seeliger, Stephan, Segerer, Hugo, Siegel, Jens, Teig, Norbert, Urlichs, Florian, Wense, Axel von der, Vochem, Matthias, Weller, Ursula, Wieg, Christian, Wintgens, Jürgen, Spiegler, Juliane, Preuß, Michael, and Herting, Egbert

Published
2016
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2. Assessment of retinopathy of prematurity regression and reactivation using an artificial intelligence–based vascular severity score

Author

Eilts, Sonja K., Pfeil, Johanna M., Poschkamp, Broder, Krohne, Tim U., Eter, Nicole, Barth, Teresa, Guthoff, Rainer, Lagrèze, Wolf, Grundel, Milena, Bründer, Marie-Christine, Busch, Martin, Kalpathy-Cramer, Jayashree, Chiang, Michael F., Chan, R. V. Paul, Coyner, Aaron S., Ostmo, Susan, Campbell, J. Peter, Stahl, Andreas, Pfeil, Johanna M, Bühler, Anima, Daniel, Moritz, Felzmann, Susanne, Gross, Nicolai, Horn, Stefanie, Lagrèze, Wolf A, Molnár, Fanni, Müller, Claudia, Reichl, Sabine, Reiff, Charlotte, Richter, Olga, Stech, Milena, Hentschel, Roland, Stavropolou, Dimitria, Tautz, Juliane, Bartsch, Kerstin, Braunstein, Jennifer, Brinken, Ralf, Brinkmann, Christian Karl, Czauderna, Joanna, Dralle, Wiebke, Gliem, Martin, Goebel, Arno, Heymer, Philipp, Hofmann, Martina, Holz, Frank G, Krohne, Tim U, Kupitz, David, Müller, Philipp, Petrak, Michael, Schmitz, Eva Janine, Schmitz-Valckenberg, Steffen, Schröder, Moritz, Steinberg, Julia, Supé, Julia, Kant, Evelyn, Kunze, Diana, Müller, Andreas, Adorf, Adeline, Alex, Anne, Alten, Florian, Clemens, Christoph R, Falkenau, Silvia, Friedhoff, Caroline, Loos, Desiree Sandra, Mihailovic, Natasa, Termühlen, Julia, Uhlig, Constantin, Hörnig-Franz, Isabell, Rieger-Fackeldey, Esther, Tekaat, Maria, Werner, Claudius, Altmann, Mathias, Blecha, Christiane, Brandl-Rühle, Sabine, Helbig, Horst, Hufendiek, Karsten, Jägle, Herbert, Konrad, Julia, Kopetzky, Eva, Lehmann, Fabian, Oberacher-Velten, Isabel, Keller-Wackerbauer, Annette, Kittel, Jochen, Segerer, Hugo, Ackermann, Phillip, Benga, Jemina, Guthoff, Tanja, Kleinert, Elena, Mayatepek, Ertan, Schrader, Stefan, Völker, Magdalena, Höhn, Thomas, Lohmeier, Klaus, Sabir, Hemmen, Brevis, Francisco, Mönig, Tina, Schwarz, Simone, Ehmer, Angela, Meltendorf, Synke, Schuart, Claudia, Avenarius, Stefan, Böttger, Ralf, Apel, Christoph, Bergmann, Anne, Herrmann, Karsten, Ockert-Schön, Franziska, Wegener, Sabine, Ehrt, Oliver, Nentwich, Martin, Pressler, Angelika, Rudolph, Günther, Genzel-Boroviczeny, Orsolya, Schmidt, Susanne, Münch, Hans-Georg, Thilmany, Claude, Aisenbrey, Sabine, Bruckmann, Anna, Dimopoulos, Spyridon, Hagemann, Ulrike, Inhoffen, Werner, Partsch, Michael, Schrader, Merle, Süsskind, Daniela, Völker, Michael, Bialkowski, Anja, Müller-Hansen, Ingo, Gerberth, Andrea, Hasselbach, Heike