Children admitted to a pediatric intensive care unit (ICU) are at high risk of developing acute k... more Children admitted to a pediatric intensive care unit (ICU) are at high risk of developing acute kidney injury (AKI). Although used in clinical practice, serum creatinine (SCr) is insensitive for early diagnosing AKI. Urinary neutrophil gelatinase-associated lipocalin (uNGAL) and kidney injury molecule-1 (KIM-1) are novel AKI biomarkers of which the performance in pediatric ICU patients is largely unknown. We aimed to characterize uNGAL and KIM-1 patterns in children following ICU admission and to assess their properties to identify children at risk for AKI development. From June 2010 until January 2014 we conducted a prospective observational cohort study of term-born children aged one day to one year on mechanical ventilation. Blood and urine samples were obtained every 6 to 12 hours up to 72 hours post-admission. Blood samples were assayed for SCr; urine samples for uNGAL and KIM-1. The RIFLE classification (Risk, Injury, or Failure as 150%, 200% or 300% of median SCr reference va...
One of the most difficult ethical dilemmas in pediatrics today arises when a child has complex ch... more One of the most difficult ethical dilemmas in pediatrics today arises when a child has complex chronic conditions that are not curable and cause discomfort with no prospect of any improvement on quality of life. In the context of medical futility, it is harmful to prolong medical treatment. The question is: How can medical treatment be discontinued when the child is not dependent on mechanical ventilation or ICU treatment? What is the appropriate palliative care and does it justify the use of sedatives or analgesics if this also might shorten life?
This article places focus on three main subjects that are all related to the ethical aspects of c... more This article places focus on three main subjects that are all related to the ethical aspects of care of newborns undergoing major surgical interventions. The first concerns the communication between the surgeon, as a representative of the treatment team, and the parents. The second is the way to handle new developments in neonatal surgery. The third issue covers several aspects of the ethical decision-making process with regard to forgoing life support in surgical neonates. These issues will be discussed on the basis of two clinical case reports.
Clinical journal of the American Society of Nephrology : CJASN, Jan 5, 2014
Many children receiving extracorporeal membrane oxygenation develop AKI. If AKI leads to permanen... more Many children receiving extracorporeal membrane oxygenation develop AKI. If AKI leads to permanent nephron loss, it may increase the risk of developing CKD. The prevalence of CKD and hypertension and its predictive factors during long-term follow-up of children and adolescents previously treated with neonatal extracorporeal membrane oxygenation were determined. Between November of 2010 and February of 2014, neonatal survivors of extracorporeal membrane oxygenation who visited the prospective follow-up program at 1, 2, 5, 8, 12, and 18 years of age were screened for CKD and hypertension (BP≥95th percentile of reference values). CKD was suspected in children with either an eGFR<90 ml/min per 1.73 m(2) or proteinuria (urinary protein-to-creatinine ratio >0.50 for children ages ≤24 months and >0.20 at >24 months). The RIFLE classification (risk, injury, or failure as 150%, 200%, or 300% of serum creatinine reference values) was used to define AKI during extracorporeal membra...
To assess longitudinally children's motor performance 5 to 12 years after neonatal extracorpo... more To assess longitudinally children's motor performance 5 to 12 years after neonatal extracorporeal membrane oxygenation (ECMO) and to evaluate associations between clinical characteristics and motor performance. Two hundred fifty-four neonatal ECMO survivors in the Netherlands were tested with the Movement Assessment Battery for Children at 5, 8, and/or 12 years. Percentile scores were transformed to z scores for longitudinal evaluation (norm population mean = 0 and SD = 1). Primary diagnoses: meconium aspiration syndrome (n = 137), congenital diaphragmatic hernia (n = 49), persistent pulmonary hypertension of the newborn (n = 36), other diagnoses (n = 32). Four hundred fifty-six tests were analyzed. At 5, 8, and 12 years motor performance was normal in 73.7, 74.8, and 40.5%, respectively (vs 85% expected based on reference values; P < .001 at all ages). In longitudinal analyses mean (95% confidence interval [CI]) z scores were -0.42 (-0.55 to -0.28), -0.25 (-0.40 to -0.10) an...
