Background Therapeutic drug monitoring (TDM) of antibiotics in children is of fundamental importa... more Background Therapeutic drug monitoring (TDM) of antibiotics in children is of fundamental importance for effective patient management. The use of dried blood spot (DBS) offers a number of advantages over conventional blood collection. The aim of this study is to develop and validate a method to measure piperacillin/tazobactam in DBS. Results The analysis was performed by using LC-MS/MS operating in multiple reaction monitoring mode. The method has been validated by applying EMA guidelines and its suitability for TDM was evaluated by using samples from low birth weight neonates. Conclusion This paper describes a fast and cost-effective micromethod for the simultaneous determination of piperacillin/tazobactam levels on dried blood spot that is suitable for TDM in children.
Intrauterine growth restriction (IUGR) is associated with increased risk of perinatal morbidity a... more Intrauterine growth restriction (IUGR) is associated with increased risk of perinatal morbidity and mortality, as well as long-term neurological deficits. However, neurostructural correlations with observed developmental disabilities have not yet been established. Magnetic resonance imaging (MRI) could prove useful for assessing brain development in the early neonatal period. We evaluated cerebral lesions and morphological maturation by MRIs in 59 preterm neonates, in order to verify the hypothesis that IUGR interferes on human brain development. A total of 26 pregnancies were complicated by IUGR and 33 pregnancies delivered preterm at a comparable gestational age with appropriate for gestational age (AGA). Magnetic resonance examination was performed at the completion of 41 weeks' gestation. White matter disease studied with MR included periventricular cavitations and punctuate lesions characterized by increased signal on T1-weighted and decreased signal on T2-weighted images. Cerebral maturation was defined by the total maturation score, on the basis of 4 morphological parameters of cerebral maturation: myelination (M), cortical infolding (C), germinal matrix distribution (GM), and glial cell migration pattern (G). No difference in brain lesions and in the level of cerebral maturation was found between preterm AGA and IUGR neonates. However, myelination was significantly reduced in IUGR neonates with brain sparing compared to IUGR neonates with normal Doppler of middle cerebral artery. Our study could not demonstrate any major significant difference between preterm AGA and IUGR neonates in terms of lesion occurrence and cerebral maturation. We observed, however, a mild delay in myelination in IUGR with brain sparing in utero. The relevance of this finding needs to be investigated with long-term follow-up.
A newborn infant is reported who had aganglionic megacolon, renal hypoplasia, severe growth retar... more A newborn infant is reported who had aganglionic megacolon, renal hypoplasia, severe growth retardation, generalised hypotonia, and various dysmorphic features. Chromosome analysis of lymphocytes and fibroblasts showed a ring chromosome 10 with breakpoints at p13-15 and q26. AluI digestion showed that the ring chromosome was monocentric. FISH with an alpha satellite probe specific for chromosome 10 showed one signal only
Neuropathological and Magnetic Resonance Imaging (MRI) studies showed a high frequency of posteri... more Neuropathological and Magnetic Resonance Imaging (MRI) studies showed a high frequency of posterior fossa abnormalities in preterms. To assess whether cerebellar haemorrhages (CH) diagnosed with ultrasound and/or MRI affect pons development in ELBW infants. The anteroposterior diameter of the pons was measured manually on the midline sagittal T1 MR image in 75 ELBW babies consecutively scanned at term postmenstrual age. Subjects with CH were identified and compared to babies with no posterior fossa bleeding. Nine ELBW infants with CH (CH-Group: median gestational age -GA- 26 wks, range 23-27; birth weight -BW- 680 g, 425-980) were compared with 66 babies with normal cerebellum (Control-Group: GA 28 wks, 23-33; BW 815 g, 430-1000). The two groups were comparable for BW (p=0.088) while GA was significantly shorter in CH babies (p=0.005). The pontine diameter was significantly lower in CH-Group compared to Control-Group (12.8 +/- 2.2 vs 14.8 +/- 1.2 mm; p<0.001). Cerebellar haemorrh...
The assessment of whether brain development is at an appropriate level for age has become an inte... more The assessment of whether brain development is at an appropriate level for age has become an integral part of clinical MR reporting, although few studies have quantitatively defined the developmental changes occurring in premature infants. We have developed a simple scoring system to assess four parameters of cerebral maturation--myelination, cortical folding, glial cell migration, and germinal matrix distribution--to determine the total maturation score (TMS). The aim of this study was to validate this scoring system in a large population of preterm infants across a range of gestational ages. A retrospective analysis was conducted of MR images acquired over a 3-year period with an identical imaging protocol. Infants born more than 14 days before the imaging examination and those with a clinical or radiologic history suggestive of neuroabnormality were excluded from the study. The TMS was derived by consensus. Interobserver agreement was evaluated by using the Bland-Altman plot. Ima...