Christine, Lindemann, Solveig, Purtskhvanidze, Konstantine, Raffel, Yvonne, Roider, Johann, Schröder, Greta, Szymanek, Beke, Tode, Jan, Bendiks, Meike, Modlich, Simon, Jandeck, Isabel, Gerding, Heinrich, Smith, Lois E H, Eilts, Sonja K., Pfeil, Johanna M., Poschkamp, Broder, Krohne, Tim U., Eter, Nicole, Barth, Teresa, Guthoff, Rainer, Lagrèze, Wolf, Grundel, Milena, Bründer, Marie-Christine, Busch, Martin, Kalpathy-Cramer, Jayashree, Chiang, Michael F., Chan, R. V. Paul, Coyner, Aaron S., Ostmo, Susan, Campbell, J. Peter, Stahl, Andreas, Pfeil, Johanna M, Bühler, Anima, Daniel, Moritz, Felzmann, Susanne, Gross, Nicolai, Horn, Stefanie, Lagrèze, Wolf A, Molnár, Fanni, Müller, Claudia, Reichl, Sabine, Reiff, Charlotte, Richter, Olga, Stech, Milena, Hentschel, Roland, Stavropolou, Dimitria, Tautz, Juliane, Bartsch, Kerstin, Braunstein, Jennifer, Brinken, Ralf, Brinkmann, Christian Karl, Czauderna, Joanna, Dralle, Wiebke, Gliem, Martin, Goebel, Arno, Heymer, Philipp, Hofmann, Martina, Holz, Frank G, Krohne, Tim U, Kupitz, David, Müller, Philipp, Petrak, Michael, Schmitz, Eva Janine, Schmitz-Valckenberg, Steffen, Schröder, Moritz, Steinberg, Julia, Supé, Julia, Kant, Evelyn, Kunze, Diana, Müller, Andreas, Adorf, Adeline, Alex, Anne, Alten, Florian, Clemens, Christoph R, Falkenau, Silvia, Friedhoff, Caroline, Loos, Desiree Sandra, Mihailovic, Natasa, Termühlen, Julia, Uhlig, Constantin, Hörnig-Franz, Isabell, Rieger-Fackeldey, Esther, Tekaat, Maria, Werner, Claudius, Altmann, Mathias, Blecha, Christiane, Brandl-Rühle, Sabine, Helbig, Horst, Hufendiek, Karsten, Jägle, Herbert, Konrad, Julia, Kopetzky, Eva, Lehmann, Fabian, Oberacher-Velten, Isabel, Keller-Wackerbauer, Annette, Kittel, Jochen, Segerer, Hugo, Ackermann, Phillip, Benga, Jemina, Guthoff, Tanja, Kleinert, Elena, Mayatepek, Ertan, Schrader, Stefan, Völker, Magdalena, Höhn, Thomas, Lohmeier, Klaus, Sabir, Hemmen, Brevis, Francisco, Mönig, Tina, Schwarz, Simone, Ehmer, Angela, Meltendorf, Synke, Schuart, Claudia, Avenarius, Stefan, Böttger, Ralf, Apel, Christoph, Bergmann, Anne, Herrmann, Karsten, Ockert-Schön, Franziska, Wegener, Sabine, Ehrt, Oliver, Nentwich, Martin, Pressler, Angelika, Rudolph, Günther, Genzel-Boroviczeny, Orsolya, Schmidt, Susanne, Münch, Hans-Georg, Thilmany, Claude, Aisenbrey, Sabine, Bruckmann, Anna, Dimopoulos, Spyridon, Hagemann, Ulrike, Inhoffen, Werner, Partsch, Michael, Schrader, Merle, Süsskind, Daniela, Völker, Michael, Bialkowski, Anja, Müller-Hansen, Ingo, Gerberth, Andrea, Hasselbach, Heike Christine, Lindemann, Solveig, Purtskhvanidze, Konstantine, Raffel, Yvonne, Roider, Johann, Schröder, Greta, Szymanek, Beke, Tode, Jan, Bendiks, Meike, Modlich, Simon, Jandeck, Isabel, Gerding, Heinrich, and Smith, Lois E H

