Modeling Developmental Changes in Caffeine Clearance Considering Differences between Pre- and Postnatal Period.

Taguchi et al. reported that postmenstrual age (PMA) is a promising factor in describing and understanding the developmental change of caffeine (CAF) clearance. The aim of the present study was to quantify how developmental changes occur and to determine the effect of the length of the gestational period on CAF clearance. We performed a nonlinear mixed effect model (NONMEM) analysis and evaluated the fit of six models. A total of 115 samples were obtained from 52 patients with a mean age of 34.3 ± 18.2 d. The median values of gestational age (GA) and postnatal age (PNA) were 196 and 31 d, respectively. Serum CAF levels corrected for dose per body surface area (BSA) (C/D ratioBSA) were dependent on PMA rather than PNA, which supports the findings of a previous study. NONMEM analysis provided the following final model of oral clearance: CL/F = 0.00603∙WT∙∙0.877GA ≤ 196 L/h. This model takes into account developmental changes during prenatal and postnatal periods separately. The model successfully described the variation in clearance of CAF. Our findings suggest that the dosage of CAF in preterm infants should be determined based not only on body weight (WT) but also on both PNA and GA.

Postnatal age-related change of brain volume and its association with neurobehavior outcome in term neonates / 西安交通大学学报(医学版)

Objective To analyze the relationship of the volume of 87 brain regions with postnatal age and neurobehavior in full-term neonates.Methods A total of 75 full-term newborns[gestational age(39.38±1.22)weeks;male/female(51/24);postnatal age(11.11±6.67)days]without abnormalities on brain MRI(three-dimensional T1-weighted imaging,3D T1WI)at our hospital between November 2010 and September 2017 were retrospectively included.Based on the template of 87 brain regions,the neonatal brains were divided into 87 brain regions and their volumes were calculated by using V-shape Bottleneck network(VB-Net)deep learning segmentation technique,Pearson partial correlation and regression analysis were used to explore the relationship of the volume of each brain region with postnatal age and neurobehavioral scores.Results After adjusting for gestational age,birth weight,head circumference,body length and sex,66.7％of the regional brain volumes(58/87 brain regions)significantly increased with the postnatal age(correlation coefficient r:0.2-0.7,P＜0.05).The volumes of gray matter in bilateral lentiform nucleus,left caudate nucleus,right occipital lobe,right inferior temporal lobe,and bilateral anterior temporal lobe strongly correlated with the postnatal age(r＞0.50,P＜0.05).The gray matter volume of the right occipital lobe linearly increased with age(slope:100.67),and was positively correlated with behavioral scores(r=0.324,P＜0.01).Conclusion Most of regional brain volumes increase with the postnatal age during the neonatal period,and the fastest growth occurs in primary sensorimotor-related brain regions,presenting the spatial heterogeneity.Partial brain region grows with the development of behavioral ability.

Postnatal age is strongly correlated with the early development of the gut microbiome in preterm infants.

BACKGROUND: The gut microbiome plays a potential role in clinical events in preterm infants and may affect their lateral development. Understanding the initial colonization of microbes in the gut, their early dynamic changes, and the major factors correlated with these changes would provide crucial information about the developmental process in early life. METHODS: The present study enrolled 151 preterm infants and examined the longitudinal dynamics of their fecal microbiome profiles during the period of hospitalization using 16S ribosomal RNA gene sequencing. Random forest modeling was used to predict postnatal age (Age), postmenstrual age (PMA), and gestational age (GA), using gut microbiome features. RESULTS: Principal coordinate analysis revealed that the gut microbiome of the preterm infants displayed an obvious time-dependent change pattern, which showed the strongest association with Age, followed by PMA, and a much weaker association with (GA). Random forest modeling further evidenced the time-dependent change pattern, with the Pearson's correlation coefficients between the actual values and the gut microbiome-predicted values being 0.68, 0.53, and 0.38 for postnatal, postmenstrual, and gestational age, respectively. The microbiome dynamism could be further divided into four Age stages, each with its own characteristic microbial taxa. The first 1-4 days (T1 stage) represented the meconium microbiome, with colonization of a high diversity of microbes before or during delivery. During 5-15 days (T2 stage), the gut microbiome of the preterm infants underwent a rapid turnover, in which microbial diversity declined, and stabilized afterward. Enterobacteriaceae, Enterococcaceae, Streptococcaceae, Staphylococcaceae, and Clostridiaceae were the major classes in the gut microbiome in the lateral stages of development (T3-T4 stage). CONCLUSIONS: Postnatal age, rather than the gestational age, is significantly correlated with the gut microbiome of preterm infants, suggesting that clinical interventions contribute more to the early dynamics of gut microbiome in preterm infants than the natural development of the gut.