The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians, Jan 23, 2013
Oxidative stress (OS) occurs at birth in all newborns as a consequence of the hyperoxic challenge... more Oxidative stress (OS) occurs at birth in all newborns as a consequence of the hyperoxic challenge due to the transition from the hypoxic intrauterine environment to extrauterine life. Free radical (FRs) sources such as inflammation, hyperoxia, hypoxia, ischaemia-reperfusion, neutrophil and macrophage activation, glutamate and free iron release, all increases the OS during the perinatal period. Newborns, and particularly preterm infants, have reduced antioxidant defences and are not able to counteract the harmful effects of FRs. Energy metabolism is central to life because cells cannot exist without an adequate supply of ATP. Due to its growth, the mammalian brain can be considered as a steady-state system in which ATP production matches ATP utilisation. The developing brain is particularly sensitive to any disturbances in energy generation, and even a short-term interruption can lead to long-lasting and irreversible damage. Whenever energy failure develops, brain damage can occur. A...
Cortex; a journal devoted to the study of the nervous system and behavior, 2014
Visual impairment in preterm infants at term equivalent age (TEA) is associated with impaired mic... more Visual impairment in preterm infants at term equivalent age (TEA) is associated with impaired microstructural development in the optic radiation, measured as reduced fractional anisotropy (FA) by Diffusion Tensor Imaging (DTI). We tested the hypothesis that these abnormalities develop during the late preterm period. DTI was performed in 53 infants born at a median (range) of 30(+1) (25(+4)-34(+6)) weeks post-menstrual age (PMA), 22 of whom were imaged twice. FA in the optic radiation at TEA was related to: visual function (p = .003); PMA at birth (p = .015); and PMA at scan (p = .008); while a significant interaction between PMA at birth and scan (p = .019) revealed an effect of the period of premature extra-uterine life additional to the degree of prematurity. We explored this further in a sub-group of 22 infants who were studied twice. FA increased from mean (95% CI) .174 (.164-.176) on the first image at 32(+5) (29(+5)-36) weeks PMA, to .198 (.190-.206) on the second image at 40(...
The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians, Jan 23, 2013
For many years cerebellar development after preterm birth has been poorly investigated and has be... more For many years cerebellar development after preterm birth has been poorly investigated and has been studied without taking germinal matrix-intraventricular haemorrhage into account. Advanced neuroimaging techniques like magnetic resonance imaging, as well as the use of various acoustic windows (mastoid fontanelle, occipital foramen) have allowed for in vivo diagnosis of acquired focal haemorrhagic lesions in the cerebellum of very preterm babies. The vulnerability of the cerebellum also seems to be related to specific gestational ages, i.e., between 23 and 27 weeks, when rapid growth in cerebellar volume occurs and at a much faster rate than mean brain volume increase. In this paper, the contribution of the cerebellum in long-term motor cognitive, learning and behavioural functions, including psychiatric ones, is discussed.
Intrauterine growth restriction (IUGR) is associated with increased risk of perinatal morbidity a... more Intrauterine growth restriction (IUGR) is associated with increased risk of perinatal morbidity and mortality, as well as long-term neurological deficits. However, neurostructural correlations with observed developmental disabilities have not yet been established. Magnetic resonance imaging (MRI) could prove useful for assessing brain development in the early neonatal period. We evaluated cerebral lesions and morphological maturation by MRIs in 59 preterm neonates, in order to verify the hypothesis that IUGR interferes on human brain development. A total of 26 pregnancies were complicated by IUGR and 33 pregnancies delivered preterm at a comparable gestational age with appropriate for gestational age (AGA). Magnetic resonance examination was performed at the completion of 41 weeks&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; gestation. White matter disease studied with MR included periventricular cavitations and punctuate lesions characterized by increased signal on T1-weighted and decreased signal on T2-weighted images. Cerebral maturation was defined by the total maturation score, on the basis of 4 morphological parameters of cerebral maturation: myelination (M), cortical infolding (C), germinal matrix distribution (GM), and glial cell migration pattern (G). No difference in brain lesions and in the level of cerebral maturation was found between preterm AGA and IUGR neonates. However, myelination was significantly reduced in IUGR neonates with brain sparing compared to IUGR neonates with normal Doppler of middle cerebral artery. Our study could not demonstrate any major significant difference between preterm AGA and IUGR neonates in terms of lesion occurrence and cerebral maturation. We observed, however, a mild delay in myelination in IUGR with brain sparing in utero. The relevance of this finding needs to be investigated with long-term follow-up.