Published
2023

7. Does Breastmilk Influence the Development of Bronchopulmonary Dysplasia?

Author

Spiegler, Juliane, Preu, Michael, Gebauer, Corinna, Bendiks, Meike, Herting, Egbert, Göpel, Wolfgang, Berghäuser, Martin A., Böckenholt, Kai, Bohnhorst, Bettina, Böttger, Ralf, Brune, Thomas, Dawczynski, Kristin, Dördelmann, Michael, Ehlers, Silke, Eichhorn, Joachim G., Felderhoff-Müser, Ursula, Franz, Axel, Gerleve, Hubert, Göpel, Wolfgang, Gortner, Ludwig, Haase, Roland, Heitmann, Friedhelm, Hentschel, Roland, Hepping, Nico, Hillebrand, Georg, Höhn, Thomas, Hörnig-Franz, Isabelle, Hubert, Mechthild, Jenke, Andreas, Jensen, Rainer, Kannt, Olaf, Körner, Hans T., Kribs, Angela, Küster, Helmut, Linnemann, Knud, Möller, Jens, Müller, Andreas, Müller, Dirk, Olbertz, Dirk M., Orlikowsky, Thorsten, Reese, Jochen, Roll, Claudia, Rossi, Rainer, Rüdiger, Mario, Schaible, Thomas, Schiffmann, Jan-Holger, Schmidkte, Susanne, Seeliger, Stephan, Segerer, Hugo, Siegel, Jens, Teig, Norbert, Urlichs, Florian, von der Wense, Axel, Vochem, Matthias, Weller, Ursula, Wieg, Christian, and Wintgens, Jürgen

Published
2016
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10. Comparing alternative ranibizumab dosages for safety and efficacy in retinopathy of prematurity : a randomized clinical trial

Author

Stahl, Andreas, Krohne, Tim U., Eter, Nicole, Oberacher-Velten, Isabel, Guthoff, Rainer, Meltendorf, Synke, Ehrt, Oliver, Aisenbrey, Sabine, Roider, Johann, Gerding, Heinrich, Jandeck, Claudia, Smith, Lois E. H., Walz, Johanna M., Bühler, Anima, Daniel, Moritz, Felzmann, Susanne, Gross, Nicolai, Horn, Stefanie, Lagrèze, Wolf, Molnár, Fanni, Müller, Claudia, Reichl, Sabine, Reiff, Charlotte, Richter, Olga, Stech, Milena, Hentschel, Roland, Stavropolou, Dimitria, Tautz, Juliane, Bartsch, Kerstin, Braunstein, Jennifer, Brinken, Ralf, Brinkmann, Christian Karl, Czauderna, Joanna, Dralle, Wiebke, Gliem, Martin, Goebel, Arno, Heymer, Philipp, Hofmann, Martina, Holz, Frank G., Kupitz, David, Müller, Philipp, Petrak, Michael, Schmitz, Eva Janine, Schmitz-Valckenberg, Steffen, Schröder, Moritz, Steinberg, Julia, Supé, Julia, Kant, Evelyn, Kunze, Diana, Müller, Andreas, Adorf, Adeline, Alex, Anne, Alten, Florian, Clemens, Christoph R., Falkenau, Silvia, Friedhoff, Caroline, Loos, Desiree Sandra, Mihailovic, Natasa, Termühlen, Julia, Uhlig, Constantin, Hörnig-Franz, Isabell, Rieger-Fackeldey, Esther, Tekaat, Maria, Werner, Claudius, Altmann, Mathias, Barth, Theresa, Blecha, Christiane, Brandl-Rühle, Sabine, Helbig, Horst, Hufendiek, Karsten, Jägle, Herbert, Konrad, Julia, Kopetzky, Eva, Lehmann, Fabian, Keller-Wackerbauer, Annette, Kittel, Jochen, Segerer, Hugo, Ackermann, Phillip, Benga, Jemina, Guthoff, Tanja, Kleinert, Elena, Mayatepek, Ertan, Schrader, Stefan, Völker, Magdalena, Höhn, Thomas, Lohmeier, Klaus, Sabir, Hemmen, Brevis, Francisco, Mönig, Tina, Schwarz, Simone, Ehmer, Angela, Schuart, Claudia, Avenarius, Stefan, Böttger, Ralf, Apel, Christoph, Bergmann, Anne, Herrmann, Karsten, Ockert-Schön, Franziska, Wegener, Sabine, Nentwich, Martin, Pressler, Angelika, Rudolph, Günther, Genzel-Boroviczeny, Orsolya, Schmidt, Susanne, Münch, Hans-Georg, Thilmany, Claude, Bruckmann, Anna, Dimopoulos, Spyridon, Hagemann, Ulrike, Inhoffen, Werner, Partsch, Michael, Schrader, Merle, Süsskind, Daniela, Völker, Michael, Bialkowski, Anja, Müller-Hansen, Ingo, Gerberth, Andrea, Hasselbach, Heike Christine, Lindemann, Solveig, Purtskhvanidze, Konstantine, Raffel, Yvonne, Schröder, Greta, Szymanek, Beke, Tode, Jan, Bendiks, Meike, and Modlich, Simon

