Smit, B.

An observational study to quantify manual adjustments of the inspired oxygen fraction in extremely low birth weight infants (Article)

2012-03-01T00:00:00Z

Aim: To quantify manual fraction of inspired oxygen (FiO2) adjustments performed by caregivers in extremely low birth weight (ELBW; ≤1000 g) infants, in relation to oxygen saturation (SpO) and bedside care. Methods: In a single-centre study, FiO, SpO and alarm limits of ELBW infants were collected for 3 days continuously, while caregivers were filmed. A descriptive analysis, focused on manual FiO adjustments, was performed. Results: Twelve ELWB infants were included. Total recording time was 726 h. FiO was increased 851 times and decreased 1309 times; median (range) step size was 5% (1% to 65%) and -3% (-1% to -65%), respectively. Wide variation of FiO adjustments for equal levels of SpO was observed in all included infants. One hundred and twenty-six of 136 FiO adjustments with a step size âyen 15% and 111 of 171 desaturations <70% were associated with medical or nursing procedures. When FiO was >21%, alarm limits for SpO were set according to protocol (88-94%) in 64% of the time. Within these periods, SpO was >94% for 30% and <88% for 16% of the time. Conclusions: Manual FiO adjustments varied widely in frequency and step size. Deep desaturations and large FiO adjustments were associated with medical or nursing procedures. When large adjustments are really necessary, it will be challenging to implement them in an automatic adjustment device. © 2011 The Author(s)/Acta Pædiatrica

Outcome of pregnancies complicated by oligohydramnios or anhydramnios of renal origin (Article)

2011-11-01T00:00:00Z

Objective: To evaluate the outcome of fetuses with oligohydramnios due to kidney anomalies. Methods: A retrospective study was performed of all pregnancies diagnosed with oligohydramnios and associated kidney anomalies during the period 2000-2008. Outcome included pregnancy outcome, mortality, and morbidity. Morbidity included renal function based on the glomerular filtration rate (GFR) during follow-up. Results: A total of 71 pregnancies were evaluated; 36 fetuses presented on ultrasound with cystic dysplasia, 15 with polycystic kidney disease (PKD) and 20 with hydronephrosis. Twenty-three (32%) had associated anomalies. In 49 fetuses (69%), the diagnosis had been made before 24 weeks of gestational age (GA); 41 of those pregnancies were terminated. Twenty-five neonates were live born: 10 survived, 15 died. Prognostic factors for survival included GA at diagnosis (32.2 weeks for survivors vs 28.1 weeks for non-survivors; P = 0.02), diagnosis of hydronephrosis (7 in the survivors vs 4 in the non-survivors: P = 0.05), isolated anomaly (9 in the survivors vs 7 in the non-survivors: P = 0.04). Severity of oligohydramnios (1 case of anhydramnios in the survivors vs 7 in the non-survivors: P = 0.08) was not significant. The 1-year GFR was below 50 mL/min.1.73 m2in four of the ten survivors. Conclusion: The prognosis of early onset renal oligohydramnios is poor. Predictive determinants of survival are: GA at diagnosis, nature of renal anomaly (hydronephrosis vs other), and presence of associated anomalies.

Brain ultrasonography findings in neonates with exposure to cocaine during pregnancy (Article)

2009-03-01T00:00:00Z

Background: Cocaine exposure during pregnancy has been reported to have detrimental effects on the fetus. Objective: To describe the findings on cranial ultrasonography (CUS) as part of a neonatal screening programme for exposed neonates. Materials and methods: The study was a semiprospective analysis of a 12-year cohort of neonates born to mothers who had used cocaine during their pregnancy and who had follow-up according to a strict clinical protocol. Results: In total, 154 neonates (78 boys, 76 girls) were included, of whom 29 (19%) were born preterm, and 125 (81%) were born full-term. Abnormalities on CUS were seen in 37 neonates (24%; 95% CI 18-31%). The abnormalities were classified as minor in 20 (13%; 95% CI 9-19%) and mildly abnormal in 17 (11%; 95% CI 7-17%). None of the infants showed severe abnormalities. The abnormalities were not associated with the duration or maximum amount of cocaine use during pregnancy. Conclusion: None of the infants had severe abnormalities. Detected abnormalities were not correlated with the duration or maximum amount of cocaine use. Given these findings, we feel that routine cranial ultrasonography in this population is not warranted.