Drug metabolism and disposition: the biological fate of chemicals, 2014
Many drugs prescribed to children are drug transporter substrates. Drug transporters are membrane... more Many drugs prescribed to children are drug transporter substrates. Drug transporters are membrane-bound proteins that mediate the cellular uptake or efflux of drugs and are important to drug absorption and elimination. Very limited data are available on the effect of age on transporter expression. Our study assessed age-related gene expression of hepatic and intestinal drug transporters. Multidrug resistance protein 2 (MRP2), organic anion transporting polypeptide 1B1 (OATP1B1), and OATP1B3 expression was determined in postmortem liver samples (fetal n = 6, neonatal n = 19, infant n = 7, child n = 2, adult n = 11) and multidrug resistance 1 (MDR1) expression in 61 pediatric liver samples. Intestinal expression of MDR1, MRP2, and OATP2B1 was determined in surgical small bowel samples (neonates n = 15, infants n = 3, adults n = 14). Using real-time reverse-transcription polymerase chain reaction, we measured fetal and pediatric gene expression relative to 18S rRNA (liver) and villin (...
Archives of pediatrics & adolescent medicine, 2003
Despite an increasing awareness regarding pain management in neonates and the availability of pub... more Despite an increasing awareness regarding pain management in neonates and the availability of published guidelines for the treatment of procedural pain, preterm neonates experience pain leading to short- and long-term detrimental effects. To assess the frequency of use of analgesics in invasive procedures in neonates and the associated pain burden in this population. For 151 neonates, we prospectively recorded all painful procedures, including the number of attempts required, and analgesic therapy used during the first 14 days of neonatal intensive care unit admission. These data were linked to estimates of the pain of each procedure, obtained from the opinions of experienced clinicians. On average, each neonate was subjected to a mean +/- SD of 14 +/- 4 procedures per day. The highest exposure to painful procedures occurred during the first day of admission, and most procedures (63.6%) consisted of suctioning. Many procedures (26 of 31 listed on a questionnaire) were estimated to b...
We present a case study of a 10-year-old child with severe burns that were misinterpreted as infl... more We present a case study of a 10-year-old child with severe burns that were misinterpreted as inflicted burns. Because of multiple injuries since early life, the family was under suspicion of child abuse and therefore under supervision of the Child Care Board for 2 years before the boy was burned. Because the boy incurred the burns without feeling pain, we conducted a thorough medical examination and laboratory testing, evaluated detection and pain thresholds, and used MRI to study brain morphology and brain activation patterns during pain between this patient and 3 healthy age- and gender-matched controls. We found elevated detection and pain thresholds and lower brain activation during pain in the patient compared with the healthy controls and reference values. The patient received the diagnosis of hereditary sensory and autonomic neuropathy type IV on the basis of clinical findings and the laboratory testing, complemented with the altered pain and detection thresholds and MRI find...
European Journal of Obstetrics & Gynecology and Reproductive Biology, 2014
To investigate the relation between prenatal ultrasound measurements of viscero-abdominal disprop... more To investigate the relation between prenatal ultrasound measurements of viscero-abdominal disproportion and the expected type of postnatal surgical closure of an omphalocele. Retrospectively, 24 fetuses diagnosed with an isolated omphalocele in the 2nd trimester of pregnancy were selected (period 2003-2013). An image of the axial plane of the abdomen at the level of the defect was retrieved. The ratio of omphalocele circumference to abdominal circumference (OC/AC), and the ratio of defect diameter to abdominal diameter (DD/DA) were calculated. Prognostic outcome was primary closure. Sensitivity and specificity and the corresponding area under the ROC curve of these ratios were calculated as measurements of prognostic accuracy. Primary closure was achieved in 15/24 cases. For the OC/AC-ratio a cut-off value of 0.82 successfully predicted outcome in 23/24 cases with an area under the ROC curve of 0.99. A cut-off value of 0.61 for the DD/DA-ratio successfully predicted type of closure in 20/24 cases with an area under the ROC curve of 0.88. In all cases without eviscerated liver tissue, the defect was primarily closed. In prenatal isolated omphalocele cases, the OC/AC-ratio is better at predicting postnatal surgical closure than the DD/DA-ratio and can be used as a prognostic tool for expected type of closure in the 2nd trimester of pregnancy.