Subjects
Male, Vascular Endothelial Growth Factor A, medicine.medical_specialty, genetic structures, Bevacizumab, Medizin, Angiogenesis Inhibitors, Pilot Projects, law.invention, 03 medical and health sciences, 0302 clinical medicine, Double-Blind Method, Randomized controlled trial, law, Germany, Ranibizumab, Internal medicine, Clinical endpoint, Humans, Medicine, Retinopathy of Prematurity, Dosing, Original Investigation, Dose-Response Relationship, Drug, business.industry, Standard treatment, Infant, Newborn, Retinopathy of prematurity, Odds ratio, medicine.disease, Treatment Outcome, Pediatrics, Perinatology and Child Health, 030221 ophthalmology & optometry, Female, business, 030217 neurology & neurosurgery, medicine.drug
Abstract

Importance Anti–vascular endothelial growth factor (VEGF) therapies are a novel treatment option in retinopathy of prematurity (ROP). Data on dosing, efficacy, and safety are insufficient. Objective To investigate lower doses of anti-VEGF therapy with ranibizumab, a substance with a significantly shorter systemic half-life than the standard treatment, bevacizumab. Design, Setting, and Participants This randomized, multicenter, double-blind, investigator-initiated trial at 9 academic medical centers in Germany compared ranibizumab doses of 0.12 mg vs 0.20 mg in infants with bilateral aggressive posterior ROP; ROP stage 1 with plus disease, 2 with plus disease, or 3 with or without plus disease in zone I; or ROP stage 3 with plus disease in posterior zone II. Patients were recruited between September 2014 and August 2016. Twenty infants were screened and 19 were randomized. Interventions All infants received 1 baseline ranibizumab injection per eye. Reinjections were allowed in case of ROP recurrence after at least 28 days. Main Outcomes and Measures The primary end point was the number of infants who did not require rescue therapy at 24 weeks. Key secondary end points included time-to-event analyses, progression of physiologic vascularization, and plasma VEGF levels. Stages of ROP were photodocumented and reviewed by an expert committee. Results Nineteen infants with ROP were enrolled (9 [47.4%] female; median [range] postmenstrual age at first treatment, 36.4 [34.7-39.7] weeks), 3 of whom died during the study (1 in the 0.12-mg group and 2 in the 0.20-mg group). Of the surviving infants, 8 (88.9%) (17 eyes [94.4%]) in the 0.12-mg group and 6 (85.7%) (13 eyes [92.9%]) in the 0.20-mg group did not require rescue therapy. Both ranibizumab doses were equally successful in controlling acute ROP (Cochran-Mantel-Haenszel analysis; odds ratio, 1.88; 95% CI, 0.26-13.49;P = .53). Physiologic intraretinal vascularization was superior in the 0.12-mg group. The VEGF plasma levels were not systematically altered in either group. Conclusions and Relevance This pilot study demonstrates that ranibizumab is effective in controlling acute ROP and that 24% of the standard adult dose (0.12 mg) appears equally effective as 40% (0.20 mg). Superior vascularization of the peripheral retina with 0.12 mg of ranibizumab indicates that the lower dose may be favorable. Unchanged plasma VEGF levels point toward a limited systemic drug exposure after ranibizumab. Trial Registration clinicaltrials.gov Identifier:NCT02134457and clinicaltrialsregister.eu Identifier:2013-002539-13.