Factors affecting the effectiveness of oral ibuprofen in the treatment of patent ductus arteriosus in preterm infants.

Background Data on the effectiveness of oral ibuprofen treatment for patent ductus arteriosus are limited, and the factors affecting its effectiveness remain unclear. Objective The aim was to identify the potential factors affecting the clinical effectiveness of oral ibuprofen in preterm infants. Setting Neonatal intensive care unit in a prefecture-level maternal and child healthcare hospital in China. Method Over a 5-years period, the medical records of 327 preterm infants with patent ductus arteriosus who were admitted to the neonatal intensive care unit of our hospital to receive a single course of oral ibuprofen were retrospectively reviewed. Main outcome measures The prevalence of risk factors affecting the effectiveness of oral ibuprofen. Results In total, 201 (61.47%) preterm infants were considered to have undergone "effective therapy" and classified accordingly, whereas 11 (3.36%) showed certain adverse events. Factors affecting therapeutic effectiveness were postnatal age at the initiation of treatment and Day 1/Day 0 ratio of urine output/fluid intake during the treatment course, with odds ratios of 0.892 (95% CI: 0.835-0.953; P = 0.001) and 0.473 (95% CI 0.265-0.845; P = 0.011), respectively. Conclusion A single course of oral ibuprofen for patent ductus arteriosus closure among preterm infants is effective and safe. Preterm infants with postnatal age of ≤ 9 days at the initiation of treatment and Day 1/Day 0 ratio of ≤ 0.708 of the urine output/fluid intake during the treatment course can be considered predictors of effectiveness of patent ductus arteriosus.

Pharmacokinetic Variability of Caffeine in Routinely Treated Preterm Infants: Preliminary Considerations on Developmental Changes of Systemic Clearance.

The purpose of this study was to clarify the variability of serum concentrations of caffeine (CAF) in preterm infants, and to deliberate on a better explanation for developmental changes of systemic clearance during the neonatal period. Forty-nine serum samples were obtained from 23 preterm neonates (age, 34.1 ± 18.8 d), and additive blood sampling was conducted periodically for 10 of the 23 patients after discontinuation of CAF treatment. The concentrations of CAF and its major metabolites were determined by liquid chromatography-tandem mass spectrometory. The serum concentrations of CAF were within therapeutic levels (5-25 µg/mL) in 37 samples and exceeded 25 µg/mL in the rest of the 12 samples, although no sample was in the toxic range (> 50 µg/mL). The inter- and intra-individual variability of the concentration to dose (C/D) ratio corrected for body surface area (BSA) was more negatively associated with postmenstrual age (PMA) rather than postnatal age (PNA). The serum concentrations of major metabolites were much smaller than those of CAF throughout the study, suggesting that the contribution of hepatic metabolism to drug elimination was small in the preterm infants under 241 d of PMA. The mean values for elimination half-life and oral clearance estimated in the 10 patients were 124.6 ± 44.6 h and 2.26 ± 0.73 mL/min/1.73 m2, respectively. Consequently, we confirmed that the exposure to CAF was considerably variable and provided additive insight that the C/D ratio corrected for patient's BSA and PMA are promising for describing and understanding the developmental change of clearance in preterm infants.

Early life stress dysregulates kappa opioid receptor signaling within the lateral habenula.