Development and growth in very preterm infants in relation to NIDCAP in a Dutch NICU: Two years of follow-up (Article)

2009-02-01T00:00:00Z

Aim: To study development and growth in relation to newborn individualized developmental and assessment program (NIDCAP®) for infants born with a gestational age of less than 30 weeks. Methods: Developmental outcome of surviving infants, 25 in the NIDCAP group and 24 in the conventional care group, in a prospective phase-lag cohort study performed in a Dutch level III neonatal intensive care unit (NICU) was compared. Main outcome measure was the Bayley scales of infant development-II (BSID-II) at 24 months corrected age. Secondary outcomes were neurobehavioral and developmental outcome and growth at term, 6, 12 and 24 months. Results: Accounting for group differences and known outcome predictors no significant differences were seen between both care groups in BSID-II at 24 months. At term age NIDCAP infants scored statistically significant lower on neurobehavioral competence; motor system (median [IQR] 4.8 [2.9-5.0] vs. 5.2 [4.3-5.7], p = 0.021) and autonomic stability (median [IQR] 5.7 [4.8-6.7] vs. 7.0 [6.0-7.7], p = 0.001). No differences were seen in other developmental outcomes. After adjustment for background differences, growth parameters were comparable between groups during the first 24 months of life. Conclusion: At present, the strength of conclusions to be drawn about the effect of NIDCAP on developmental outcome or growth at 24 months of age is restricted. Further studies employing standardized assessment approaches including choice of measurement instruments and time points are needed.

Using virtual reality for evaluation of fetal ambiguous genitalia (Article)

2008-09-01T00:00:00Z

Objective The utility of a virtual reality system was examined in the visualization of three-dimensional (3D) ultrasound images of fetal ambiguous genitalia. Methods In 2005, fetal ambiguous genitalia were diagnosed in four patients referred to our department for prenatal ultrasound assessment. The patients were examined by two-dimensional (2D) and 3D ultrasound and, subsequently, the volumes obtained on 3D ultrasound were visualized in the BARCO I-Space virtual reality system. This system projects stereoscopic images on three walls and the floor of a small 'room', allowing several viewers to see a 3D 'hologram' of the data being visualized. The results of 2D and 3D ultrasound examination and the virtual reality images of the I-Space were compared with diagnoses made postpartum. Results In all cases, prenatal diagnosis was unclear based on 2D ultrasound alone. Surface rendering of 3D data provided an impression of ambiguity, but diagnosis based on these data proved incorrect at birth in three cases. Conclusions based on the evaluation of 3D volumes in virtual reality best fitted the postpartum diagnosis in all cases. Conclusions This study suggests that by evaluation of the genitals in the I-Space, a better impression of genital ambiguity can be established. Binocular depth perception appeared particularly useful in distinguishing either a micropenis or enlarged clitoris from labia minora, since it helps in the estimation of size and position. Therefore, we see potential for the application of virtual reality not only for the evaluation of fetal ambiguous genitalia, but in all those cases where depth perception would improve the visualization of anatomical structures.

Maternal temperature during labour (Article)

2008-08-01T00:00:00Z

Objective: The aim of this study was to describe the variation of normal maternal temperature during labour. Design: A prospective cohort study. Setting: Two hospitals in Amsterdam, the Netherlands. Population: All women with a live singleton pregnancy and a gestational age of 36 weeks or more admitted to the delivery ward from June 2000 to January 2002. Methods: Maternal temperature was measured rectally every 2-3 hours from admission until the beginning of second stage, and 1-hour postpartum. Normal labour (n = 843) was defined as gestational age ≥37 weeks, spontaneous onset of labour, rupture of membranes <18 hours before birth, normal progress of labour without the need for augmentation or epidural analgesia and spontaneous vaginal delivery of a healthy infant. The remaining group was classified as abnormal (n = 2209). Main outcome measures: Rectal measured temperature in degrees Celsius. Results: The mean temperature during labour in the complete study population increased from 37.1°C at the beginning of labour to 37.4°C after 22 hours. Temperature in the abnormal labour group was equal to the normal labour group during the first 3 hours of labour (P > 0.05) but increased thereafter. Conclusions: At the beginning of labour, temperature was 37.1°C. Temperature increased slowly during labour and was 37.4°C (2SD 1.2) after 22 hours. The upper 2SD limit for normal temperature did not follow a circadian pattern and time of day is not relevant for the classification of normal versus elevated temperature.