Esophageal Atresia (EA) is a severe developmental defect of the foregut that presents with or wit... more Esophageal Atresia (EA) is a severe developmental defect of the foregut that presents with or without a Tracheo-Esophageal Fistula (TEF). The prevalence of EA/TEF over time and around the world has been relatively stable. EA/TEF is manifested in a broad spectrum of anomalies: in some patients it manifests as an isolated atresia or fistula, but in over half it affects several organ systems. While the associated malformations are often those of the VACTERL spectrum (Vertebral, Anorectal, Cardiac, Tracheo-Esophageal, Renal and Limb), many patients are affected by other malformations, such as microcephaly, micrognathia, pyloric stenosis, duodenal atresia, a single umbilical artery, and anomalies of the genitourinary, respiratory and gastrointestinal systems. Though EA/TEF is a genetically heterogeneous condition, recurrent genes and loci are sometimes affected. Tracheo-Esophageal (TE) defects are in fact a variable feature in several known single gene disorders and in patients with specific recurrent Copy Number Variations and structural chromosomal aberrations. At present, a causal genetic aberration can be identified in 11-12% of patients. In most, EA/TEF is a sporadic finding; the familial recurrence rate is low (1%). As this suggests that epigenetic and environmental factors also contribute to the disease, non-syndromic EA/TEF is generally believed to be a multifactorial condition. Several population-based studies and case reports describe a wide range of associated risks, including age, diabetes, drug use, herbicides, smoking and fetal alcohol exposure. The phenotypical and genetic heterogeneity seen in EA/TEF patients indicates not one underlying cause, but several. Unraveling the complex multifactorial and heterogeneous etiology of EA/TEF and associated features will require large cohorts of patients. Combined statistical analysis of component findings, genome sequencing, and genome wide association studies will elucidate new causal genetic defects and predisposing loci in the etiology within specific sub-populations. Improved knowledge of environmental risk factors, genetic predisposition and causal genetic syndromes may improve prediction and parental counseling, and prevent co-morbidity.
A retrospective analysis of the prognostic significance of the lung-to-head ratio (LHR) and other... more A retrospective analysis of the prognostic significance of the lung-to-head ratio (LHR) and other prenatal parameters on the outcome of fetuses with left-sided congenital diaphragmatic hernia (CDH). A total of 26 fetuses with isolated left CDH without chromosomal abnormalities were included. Twenty-one LHR measurements could retrospectively be calculated from the last available ultrasonographic recordings before birth. The relationship between LHR and fetal outcome and the gestational age dependency of this relation was tested. Cutoff levels as previously published were applied to determine their predictive value in this population. The association between other prenatal predictive variables and fetal outcome was also determined. Survival was defined as discharge from the hospital. The overall survival rate was 50%. There was a statistically significant difference between the mean LHR of the survivors compared to the mean LHR of the nonsurvivors (1.78 vs 1.02), whereas the mean gestational age of these two groups did not differ. LHR was not gestational age dependent in the prediction of fetal outcome. The cutoff levels LHR &amp;amp;lt;1, 1-1.4, &amp;amp;gt;1.4 showed a good applicability in the prediction of fetal outcome within the present study population with a 100% survival if LHR &amp;amp;gt;1.4 and a 100% mortality if LHR &amp;amp;lt;1. An intrathoracic position of the stomach, mediastinal shift, polyhydramnios as individual variables and early diagnosis (&amp;amp;lt;25 weeks&amp;amp;#39; gestation) revealed to be poor sonographic predictors for fetal outcome. LHR proved to be a good predictor for fetal outcome, independent of gestational age at the time of the measurement. To substantiate our observation, a prospective multicenter study is warranted.
Ghrelin is a strong physiologic growth hormone secretagogue that exhibits endocrine and non-endoc... more Ghrelin is a strong physiologic growth hormone secretagogue that exhibits endocrine and non-endocrine actions. In this study, ghrelin expression in humans and rats was evaluated throughout development of normal and hypoplastic lungs associated with congenital diaphragmatic hernia (CDH). Additionally, the effect of antenatal treatment with ghrelin in the nitrofen-induced CDH rat model was tested. In normal lungs, ghrelin was expressed in the primitive epithelium at early stages of development and decreased in levels of expression with gestational age. In hypoplastic lungs ghrelin was overexpressed in both human and rat CDH fetuses when compared with controls. Exogenous administration of ghrelin to nitrofen-treated dams led to an attenuation of pulmonary hypoplasia of CDH pups. Furthermore, the growth hormone, secretagogue receptor (GHSR1a), could not be amplified from human or rat fetal lungs by RT-PCR. In conclusion, of all the lungs studied so far, the fetal lung is one of the first to express ghrelin during development and might be considered a new source of circulating fetal ghrelin. Overexpression of ghrelin in hypoplastic lungs and the effect of exogenous administration of ghrelin to nitrofen-treated dams strongly suggest a role for ghrelin in mechanisms involved in attenuation of fetal lung hypoplasia, most likely through a GHSR1a-independent pathway.