The lateral habenula (LHb) is an epithalamic brain region associated with value-based decision making and stress evasion through its modulation of dopamine (DA)-mediated reward circuitry. Specifically, increased activity of the LHb is associated with drug addiction, schizophrenia and stress-related disorders such as depression, anxiety and posttraumatic stress disorder. Dynorphin (Dyn)/Kappa opioid receptor (KOR) signaling is a mediator of stress response in reward circuitry. Previously, we have shown that maternal deprivation (MD), a severe early life stress, increases LHb spontaneous neuronal activity and intrinsic excitability while blunting the response of LHb neurons to extrahypothalamic corticotropin-releasing factor (CRF) signaling, another stress mediator. CRF pathways also interact with Dyn/KOR signaling. Surprisingly, there has been little study of direct KOR regulation of the LHb despite its distinct role in stress, reward and aversion processing. To test the functional role of Dyn/KOR signaling in the LHb, we utilized ex-vivo electrophysiology combined with pharmacological tools in rat LHb slices. We show that activation of KORs by a KOR agonist (U50,488) exerted differential effects on the excitability of two distinct sub-populations of LHb neurons that differed in their expression of hyperpolarization-activated cation currents (HCN, Ih). Specifically, KOR stimulation increased neuronal excitability in LHb neurons with large Ih currents (Ih+) while decreasing neuronal excitability in small/negative Ih (Ih-) neurons. We found that an intact fast-synaptic transmission was required for the effects of U50,488 on the excitability of both Ih- and Ih+ LHb neuronal subpopulations. While AMPAR-, GABAAR-, or NMDAR-mediated synaptic transmission alone was sufficient to mediate the effects of U50,488 on excitability of Ih- neurons, either GABAAR- or NMDAR-mediated synaptic transmission could mediate these effects in Ih+ neurons. Consistently, KOR activation also altered both glutamatergic and GABAergic synaptic transmission where stimulation of presynaptic KORs uniformly suppressed glutamate release onto LHb neurons while primarily decreased or in some cases increased GABA release. We also found that MD significantly increased immunolabeled Dyn (the endogenous KOR agonist) labeling in neuronal fibers in LHb while significantly decreasing mRNA levels of KORs in LHb tissues compared to those from non-maternally deprived (non-MD) control rats. Moreover, the U50,488-mediated increase in LHb neuronal firing observed in non-MD rats was absent following MD. Altogether, this is the first demonstration of the existence of functional Dyn/KOR signaling in the LHb that can be modulated in response to severe early life stressors such as MD.

Reference ranges of presepsin (soluble CD14 subtype) in term and preterm neonates without infection, in relation to gestational and postnatal age, in the first 28 days of life.

OBJECTIVE: To determine the reference ranges of presepsin in term and preterm neonates without infection, with respect to gestational and postnatal age, within the first 28 days of life. METHODS: A total of 144 neonates born at 24-42 weeks' gestation, including healthy term and preterm neonates without clinical signs or symptoms of infection, were included in this prospective observational study. Presepsin measurements included cord blood levels and serum levels on postnatal days 1, 3, 5, 7, 14, 21, and 28. RESULTS: The presepsin values corresponding to the 10th percentile ranged from 240.8 pg/mL (on day 1) to 129.9 pg/mL (on day 28), whereas those corresponding to the 90th percentile ranged from 725.8 pg/mL (on day 1) to 471.6 pg/mL (on day 28). Significantly higher presepsin levels were observed in cesarean deliveries than in spontaneous deliveries (p: 0.012 to <0.001), in gestational ages ≤ 32 weeks than in gestational ages ≥37 weeks (p: <0.05 to <0.001), and in cases with a maternal history of chorioamnionitis than in those without (p: <0.05 to <0.001). CONCLUSION: In conclusion, our findings revealed, for the first time, the reference ranges of presepsin in healthy term and preterm neonates without infection with respect to gestational and postnatal age, sex, and body weight. Presepsin levels within the first 28 days of life seem likely to be affected by the type of delivery, gestational and postnatal age, birth weight, and presence of respiratory distress syndrome or maternal chorioamnionitis.

The effect of enteral bolus feeding on regional intestinal oxygen saturation in preterm infants is age-dependent: a longitudinal observational study.