Published
2018

11. Preterm prelabor rupture of membranes and outcome of very-low-birth-weight infants in the German Neonatal Network

Author

Hanke, Kathrin, Hartz, Annika, von der Wense, Axel, Wieg, Christian, Kribs, Angela, Stein, Anja, Pagel, Julia, Herting, Egbert, Göpel, Wolfgang, Härtel, Christoph, German Neonatal Network (GNN), Avenarius, Stefan, Manz, Maike, Bockenholt, Kai, Bohnhorst, Bettina, Dördelmann, Michael, Ehlers, Silke, Gerleve, Hubert, Gortner, Ludwig, Groneck, Peter, Hillebrand, Georg, Hoehn, Thomas, Hubert, Mechthild, Bendiks, Meike, Hummler, Helmut, Jenke, Andreas, Jensen, Reinhard, Kannt, Olaf, Küster, Helmut, Laux, Reinhard, Lieser, Ursula, Mögel, Michael, Möller, Jens, Müller, Dirk, Heitmann, Friedhelm, Reese, Jochen, Roll, Claudia, Schaible, Thomas, Seeliger, Stefan, Segerer, Hugo, Teig, Norbert, Weller, Ursula, Vochem, Matthias, Wintgens, Jürgen, Orlikowsky, Thorsten, Müller, Andreas, Olbertz, Dirk, Kühn, Thomas, and Siegel, Jens

Subjects
medicine.medical_specialty, Pediatrics, Fetal Membranes, Premature Rupture, Birth weight, Population, Medizin, lcsh:Medicine, Cohort Studies, Pregnancy, Germany, medicine, Rupture of membranes, Humans, Infant, Very Low Birth Weight, Mortality, education, lcsh:Science, education.field_of_study, Multidisciplinary, Placental abruption, Obstetrics, business.industry, lcsh:R, Infant, Newborn, Gestational age, medicine.disease, Low birth weight, Logistic Models, Bronchopulmonary dysplasia, Premature Birth, Multiple birth, lcsh:Q, Female, medicine.symptom, business, Research Article
Abstract

PLoS ONE 10(4), e0122564 (2015). doi:10.1371/journal.pone.0122564, Published by PLoS, Lawrence, Kan.

Published
2014
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15. Preterm Prelabor Rupture of Membranes and Outcome of Very-Low-Birth-Weight Infants in the German Neonatal Network.

Author

Hanke, Kathrin, Hartz, Annika, Manz, Maike, Bendiks, Meike, Heitmann, Friedhelm, Orlikowsky, Thorsten, Müller, Andreas, Olbertz, Dirk, Kühn, Thomas, Siegel, Jens, von der Wense, Axel, Wieg, Christian, Kribs, Angela, Stein, Anja, Pagel, Julia, Herting, Egbert, Göpel, Wolfgang, Härtel, Christoph, and null, null

Subjects
HEALTH outcome assessment, PREMATURE infants, LOW birth weight, EPIDEMIOLOGY, LIVER enzymes, REGRESSION analysis
Abstract

Objective: It was the aim of our study to evaluate the independent effect of preterm prelabor rupture of membranes (PPROM) as a cause of preterm delivery on mortality during primary hospital stay and significant morbidities in very-low-birth-weight (VLBW) infants < 32 weeks of gestation. Design: Observational, epidemiological study design. Setting: Population-based cohort, German Neonatal Network (GNN). Population: 6102 VLBW infants were enrolled in GNN from 2009-2012, n=4120 fulfilled criteria for primary analysis (< 32 gestational weeks, no pre-eclampsia, HELLP (highly elevated liver enzymes and low platelets syndrome) or placental abruption as cause of preterm birth). Methods: Multivariable logistic regression analyses included PPROM as potential risk factors for adverse outcomes and well established items such as gestational age in weeks, birth weight, antenatal steroids, center, inborn delivery, multiple birth, gender and being small-for-gestational-age. Results: PPROM as cause of preterm delivery had no independent effect on the risk of early-onset sepsis, clinical sepsis and blood-culture proven sepsis, while gestational age proved to be the most important contributor to sepsis risk. The diagnosis of PPROM was associated with an increased risk for bronchopulmonary dysplasia (BPD; OR: 1.25, 95% CI: 1.02-1.55, p=0.03) but not with other major outcomes. Conclusions: The diagnosis of PPROM per se is not associated with adverse outcome in VLBW infants < 32 weeks apart from a moderately increased risk for BPD. Randomized controlled trials with primary neonatal outcomes are needed to determine which subgroup of VLBW infants benefit from expectant or intentional management of PPROM. [ABSTRACT FROM AUTHOR]

Published
2015
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16. Intrauterine Growth Restriction and the Innate Immune System in Preterm Infants of ≤32 Weeks Gestation.