Design and evaluation of a regional perinatal audit (Article)

2008-04-01T00:00:00Z

Objective: To describe the experiences of a regional audit of perinatal deaths, including the experiences of the audit members, to discuss similarities and differences with other, existing perinatal audits and to summarize the implications for future implementation. Study design: Perinatal audit with blinded regional auditors. Consecutive cases of perinatal death were analysed for the presence of substandard care. A random selection of cases was reviewed by an external audit panel. The prevalence of substandard care in the Amsterdam audit was compared with other, existing audits. A survey among audit members was executed. Results: Care providers from all Amsterdam hospitals, as well as general practitioners and independent midwives cooperated. One hundred thirty-seven perinatal deaths were reviewed. In 25% of all perinatal death cases, substandard care factors were present. After 23 completed weeks substandard care factors were present in 35% of cases, and in 52% of intrapartum deaths. These figures are comparable with other, non-regional oriented audits. The review of the external panel was also comparable to the review of the regional audit committee. All audit members felt secure to discuss freely the presence of substandard care. Conclusion: First systematic experiences with a regional perinatal audit are described. We conclude that a regional perinatal audit is executable. Cooperation of regional care providers is good. Review of substandard care factors is comparable to other, non-regional oriented perinatal audits.

Individualized developmental care in a Dutch NICU: Short-term clinical outcome (Article)

2007-10-01T00:00:00Z

Aim: To compare the short-term clinical outcomes of Newborn Individualized Developmental Care and Assessment Program (NIDCAP®) and conventional care. Methods: A prospective phase-lag cohort study was performed in a Dutch tertiary level neonatal intensive care unit (NICU). Infants born before 30 weeks of gestational age (GA) were included, 26 in the conventional and 25 in the NIDCAP group. Outcomes were respiratory status, cerebral ultrasound findings, growth and length of NICU stay. Results: At study entry, NIDCAP infants had a lower birth weight (mean [SD]: 1043 [191] vs. 1154 [174] g, p = 0.044), were more often small for GA (8 vs. 2, p = 0.038), had smaller head circumferences (mean [SD]: 25.1 [1.3] vs. 26.1 [1.8] cm, p = 0.041) and were less often multiples (6 vs. 14, p = 0.029) than conventional care infants. During NICU stay, more infants in the NIDCAP group developed pneumonia (9 vs. 3, p = 0.040) due to nosocomial infections. After adjustment for these differences, a decreased risk for more severe cerebral damage in favour of NIDCAP was seen (Odds ratio: 0.12, 95% CI: 0.03-0.46, p = 0.002). No differences were observed for the other outcomes. Conclusions: We conclude with precaution that in this phase-lag cohort study NIDCAP may have resulted in less severe cerebral damage, but was not associated with other clinical outcomes. In light of these findings, NIDCAP deserves further exploration.

Loss of integrity of thyroid morphology and function in children born to mothers with inadequately treated Graves' disease (Article)

2007-08-01T00:00:00Z

Context: Central congenital hypothyroidism (CH-C) in neonates born to mothers with inadequately treated Graves' disease usually needs T4supplementation. The thyroid and its regulatory system have not yet been extensively studied after T4withdrawal, until we observed disintegrated thyroid glands in some patients. Objective: The aim was to study the occurrence and pathogenesis of disintegrated thyroid glands in CH-C patients. Design, Setting, Patients, Participants: Thyroid function was measured and thyroid ultrasound imaging was performed in 13 children with CH-C due to inadequately treated maternal Graves' disease after T4- supplementation withdrawal (group Aa). In addition, thyroid ultrasound imaging was performed in six children with CH-C born to inadequately treated mothers with Graves' disease, in whom T4supplementation was not withdrawn yet (group Ab) or never initiated (group Ac), in six euthyroid children born to adequately treated mothers with Graves' disease (group B), and in 10 T4-supplemented children with CH-C as part of multiple pituitary hormone deficiency (group C). Main Outcome Measures: Thyroid function and aspect (volume, echogenicity, echotexture) were measured. Results: In group A, five children had developed thyroidal hypothyroidism characterized by persistently elevated TSH concentrations and exaggerated TSH responses after TRH stimulation. In the majority of patients in groups A and C, thyroid echogenicity and volume were decreased, and echotexture was inhomogeneous. Thyroid ultrasound imaging was normal in group B children. Conclusions: Inadequately treated maternal Graves' disease not only may lead to CH-C but also carries an, until now, unrecognized risk of thyroid disintegration in the offspring as well. We speculate that insufficient TSH secretion due to excessive maternal-fetal thyroid hormone transfer inhibits physiological growth and development of the child's thyroid. Copyright

Analysis of mouse Rad54 expression and its implications for homologous recombination. (Article)