Withdrawal and infusion of blood via umbilical catheters can affect cerebral blood flow in preter... more Withdrawal and infusion of blood via umbilical catheters can affect cerebral blood flow in preterm infants. We compared the effects on cerebral perfusion of 3 ml/kg blood withdrawal and infusion via umbilical arterial (UAC) and venous (UVC) catheters in 16 infants &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; or =32 weeks gestation, age &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;24 h, on mechanical ventilation. Near infrared spectroscopy was used to monitor changes in cerebral oxy- and deoxyhemoglobin, total cerebral hemoglobin (an index of cerebral blood volume; CBV) and HbD (an index of cerebral intravascular oxygenation). In 10 infants the study was repeated 1 h after intravenous administration of 10 mg/kg ibuprofen as prophylaxis against PDA. Withdrawal and infusion via the UVC caused significant MABP and concordant HbD and CBV changes. Smaller modifications were seen following blood withdrawal and infusion via the UAC. Ibuprofen attenuated cerebral hemodynamic changes associated with withdrawal, but not infusion, from UAC and UVC.
Conventional coagulation tests might be inadequate to explore mechanisms regulating thrombin gene... more Conventional coagulation tests might be inadequate to explore mechanisms regulating thrombin generation in neonates, because they do not allow full activation of the reduced levels of protein C. Therefore, they do not reflect the action of pro- and anti-coagulants as does the endogenous thrombin potential assessed in the presence of thrombomodulin. Endogenous thrombin potential measured without thrombomodulin was greater than the lower-limit of the adult reference interval in 30% of 109 full-term and 49% of 55 pre-term neonates, a finding consistent with the reduced levels of procoagulants in this setting. When the test was modified adding thrombomodulin, endogenous thrombin potential reverted into the adult reference interval in 97% and 100% full-term and pre-term neonates. In conclusion, the coagulation balance in neonates is restored by the concomitant reduction of pro- and anticoagulants. The restored balance can be shown in vitro by the endogenous thrombin potential test that includes thrombomodulin, but not by conventional coagulation tests.
Background Therapeutic drug monitoring (TDM) of antibiotics in children is of fundamental importa... more Background Therapeutic drug monitoring (TDM) of antibiotics in children is of fundamental importance for effective patient management. The use of dried blood spot (DBS) offers a number of advantages over conventional blood collection. The aim of this study is to develop and validate a method to measure piperacillin/tazobactam in DBS. Results The analysis was performed by using LC-MS/MS operating in multiple reaction monitoring mode. The method has been validated by applying EMA guidelines and its suitability for TDM was evaluated by using samples from low birth weight neonates. Conclusion This paper describes a fast and cost-effective micromethod for the simultaneous determination of piperacillin/tazobactam levels on dried blood spot that is suitable for TDM in children.
Intrauterine growth restriction (IUGR) is associated with increased risk of perinatal morbidity a... more Intrauterine growth restriction (IUGR) is associated with increased risk of perinatal morbidity and mortality, as well as long-term neurological deficits. However, neurostructural correlations with observed developmental disabilities have not yet been established. Magnetic resonance imaging (MRI) could prove useful for assessing brain development in the early neonatal period. We evaluated cerebral lesions and morphological maturation by MRIs in 59 preterm neonates, in order to verify the hypothesis that IUGR interferes on human brain development. A total of 26 pregnancies were complicated by IUGR and 33 pregnancies delivered preterm at a comparable gestational age with appropriate for gestational age (AGA). Magnetic resonance examination was performed at the completion of 41 weeks&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; gestation. White matter disease studied with MR included periventricular cavitations and punctuate lesions characterized by increased signal on T1-weighted and decreased signal on T2-weighted images. Cerebral maturation was defined by the total maturation score, on the basis of 4 morphological parameters of cerebral maturation: myelination (M), cortical infolding (C), germinal matrix distribution (GM), and glial cell migration pattern (G). No difference in brain lesions and in the level of cerebral maturation was found between preterm AGA and IUGR neonates. However, myelination was significantly reduced in IUGR neonates with brain sparing compared to IUGR neonates with normal Doppler of middle cerebral artery. Our study could not demonstrate any major significant difference between preterm AGA and IUGR neonates in terms of lesion occurrence and cerebral maturation. We observed, however, a mild delay in myelination in IUGR with brain sparing in utero. The relevance of this finding needs to be investigated with long-term follow-up.