Children admitted to a pediatric intensive care unit (ICU) are at high risk of developing acute k... more Children admitted to a pediatric intensive care unit (ICU) are at high risk of developing acute kidney injury (AKI). Although used in clinical practice, serum creatinine (SCr) is insensitive for early diagnosing AKI. Urinary neutrophil gelatinase-associated lipocalin (uNGAL) and kidney injury molecule-1 (KIM-1) are novel AKI biomarkers of which the performance in pediatric ICU patients is largely unknown. We aimed to characterize uNGAL and KIM-1 patterns in children following ICU admission and to assess their properties to identify children at risk for AKI development. From June 2010 until January 2014 we conducted a prospective observational cohort study of term-born children aged one day to one year on mechanical ventilation. Blood and urine samples were obtained every 6 to 12 hours up to 72 hours post-admission. Blood samples were assayed for SCr; urine samples for uNGAL and KIM-1. The RIFLE classification (Risk, Injury, or Failure as 150%, 200% or 300% of median SCr reference va...
One of the most difficult ethical dilemmas in pediatrics today arises when a child has complex ch... more One of the most difficult ethical dilemmas in pediatrics today arises when a child has complex chronic conditions that are not curable and cause discomfort with no prospect of any improvement on quality of life. In the context of medical futility, it is harmful to prolong medical treatment. The question is: How can medical treatment be discontinued when the child is not dependent on mechanical ventilation or ICU treatment? What is the appropriate palliative care and does it justify the use of sedatives or analgesics if this also might shorten life?
This article places focus on three main subjects that are all related to the ethical aspects of c... more This article places focus on three main subjects that are all related to the ethical aspects of care of newborns undergoing major surgical interventions. The first concerns the communication between the surgeon, as a representative of the treatment team, and the parents. The second is the way to handle new developments in neonatal surgery. The third issue covers several aspects of the ethical decision-making process with regard to forgoing life support in surgical neonates. These issues will be discussed on the basis of two clinical case reports.
Clinical journal of the American Society of Nephrology : CJASN, Jan 5, 2014
Many children receiving extracorporeal membrane oxygenation develop AKI. If AKI leads to permanen... more Many children receiving extracorporeal membrane oxygenation develop AKI. If AKI leads to permanent nephron loss, it may increase the risk of developing CKD. The prevalence of CKD and hypertension and its predictive factors during long-term follow-up of children and adolescents previously treated with neonatal extracorporeal membrane oxygenation were determined. Between November of 2010 and February of 2014, neonatal survivors of extracorporeal membrane oxygenation who visited the prospective follow-up program at 1, 2, 5, 8, 12, and 18 years of age were screened for CKD and hypertension (BP≥95th percentile of reference values). CKD was suspected in children with either an eGFR<90 ml/min per 1.73 m(2) or proteinuria (urinary protein-to-creatinine ratio >0.50 for children ages ≤24 months and >0.20 at >24 months). The RIFLE classification (risk, injury, or failure as 150%, 200%, or 300% of serum creatinine reference values) was used to define AKI during extracorporeal membra...
To assess longitudinally children's motor performance 5 to 12 years after neonatal extracorpo... more To assess longitudinally children's motor performance 5 to 12 years after neonatal extracorporeal membrane oxygenation (ECMO) and to evaluate associations between clinical characteristics and motor performance. Two hundred fifty-four neonatal ECMO survivors in the Netherlands were tested with the Movement Assessment Battery for Children at 5, 8, and/or 12 years. Percentile scores were transformed to z scores for longitudinal evaluation (norm population mean = 0 and SD = 1). Primary diagnoses: meconium aspiration syndrome (n = 137), congenital diaphragmatic hernia (n = 49), persistent pulmonary hypertension of the newborn (n = 36), other diagnoses (n = 32). Four hundred fifty-six tests were analyzed. At 5, 8, and 12 years motor performance was normal in 73.7, 74.8, and 40.5%, respectively (vs 85% expected based on reference values; P < .001 at all ages). In longitudinal analyses mean (95% confidence interval [CI]) z scores were -0.42 (-0.55 to -0.28), -0.25 (-0.40 to -0.10) an...