2002-10-01T00:00:00Z

Homologous recombination is one of the major pathways for repair of DNA double-strand breaks (DSBs). Important proteins in this pathway are Rad51 and Rad54. Rad51 forms a nucleoprotein filament on single-stranded DNA (ssDNA) that mediates pairing with and strand invasion of homologous duplex DNA with the assist of Rad54. We estimated that the nucleus of a mouse embryonic stem (ES) cells contains on average 4.7x10(5) Rad51 and 2.4x10(5) Rad54 molecules. Furthermore, we showed that the amount of Rad54 was subject to cell cycle regulation. We discuss our results with respect to two models that describe how Rad54 stimulates Rad51-mediated DNA strand invasion. The models differ in whether Rad54 functions locally or globally. In the first model, Rad54 acts in cis relative to the site of strand invasion. Rad54 coats the Rad51 nucleoprotein filament in stoichiometric amounts and binds to the target duplex DNA at the site that is homologous to the ssDNA in the Rad51 nucleoprotein filament. Subsequently, it promotes duplex DNA unwinding. In the second model, Rad54 acts in trans relative to the site of strand invasion. Rad54 binds duplex DNA distant from the site that will be unwound. Translocation of Rad54 along the duplex DNA increases superhelical stress thereby promoting duplex DNA unwinding.

UVB radiation-induced cancer predisposition in Cockayne syndrome group A (Csa) mutant mice. (Article)

2002-05-16T00:00:00Z

Cockayne syndrome (CS) is an inherited photosensitive neurodevelopmental disorder caused by a specific defect in the transcription-coupled repair (TCR) sub-pathway of NER. Remarkably, despite their DNA repair deficiency, CS patients do not develop skin cancer. Here, we present a mouse model for CS complementation group A. Like cells from CS-A patients, Csa-/- mouse embryonic fibroblasts (MEFs): (i) are ultraviolet (UV)-sensitive; (ii) show normal unscheduled DNA synthesis (indicating that the global genome repair sub-pathway is unaffected); (iii) fail to resume RNA synthesis after UV-exposure and (iv) are unable to remove cyclobutane pyrimidine dimers (CPD) photolesions from the transcribed strand of active genes. CS-A mice exhibit UV-sensitivity and pronounced age-dependent loss of retinal photoreceptor cells but otherwise fail to show the severe developmental and neurological abnormalities of the human syndrome. In contrast to human CS, Csa-/- animals develop skin tumors after chronic exposure to UV light, indicating that TCR in mice protects from UV-induced skin cancer development. Strikingly, inactivation of one Xpc allele (encoding a component of the damage recognition complex involved in the global genome repair sub-pathway) in Csa-/- mice resulted in a strongly enhanced UV-mediated skin cancer sensitivity, indicating that in a TC repair defective background, the Xpc gene product may be a rate-limiting factor in the removal of UV-induced DNA lesions.

A human homolog of the yeast nucleotide excision repair gene MMS19 interacts with transcription repair factor TFIIH through the XPB and XPD helicases. (Article)

2000-01-01T00:00:00Z

Nucleotide excision repair (NER) removes UV-induced photoproducts and numerous other DNA lesions in a highly conserved 'cut-and-paste' reaction that involves approximately 25 core components. In addition, several other proteins have been identified which are dispensable for NER in vitro but have an undefined role in vivo and may act at the interface of NER and other cellular processes. An intriguing example is the Saccharomyces cerevisiae Mms19 protein that has an unknown dual function in NER and RNA polymerase II transcription. Here we report the cloning and characterization of a human homolog, designated hMMS19, that encodes a 1030 amino acid protein with 26% identity and 51% similarity to S.cerevisiae Mms19p and with a strikingly similar size. The expression profile and nuclear location are consistent with a repair function. Co-immunoprecipitation experiments revealed that hMMS19 directly interacts with the XPB and XPD subunits of NER-transcription factor TFIIH. These findings extend the conservation of the NER apparatus and the link between NER and basal transcription and suggest that hMMS19 exerts its function in repair and transcription by interacting with the XPB and XPD helicases.

Cloning of a human homolog of the yeast nucleotide excision repair gene MMS19 and interaction with transcription repair factor TFIIH via the XPB and XPD helicases (Article)

2000-01-01T00:00:00Z

Sequence conservation of the rad21 Schizosaccharomyces pombe DNA double-strand break repair gene in human and mouse. (Article)