A newborn infant is reported who had aganglionic megacolon, renal hypoplasia, severe growth retar... more A newborn infant is reported who had aganglionic megacolon, renal hypoplasia, severe growth retardation, generalised hypotonia, and various dysmorphic features. Chromosome analysis of lymphocytes and fibroblasts showed a ring chromosome 10 with breakpoints at p13-15 and q26. AluI digestion showed that the ring chromosome was monocentric. FISH with an alpha satellite probe specific for chromosome 10 showed one signal only
Neuropathological and Magnetic Resonance Imaging (MRI) studies showed a high frequency of posteri... more Neuropathological and Magnetic Resonance Imaging (MRI) studies showed a high frequency of posterior fossa abnormalities in preterms. To assess whether cerebellar haemorrhages (CH) diagnosed with ultrasound and/or MRI affect pons development in ELBW infants. The anteroposterior diameter of the pons was measured manually on the midline sagittal T1 MR image in 75 ELBW babies consecutively scanned at term postmenstrual age. Subjects with CH were identified and compared to babies with no posterior fossa bleeding. Nine ELBW infants with CH (CH-Group: median gestational age -GA- 26 wks, range 23-27; birth weight -BW- 680 g, 425-980) were compared with 66 babies with normal cerebellum (Control-Group: GA 28 wks, 23-33; BW 815 g, 430-1000). The two groups were comparable for BW (p=0.088) while GA was significantly shorter in CH babies (p=0.005). The pontine diameter was significantly lower in CH-Group compared to Control-Group (12.8 +/- 2.2 vs 14.8 +/- 1.2 mm; p<0.001). Cerebellar haemorrh...
The assessment of whether brain development is at an appropriate level for age has become an inte... more The assessment of whether brain development is at an appropriate level for age has become an integral part of clinical MR reporting, although few studies have quantitatively defined the developmental changes occurring in premature infants. We have developed a simple scoring system to assess four parameters of cerebral maturation--myelination, cortical folding, glial cell migration, and germinal matrix distribution--to determine the total maturation score (TMS). The aim of this study was to validate this scoring system in a large population of preterm infants across a range of gestational ages. A retrospective analysis was conducted of MR images acquired over a 3-year period with an identical imaging protocol. Infants born more than 14 days before the imaging examination and those with a clinical or radiologic history suggestive of neuroabnormality were excluded from the study. The TMS was derived by consensus. Interobserver agreement was evaluated by using the Bland-Altman plot. Ima...
The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians, Jan 23, 2013
Oxidative stress (OS) occurs at birth in all newborns as a consequence of the hyperoxic challenge... more Oxidative stress (OS) occurs at birth in all newborns as a consequence of the hyperoxic challenge due to the transition from the hypoxic intrauterine environment to extrauterine life. Free radical (FRs) sources such as inflammation, hyperoxia, hypoxia, ischaemia-reperfusion, neutrophil and macrophage activation, glutamate and free iron release, all increases the OS during the perinatal period. Newborns, and particularly preterm infants, have reduced antioxidant defences and are not able to counteract the harmful effects of FRs. Energy metabolism is central to life because cells cannot exist without an adequate supply of ATP. Due to its growth, the mammalian brain can be considered as a steady-state system in which ATP production matches ATP utilisation. The developing brain is particularly sensitive to any disturbances in energy generation, and even a short-term interruption can lead to long-lasting and irreversible damage. Whenever energy failure develops, brain damage can occur. A...
Cortex; a journal devoted to the study of the nervous system and behavior, 2014
Visual impairment in preterm infants at term equivalent age (TEA) is associated with impaired mic... more Visual impairment in preterm infants at term equivalent age (TEA) is associated with impaired microstructural development in the optic radiation, measured as reduced fractional anisotropy (FA) by Diffusion Tensor Imaging (DTI). We tested the hypothesis that these abnormalities develop during the late preterm period. DTI was performed in 53 infants born at a median (range) of 30(+1) (25(+4)-34(+6)) weeks post-menstrual age (PMA), 22 of whom were imaged twice. FA in the optic radiation at TEA was related to: visual function (p = .003); PMA at birth (p = .015); and PMA at scan (p = .008); while a significant interaction between PMA at birth and scan (p = .019) revealed an effect of the period of premature extra-uterine life additional to the degree of prematurity. We explored this further in a sub-group of 22 infants who were studied twice. FA increased from mean (95% CI) .174 (.164-.176) on the first image at 32(+5) (29(+5)-36) weeks PMA, to .198 (.190-.206) on the second image at 40(...