BACKGROUND: The factors that determine the effect of enteral feeding on intestinal perfusion after preterm birth remain largely unknown. We aimed to determine the effect of enteral feeding on intestinal oxygen saturation (rintSO2) in preterm infants and evaluated whether this effect depended on postnatal age (PNA), postmenstrual age (PMA), and/or feeding volumes. We also evaluated whether changes in postprandial rintSO2 affected cerebral oxygen saturation (rcSO2). METHODS: In a longitudinal observational pilot study using near-infrared spectroscopy we measured rintSO2 and rcSO2 continuously for two hours on postnatal Days 2 to 5, 8, 15, 22, 29, and 36. We compared preprandial with postprandial values over time using multi-level analyses. To assess the effect of PNA, PMA, and feeding volumes, we performed Wilcoxon signed-rank tests or logistic regression analyses. To evaluate the effect on rcSO2, we also used logistic regression analyses. RESULTS: We included 29 infants: median (range) gestational age 28.1 weeks (25.1-30.7) and birth weight 1025 g (580-1495). On Day 5, rintSO2 values decreased postprandially: mean (SE) 44% (10) versus 35% (7), P = .01. On Day 29, rintSO2 values increased: 44% (11) versus 54% (7), P = .01. Infants with a PMA ≥ 32 weeks showed a rintSO2 increase after feeding (37% versus 51%, P = .04) whereas infants with a PMA < 32 weeks did not. Feeding volumes were associated with an increased postprandial rintSO2 (per 10 mL/kg: OR 1.63, 95% CI, 1.02-2.59). We did not find an effect on rcSO2 when rintSO2 increased postprandially. CONCLUSIONS: Our study suggests that postprandial rintSO2 increases in preterm infants only from the fifth week after birth, particularly at PMA ≥ 32 weeks when greater volumes of enteral feeding are tolerated. We speculate that at young gestational and postmenstrual ages preterm infants are still unable to increase intestinal oxygen saturation after feeding, which might be essential to meet metabolic demands. TRIAL REGISTRATION: For this prospective longitudinal pilot study we derived patients from a larger observational cohort study: CALIFORNIA-Trial, Dutch Trial Registry NTR4153 .

The cerebral hemodynamic response to phonetic changes of speech in preterm and term infants: The impact of postmenstrual age.

Higher brain dysfunction, such as language delay, is a major concern among preterm infants. Cerebral substrates of cognitive development in preterm infants remain elusive, partly because of limited methods. The present study focuses on hemodynamic response patterns for brain function by using near-infrared spectroscopy. Specifically, the study investigates gestational differences in the hemodynamic response pattern evoked in response to phonetic changes of speech and cerebral hemispheric specialization of the auditory area in preterm infants (n = 60) and term infants (n = 20). Eighty neonates born between 26 and 41 weeks of gestational age (GA) were tested from 33 to 41 weeks of postmenstrual age (PMA). We analyzed the hemodynamic response pattern to phonemic and prosodic contrasts for multiple channels on temporal regions and the laterality index of the auditory area. Preterm infants younger than 39 weeks of PMA showed significantly atypical hemodynamic patterns, with an inverted response shape. Partial correlation analysis of the typicality score of hemodynamic response revealed a significant positive correlation with PMA. The laterality index of preterm infants from 39 weeks of PMA demonstrated a tendency rightward dominance for prosodic changes similar to term infants. We provide new evidence that alterations in hemodynamic regulation and the functional system for phonemic and prosodic processing in preterm infants catch up by their projected due dates.

Is procalcitonin to C-reactive protein ratio useful for the detection of late onset neonatal sepsis?

Procalcitonin (PCT) has been reported as a sensitive marker for neonatal bacterial infections. Recently, small numbers of studies reported usefulness of PCT/C-reactive protein (CRP) ratio in detection of infectious conditions in adults. Thus, we conducted this study to evaluate PCT/CRP ratio in late onset neonatal sepsis. Serum PCT and CRP was measured in blood samples from 7 to 60 days after birth in 106 of neonates with late onset sepsis and 212 of controls who were matched with gestational age, postnatal age, birth weight, and gender. Areas under ROC curve (AUC) were calculated, and pairwise comparisons between ROC curves were performed. As a result, CRP (AUC 0.96) showed best performance in detection of sepsis from healthy controls compared with PCT (AUC 0.87) and PCT/CRP ratio (AUC 0.62); CRP > PCT > PCT/CRP ratio in pairwise comparison (p < .001). Both of CRP (AUC 0.94) and PCT (AUC 0.96) were found to discriminate proven sepsis from healthy controls compared with PCT/CRP ratio (AUC 0.54); CRP = PCT > PCT/CRP ratio in pairwise comparison (p < .001). However, in the detection of blood culture proven sepsis from suspected sepsis, PCT (AUC 0.70), and PCT/CRP ratio (AUC 0.73) showed better performance compared with CRP (AUC 0.51); PCT = PCT/CRP ratio > CRP in pairwise comparison (p < .001 and p = .006, respectively). In conclusion, CRP and PCT showed good performance in discrimination between sepsis and healthy controls. However, PCT/CRP ratio seems to be helpful in distinguishing proven sepsis from suspected sepsis together with PCT. Further studies are warranted to elucidate the efficacy of PCT/CRP ratio with enrollment of enough numbers of infants.