Drug metabolism and disposition: the biological fate of chemicals, 2014
Many drugs prescribed to children are drug transporter substrates. Drug transporters are membrane... more Many drugs prescribed to children are drug transporter substrates. Drug transporters are membrane-bound proteins that mediate the cellular uptake or efflux of drugs and are important to drug absorption and elimination. Very limited data are available on the effect of age on transporter expression. Our study assessed age-related gene expression of hepatic and intestinal drug transporters. Multidrug resistance protein 2 (MRP2), organic anion transporting polypeptide 1B1 (OATP1B1), and OATP1B3 expression was determined in postmortem liver samples (fetal n = 6, neonatal n = 19, infant n = 7, child n = 2, adult n = 11) and multidrug resistance 1 (MDR1) expression in 61 pediatric liver samples. Intestinal expression of MDR1, MRP2, and OATP2B1 was determined in surgical small bowel samples (neonates n = 15, infants n = 3, adults n = 14). Using real-time reverse-transcription polymerase chain reaction, we measured fetal and pediatric gene expression relative to 18S rRNA (liver) and villin (...
Archives of pediatrics & adolescent medicine, 2003
Despite an increasing awareness regarding pain management in neonates and the availability of pub... more Despite an increasing awareness regarding pain management in neonates and the availability of published guidelines for the treatment of procedural pain, preterm neonates experience pain leading to short- and long-term detrimental effects. To assess the frequency of use of analgesics in invasive procedures in neonates and the associated pain burden in this population. For 151 neonates, we prospectively recorded all painful procedures, including the number of attempts required, and analgesic therapy used during the first 14 days of neonatal intensive care unit admission. These data were linked to estimates of the pain of each procedure, obtained from the opinions of experienced clinicians. On average, each neonate was subjected to a mean +/- SD of 14 +/- 4 procedures per day. The highest exposure to painful procedures occurred during the first day of admission, and most procedures (63.6%) consisted of suctioning. Many procedures (26 of 31 listed on a questionnaire) were estimated to b...
We present a case study of a 10-year-old child with severe burns that were misinterpreted as infl... more We present a case study of a 10-year-old child with severe burns that were misinterpreted as inflicted burns. Because of multiple injuries since early life, the family was under suspicion of child abuse and therefore under supervision of the Child Care Board for 2 years before the boy was burned. Because the boy incurred the burns without feeling pain, we conducted a thorough medical examination and laboratory testing, evaluated detection and pain thresholds, and used MRI to study brain morphology and brain activation patterns during pain between this patient and 3 healthy age- and gender-matched controls. We found elevated detection and pain thresholds and lower brain activation during pain in the patient compared with the healthy controls and reference values. The patient received the diagnosis of hereditary sensory and autonomic neuropathy type IV on the basis of clinical findings and the laboratory testing, complemented with the altered pain and detection thresholds and MRI find...
European Journal of Obstetrics & Gynecology and Reproductive Biology, 2014
To investigate the relation between prenatal ultrasound measurements of viscero-abdominal disprop... more To investigate the relation between prenatal ultrasound measurements of viscero-abdominal disproportion and the expected type of postnatal surgical closure of an omphalocele. Retrospectively, 24 fetuses diagnosed with an isolated omphalocele in the 2nd trimester of pregnancy were selected (period 2003-2013). An image of the axial plane of the abdomen at the level of the defect was retrieved. The ratio of omphalocele circumference to abdominal circumference (OC/AC), and the ratio of defect diameter to abdominal diameter (DD/DA) were calculated. Prognostic outcome was primary closure. Sensitivity and specificity and the corresponding area under the ROC curve of these ratios were calculated as measurements of prognostic accuracy. Primary closure was achieved in 15/24 cases. For the OC/AC-ratio a cut-off value of 0.82 successfully predicted outcome in 23/24 cases with an area under the ROC curve of 0.99. A cut-off value of 0.61 for the DD/DA-ratio successfully predicted type of closure in 20/24 cases with an area under the ROC curve of 0.88. In all cases without eviscerated liver tissue, the defect was primarily closed. In prenatal isolated omphalocele cases, the OC/AC-ratio is better at predicting postnatal surgical closure than the DD/DA-ratio and can be used as a prognostic tool for expected type of closure in the 2nd trimester of pregnancy.