1996-09-01T00:00:00Z

The rad21 gene of Schizosaccharomyces pombe is involved in the repair of ionizing radiation-induced DNA double-strand breaks. The isolation of mouse and human putative homologs of rad21 is reported here. Alignment of the predicted amino acid sequence of Rad21 with the mammalian proteins showed that the similarity was distributed across the length of the proteins, with more highly conserved regions at both termini. The mHR21(sp) (mouse homolog of Rad21, S. pombe) and hHR21(sp) (human homolog of Rad21, S. pombe) predicted proteins were 96% identical, whereas the human and S. pombe proteins were 25% identical and 47% similar. RNA blot analysis showed that mHR21sp mRNA was abundant in all adult mouse tissues examined, with highest expression in testis and thymus. In addition to a 3.1-kb constitutive mRNA transcript, a 2.2-kb transcript was present at a high level in postmeiotic spermatids, while expression of the 3.1-kb mRNA in testis was confined to the meiotic compartment. hHR21sp mRNA was cell cycle regulated in human cells, increasing in late S phase to a peak in G2 phase. The level of hHR21sp transcripts was not altered by exposure of normal diploid fibroblasts to 10 Gy ionizing radiation. In situ hybridization showed that mHR21sp resided on chromosome 15D3, whereas hHR21sp localized to the syntenic 8q24 region. Elevated expression of mHR21sp in testis and thymus supports a possible role for the rad21 mammalian homologs in V(D)J and meiotic recombination, respectively. Cell cycle regulation of rad21, retained from S. pombe to human, is consistent with a conservation of function between S. pombe and human rad21 genes.

Human and mouse homologs of the Saccharomyces cerevisiae RAD54 DNA repair gene: evidence for functional conservation. (Article)

1996-07-01T00:00:00Z

BACKGROUND: Homologous recombination is of eminent importance both in germ cells, to generate genetic diversity during meiosis, and in somatic cells, to safeguard DNA from genotoxic damage. The genetically well-defined RAD52 pathway is required for these processes in the yeast Saccharomyces cerevisiae. Genes similar to those in the RAD52 group have been identified in mammals. It is not known whether this conservation of primary sequence extends to conservation of function. RESULTS: Here we report the isolation of cDNAs encoding a human and a mouse homolog of RAD54. The human (hHR54) and mouse (mHR54) proteins were 48% identical to Rad54 and belonged to the SNF2/SW12 family, which is characterized by amino-acid motifs found in DNA-dependent ATPases. The hHR54 gene was mapped to chromosome 1p32, and the hHR54 protein was located in the nucleus. We found that the levels of hHR54 mRNA increased in late G1 phase, as has been found for RAD54 mRNA. The level of mHR54 mRNA was elevated in organs of germ cell and lymphoid development and increased mHR54 expression correlated with the meiotic phase of spermatogenesis. The hHR54 cDNA could partially complement the methyl methanesulfonate-sensitive phenotype of S. cerevisiae rad54 delta cells. CONCLUSIONS: The tissue-specific expression of mHR54 is consistent with a role for the gene in recombination. The complementation experiments show that the DNA repair function of Rad54 is conserved from yeast to humans. Our findings underscore the fundamental importance of DNA repair pathways: even though they are complex and involve multiple proteins, they seem to be functionally conserved throughout the eukaryotic kingdom.

Cloning, comparative mapping, and RNA expression of the mouse homologues of the Saccharomyces cerevisiae nucleotide excision repair gene RAD23. (Article)

1996-01-01T00:00:00Z

The Saccharomyces cerevisiae RAD23 gene is involved in nucleotide excision repair (NER). Two human homologs of RAD23, HHR23A and HHR23B (HGMW-approved symbols RAD23A and RAD23B), were previously isolated. The HHR23B protein is complexed with the protein defective in the cancer-prone repair syndrome xeroderma pigmentosum, complementation group C, and is specifically involved in the global genome NER subpathway. The cloning of both mouse homologs (designated MHR23A and MHR23B) and detailed sequence comparison permitted the deduction of the following overall structure for all RAD23 homologs: an ubiquitin-like N-terminus followed by a strongly conserved 50-amino-acid domain that is repeated at the C-terminus. We also found this domain as a specific C-terminal extension of one of the ubiquitin-conjugating enzymes, providing a second link with the ubiquitin pathway. By means of in situ hybridization, MHR23A was assigned to mouse chromosome 8C3 and MHR23B to 4B3. Because of the close chromosomal proximity of human XPC and HHR23B, the mouse XPC chromosomal location was determined (6D). Physical disconnection of the genes in mouse argues against a functional significance of the colocalization of these genes in human. Northern blot analysis revealed constitutive expression of both MHR23 genes in all tissues examined. Elevated RNA expression of both MHR23 genes was observed in testis. Although the RAD23 equivalents are well conserved during evolution, the mammalian genes did not express the UV-inducible phenotype of their yeast counterpart. This may point to a fundamental difference between the UV responses of yeast and human. No stage-specific mRNA expression during the cell cycle was observed for the mammalian RAD23 homologs.