Foetal haemoglobin concentration at postmenstrual age is unaffected by gestational age at birth.

Background Our aim was to determine whether the postnatal age or postmenstrual age is a more appropriate criterion for evaluating foetal haemoglobin concentrations. Methods Blood samples ( n = 1095) were obtained from 394 infants and were divided into two groups based on gestational age at birth: <37 weeks ( n = 491) and ≥37 weeks ( n = 604). (1) Foetal haemoglobin concentrations divided by one month at age after birth were compared between the groups. (2) Foetal haemoglobin concentrations divided into ≤9 months from last menstruation and one month thereafter were compared between the groups. Results In samples from infants ≥37 weeks' gestational age at birth, the median foetal haemoglobin concentrations were 69.5%, 21.4% and 3.6% at 0-1 month, 2-3 months and ≥5 months after birth, respectively. The median foetal haemoglobin concentrations in infants <37 weeks' gestational age at birth were 75.5%, 62.7% and 5.1% at 0-1 month, 2-3 months and ≥5 months after birth, respectively. The median foetal haemoglobin concentrations in infants <37 weeks' gestational age at birth were significantly higher than that in infants ≥37 weeks' gestational age at birth at all postnatal age points. (2) There was no significant difference between the groups at all age points after nine months of postmenstrual age: 72.5 and 75.3% at 9-10 months, 25.1 and 26.6% at 11-12 months and 5.5 and 4.6% at >13 months after last menstruation in infants ≥37 and <37 weeks' gestational age at birth, respectively. Conclusions Evaluation of foetal haemoglobin concentrations at postmenstrual age is unaffected by gestational age at birth.

Reticulocyte Haemoglobin Content Declines More Markedly in Preterm than in Term Infants in the First Days after Birth.

BACKGROUND: Reticulocyte haemoglobin content, i.e., the reticulocyte equivalent (Ret-He), seems to be a promising parameter for the detection of iron deficiency (ID) in neonates because it can be obtained as part of a reticulocyte count, with no additional blood loss and at no extra cost. Due to the short life span of reticulocytes, Ret-He reflects current iron availability for erythropoiesis more accurately than other common erythrocyte indices. OBJECTIVE: We aimed to evaluate postnatal changes in Ret-He within the first days after birth in term and preterm infants with the hypothesis that preterm infants experience a more pronounced postnatal reduction in Ret-He when compared to term infants. METHODS: We conducted retrospective analyses of clinically indicated blood samples. Paired t test and mixed regression modelling were used. RESULTS: In total, 805 blood samples obtained from 207 term and 295 preterm infants were analysed. Ret-He decreased by 1.5 pg per day (regression coefficient [95% CI] -1.5 [-1.8 to -1.2] pg, p < 0.0001). This drop was more significant in preterm infants (regression coefficient -2.2 [-2.6 to -1.8] pg, p < 0.0001) than in term infants (regression coefficient -0.8 [-1.3 to -0.2] pg, p < 0.01, pinteraction < 0.0001). CONCLUSION: Ret-He declined within the first days after birth. The observed changes with postnatal age were more pronounced in preterm than in term infants. Further studies are needed to evaluate if these changes are due to developing ID or other causes.

Impact of neonate haematocrit variability on the longitudinal relaxation time of blood: Implications for arterial spin labelling MRI.

BACKGROUND AND PURPOSE: The longitudinal relaxation time of blood (T 1b) is influenced by haematocrit (Hct) which is known to vary in neonates. The purpose of this study was threefold: to obtain T 1b values in neonates, to investigate how the T 1b influences quantitative arterial spin labelling (ASL), and to evaluate if known relationships between T 1b and haematocrit (Hct) hold true when Hct is measured by means of a point-of-care device. MATERIALS AND METHODS: One hundred and four neonates with 120 MR scan sessions (3 T) were included. The T 1b was obtained from a T 1 inversion recovery sequence. T 1b-induced changes in ASL cerebral blood flow estimates were evaluated. The Hct was obtained by means of a point-of-care device. Linear regression analysis was used to investigate the relation between Hct and MRI-derived R1 of blood (the inverse of the T 1b). RESULTS: Mean T 1b was 1.85 s (sd 0.2 s). The mean T 1b in preterm neonates was 1.77 s, 1.89 s in preterm neonates scanned at term-equivalent age (TEA) and 1.81 s in diseased neonates. The T 1b in the TEA was significantly different from the T 1b in the preterm (p < 0.05). The change in perfusion induced by the T 1b was -11% (sd 9.1%, p < 0.001). The relation between arterial-drawn Hct and R1b was R1b = 0.80 × Hct + 0.22, which falls within the confidence interval of the previously established relationships, whereas capillary-drawn Hct did not correlate with R1b. CONCLUSION: We demonstrated a wide variability of the T 1b in neonates and the implications it could have in methods relying on the actual T 1b as for instance ASL. It was concluded that arterial-drawn Hct values obtained from a point-of-care device can be used to infer the T 1b whereas our data did not support the use of capillary-drawn Hct for T 1b correction.