Esophageal Atresia (EA) is a severe developmental defect of the foregut that presents with or wit... more Esophageal Atresia (EA) is a severe developmental defect of the foregut that presents with or without a Tracheo-Esophageal Fistula (TEF). The prevalence of EA/TEF over time and around the world has been relatively stable. EA/TEF is manifested in a broad spectrum of anomalies: in some patients it manifests as an isolated atresia or fistula, but in over half it affects several organ systems. While the associated malformations are often those of the VACTERL spectrum (Vertebral, Anorectal, Cardiac, Tracheo-Esophageal, Renal and Limb), many patients are affected by other malformations, such as microcephaly, micrognathia, pyloric stenosis, duodenal atresia, a single umbilical artery, and anomalies of the genitourinary, respiratory and gastrointestinal systems. Though EA/TEF is a genetically heterogeneous condition, recurrent genes and loci are sometimes affected. Tracheo-Esophageal (TE) defects are in fact a variable feature in several known single gene disorders and in patients with specific recurrent Copy Number Variations and structural chromosomal aberrations. At present, a causal genetic aberration can be identified in 11-12% of patients. In most, EA/TEF is a sporadic finding; the familial recurrence rate is low (1%). As this suggests that epigenetic and environmental factors also contribute to the disease, non-syndromic EA/TEF is generally believed to be a multifactorial condition. Several population-based studies and case reports describe a wide range of associated risks, including age, diabetes, drug use, herbicides, smoking and fetal alcohol exposure. The phenotypical and genetic heterogeneity seen in EA/TEF patients indicates not one underlying cause, but several. Unraveling the complex multifactorial and heterogeneous etiology of EA/TEF and associated features will require large cohorts of patients. Combined statistical analysis of component findings, genome sequencing, and genome wide association studies will elucidate new causal genetic defects and predisposing loci in the etiology within specific sub-populations. Improved knowledge of environmental risk factors, genetic predisposition and causal genetic syndromes may improve prediction and parental counseling, and prevent co-morbidity.
A retrospective analysis of the prognostic significance of the lung-to-head ratio (LHR) and other... more A retrospective analysis of the prognostic significance of the lung-to-head ratio (LHR) and other prenatal parameters on the outcome of fetuses with left-sided congenital diaphragmatic hernia (CDH). A total of 26 fetuses with isolated left CDH without chromosomal abnormalities were included. Twenty-one LHR measurements could retrospectively be calculated from the last available ultrasonographic recordings before birth. The relationship between LHR and fetal outcome and the gestational age dependency of this relation was tested. Cutoff levels as previously published were applied to determine their predictive value in this population. The association between other prenatal predictive variables and fetal outcome was also determined. Survival was defined as discharge from the hospital. The overall survival rate was 50%. There was a statistically significant difference between the mean LHR of the survivors compared to the mean LHR of the nonsurvivors (1.78 vs 1.02), whereas the mean gestational age of these two groups did not differ. LHR was not gestational age dependent in the prediction of fetal outcome. The cutoff levels LHR &amp;amp;lt;1, 1-1.4, &amp;amp;gt;1.4 showed a good applicability in the prediction of fetal outcome within the present study population with a 100% survival if LHR &amp;amp;gt;1.4 and a 100% mortality if LHR &amp;amp;lt;1. An intrathoracic position of the stomach, mediastinal shift, polyhydramnios as individual variables and early diagnosis (&amp;amp;lt;25 weeks&amp;amp;#39; gestation) revealed to be poor sonographic predictors for fetal outcome. LHR proved to be a good predictor for fetal outcome, independent of gestational age at the time of the measurement. To substantiate our observation, a prospective multicenter study is warranted.
Ghrelin is a strong physiologic growth hormone secretagogue that exhibits endocrine and non-endoc... more Ghrelin is a strong physiologic growth hormone secretagogue that exhibits endocrine and non-endocrine actions. In this study, ghrelin expression in humans and rats was evaluated throughout development of normal and hypoplastic lungs associated with congenital diaphragmatic hernia (CDH). Additionally, the effect of antenatal treatment with ghrelin in the nitrofen-induced CDH rat model was tested. In normal lungs, ghrelin was expressed in the primitive epithelium at early stages of development and decreased in levels of expression with gestational age. In hypoplastic lungs ghrelin was overexpressed in both human and rat CDH fetuses when compared with controls. Exogenous administration of ghrelin to nitrofen-treated dams led to an attenuation of pulmonary hypoplasia of CDH pups. Furthermore, the growth hormone, secretagogue receptor (GHSR1a), could not be amplified from human or rat fetal lungs by RT-PCR. In conclusion, of all the lungs studied so far, the fetal lung is one of the first to express ghrelin during development and might be considered a new source of circulating fetal ghrelin. Overexpression of ghrelin in hypoplastic lungs and the effect of exogenous administration of ghrelin to nitrofen-treated dams strongly suggest a role for ghrelin in mechanisms involved in attenuation of fetal lung hypoplasia, most likely through a GHSR1a-independent pathway.
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Papers by Dick Tibboel