The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians, Jan 23, 2013
For many years cerebellar development after preterm birth has been poorly investigated and has be... more For many years cerebellar development after preterm birth has been poorly investigated and has been studied without taking germinal matrix-intraventricular haemorrhage into account. Advanced neuroimaging techniques like magnetic resonance imaging, as well as the use of various acoustic windows (mastoid fontanelle, occipital foramen) have allowed for in vivo diagnosis of acquired focal haemorrhagic lesions in the cerebellum of very preterm babies. The vulnerability of the cerebellum also seems to be related to specific gestational ages, i.e., between 23 and 27 weeks, when rapid growth in cerebellar volume occurs and at a much faster rate than mean brain volume increase. In this paper, the contribution of the cerebellum in long-term motor cognitive, learning and behavioural functions, including psychiatric ones, is discussed.
Intrauterine growth restriction (IUGR) is associated with increased risk of perinatal morbidity a... more Intrauterine growth restriction (IUGR) is associated with increased risk of perinatal morbidity and mortality, as well as long-term neurological deficits. However, neurostructural correlations with observed developmental disabilities have not yet been established. Magnetic resonance imaging (MRI) could prove useful for assessing brain development in the early neonatal period. We evaluated cerebral lesions and morphological maturation by MRIs in 59 preterm neonates, in order to verify the hypothesis that IUGR interferes on human brain development. A total of 26 pregnancies were complicated by IUGR and 33 pregnancies delivered preterm at a comparable gestational age with appropriate for gestational age (AGA). Magnetic resonance examination was performed at the completion of 41 weeks&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; gestation. White matter disease studied with MR included periventricular cavitations and punctuate lesions characterized by increased signal on T1-weighted and decreased signal on T2-weighted images. Cerebral maturation was defined by the total maturation score, on the basis of 4 morphological parameters of cerebral maturation: myelination (M), cortical infolding (C), germinal matrix distribution (GM), and glial cell migration pattern (G). No difference in brain lesions and in the level of cerebral maturation was found between preterm AGA and IUGR neonates. However, myelination was significantly reduced in IUGR neonates with brain sparing compared to IUGR neonates with normal Doppler of middle cerebral artery. Our study could not demonstrate any major significant difference between preterm AGA and IUGR neonates in terms of lesion occurrence and cerebral maturation. We observed, however, a mild delay in myelination in IUGR with brain sparing in utero. The relevance of this finding needs to be investigated with long-term follow-up.
Withdrawal and infusion of blood via umbilical catheters can affect cerebral blood flow in preter... more Withdrawal and infusion of blood via umbilical catheters can affect cerebral blood flow in preterm infants. We compared the effects on cerebral perfusion of 3 ml/kg blood withdrawal and infusion via umbilical arterial (UAC) and venous (UVC) catheters in 16 infants &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; or =32 weeks gestation, age &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;24 h, on mechanical ventilation. Near infrared spectroscopy was used to monitor changes in cerebral oxy- and deoxyhemoglobin, total cerebral hemoglobin (an index of cerebral blood volume; CBV) and HbD (an index of cerebral intravascular oxygenation). In 10 infants the study was repeated 1 h after intravenous administration of 10 mg/kg ibuprofen as prophylaxis against PDA. Withdrawal and infusion via the UVC caused significant MABP and concordant HbD and CBV changes. Smaller modifications were seen following blood withdrawal and infusion via the UAC. Ibuprofen attenuated cerebral hemodynamic changes associated with withdrawal, but not infusion, from UAC and UVC.
Conventional coagulation tests might be inadequate to explore mechanisms regulating thrombin gene... more Conventional coagulation tests might be inadequate to explore mechanisms regulating thrombin generation in neonates, because they do not allow full activation of the reduced levels of protein C. Therefore, they do not reflect the action of pro- and anti-coagulants as does the endogenous thrombin potential assessed in the presence of thrombomodulin. Endogenous thrombin potential measured without thrombomodulin was greater than the lower-limit of the adult reference interval in 30% of 109 full-term and 49% of 55 pre-term neonates, a finding consistent with the reduced levels of procoagulants in this setting. When the test was modified adding thrombomodulin, endogenous thrombin potential reverted into the adult reference interval in 97% and 100% full-term and pre-term neonates. In conclusion, the coagulation balance in neonates is restored by the concomitant reduction of pro- and anticoagulants. The restored balance can be shown in vitro by the endogenous thrombin potential test that includes thrombomodulin, but not by conventional coagulation tests.
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