Author

Tröger, Birte, Müller, Thilo, Faust, Kirstin, Bendiks, Meike, Bohlmann, Michael K., Thonnissen, Susanne, Herting, Egbert, Göpel, Wolfgang, and Härtel, Christoph

Subjects
PREMATURE infant diseases, FETAL growth retardation, IMMUNE system, IMMUNE response, GESTATIONAL age, CYTOKINES
Abstract

Objective: Intrauterine growth restriction (IUGR) is a well-known cause of adverse neonatal outcomes. As it may have an impact on innate immune responses, we aimed to investigate several parameters of the innate immune response in preterm infants of ≤32 weeks gestation who were small for gestational age (SGA). Methods: We compared clinical data of SGA (n = 20) and appropriate for gestational age (AGA; n = 124) newborns with a gestational age of ≤32 weeks. We investigated full blood counts at birth and on days 3 and 7 of life and cytokine immune responses in a human whole cord blood assay. Results: SGA preterm infants had a higher risk of the combined outcome mortality or bronchopulmonary dysplasia. Numbers of white blood cells and neutrophils were diminished in SGA infants at birth and on day 3. At birth, platelet counts were also diminished while the number of nucleated red blood cells tended to be elevated in SGA infants. After stimulation of whole blood cell cultures with lipopolysaccharides, the concentrations of interleukin-6 and interleukin-10 were significantly lower in SGA preterm infants compared to AGA infants. Conclusions: SGA infants differ remarkably from AGA infants in full blood counts and in their ability to mount an immune response. Whether the quantitative deficiency in innate immunity plays a role for adverse outcomes needs to be investigated in larger future trials. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Published
2013
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17. Innate immune responses to Stenotrophomonas maltophiliain immunocompromised pediatric patients and the effect of taurolidine

Author

Härtel, Christoph, Scholz, Tasja, Kuhn, Marie, Bendiks, Meike, Göpel, Wolfgang, Lauten, Melchior, and Herting, Egbert

Abstract

Stenotrophomonas maltophiliais an emerging pathogen causing invasive infections in immunocompromised pediatric patients, including neonates and pediatric oncology patients. Information on innate immune responses to S. maltophiliaand its potential modulation are scarce.

Published
2013
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18. Efficient Mitochondrial Import of Newly Synthesized Ornithine Transcarbamylase (OTC) and Correction of Secondary Metabolic Alterations in spfashMice following Gene Therapy of OTC Deficiency

Author

Zimmer, Klaus Peter, Bendiks, Meike, Mori, Masataka, Kominami, Eiki, Robinson, Michael B., Ye, Xuehai, and Wilson, James M.

Abstract

Background: The mouse strain sparse fur with abnormal skin and hair (spfash) is a model for the human ornithine transcarbamylase (OTC) deficiency, an X-linked inherited urea cycle disorder. The spfashmouse carries a single base-pair mutation in the OTC gene that leads to the production of OTC enzyme at 10% of the normal level. Materials and Methods: Recombinant adenoviruses carrying either mouse (Ad.mOTC) or human (Ad.hOTC) OTC cDNA were injected intravenously into the spfashmice. Expression of OTC enzyme precursor and its translocation to mitochondria in the vector-transduced hepatocytes were analyzed on an ultrastructural level. Liver OTC activity and mitochondrial OTC concentration were significantly increased (300% of normal) in mice treated with Ad.mOTC and were moderately increased in mice receiving Ad.hOTC (34% of normal). The concentration and subcellular location of OTC and associated enzymes were studied by electron microscope immunolocalization and quantitative morphometry. Results: Cytosolic OTC concentration remained unchanged in Ad.mOTC-injected mice but was significantly increased in mice receiving Ad.hOTC, suggesting a block of mitochondria translocation for the human OTC precursor. Mitochondrial ATPase subunit c [ATPase(c)] was significantly reduced and mitochondrial carbamyΔphosphate synthetase I (CPSI) was significantly elevated in spfashmice relative to C3H. In Ad.mOTC-treated mice, the hepatic mitochondrial concentration of ATPase(c) was completely normalized and the CPSI concentration was partially corrected. Conclusions: Taken together, we conclude that newly synthesized mouse OTC enzyme was efficiently imported into mitochondria following vector-mediated gene delivery in spfashmice, correcting secondary metabolic alterations.

Published
1999
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