The effect of postnatal age on the early tactile manual abilities of preterm infants.

BACKGROUND: Although preterm infants possess early tactile manual abilities, the influence of the postnatal experience has not yet been systematically examined. AIMS: To investigate whether early tactile manual habituation, discrimination and recognition (following interference) of shape in preterm infants are modified by postnatal age. STUDY DESIGN: Prospective study. SUBJECTS: Forty preterm infants were assessed from the post-conceptional age (PCA) of 34 weeks. Two groups were made up according to postnatal age (PNA): low PNA (PNA≤10 days of life) and high PNA (PNA≥12 days of life). OUTCOME MEASURES: An object (prism or cylinder) was presented repeatedly in the left hand, and holding times of the object were recorded during each trial. RESULTS: Holding time was shorter for all preterm infants following successive presentation of the same object irrespective of postnatal age range. In the discrimination phase, the mean holding time for the novel object was longer than holding times in the last two habituation trials, in both PNA groups. Finally, the mean holding time of the familiar object presented in the recognition phase was shorter than the holding time of the novel object presented previously, but only in the low PNA group. CONCLUSIONS: Tactile manual habituation and discrimination of shape information is present in preterm infants at a post-conceptional age of 34 weeks, independently of postnatal age. However, tactile manual recognition of familiar shapes following interference is affected by length of postnatal experience. The significance of this last result is discussed in detail.

Assessment of brain maturation in the preterm infants using diffusion tensor imaging (DTI) and enhanced T2 star weighted angiography (ESWAN).

PURPOSE: To assess the brain maturation of preterm infants using diffusion tensor imaging (DTI) and enhanced T2 star weighted angiography (ESWAN). MATERIALS AND METHODS: Conventional magnetic resonance imaging (MRI), DTI and ESWAN were performed in 60 preterm infants and 21 term controls. 60 preterm infants were subgrouped to two groups according to the age at imaging: before and at term-equivalent age (TEA). Fractional anisotropy (FA), apparent diffusion coefficient (ADC) map from DTI, T2 and R2 maps from ESWAN were post-processed at an off-line workstation. The values of FA, ADC, T2 and R2 from the posterior limb of internal capsule (PLIC), frontal white matter (FWM), occipital white matter (OWM) and lentiform nuclei (LN) were determined. These parameters were compared between preterm and term infants. Correlations of DTI and ESWAN parameters with the gestational age, postmenstrual age and postnatal age were analyzed. RESULTS: ADCs of FWM, OWM and LN, and T2 values of the PLIC and LN were higher in the preterm infants at TEA compared with the term controls. The correlations were existed between the postmenstrual age and the values of FA, ADC, T2, R2 from the PLIC, values of ADC, T2, R2 from the LN, T2 value from the OWM. The correlations were also found between the postnatal age and the values of FA, ADC, T2 from the PLIC, and T2 value from the LN. CONCLUSION: The maturity of preterm brain around TEA was different from that of term controls and appeared to be independent of the prematurity at birth. T2 was one of valuable indices to evaluate brain maturation in preterm infants.

Growth defects in the dorsal pallium after genetically targeted ablation of principal preplate neurons and neuroblasts: a morphometric analysis.

The present study delineates the large-scale, organic responses of growth in the dorsal pallium to targeted genetic ablations of the principal PP (preplate) neurons of the neocortex. Ganciclovir treatment during prenatal development [from E11 (embryonic age 11) to E13] of mice selectively killed cells with shared S-phase vulnerability and targeted expression of a GPT [golli promoter transgene; GPT linked to HSV-TK (herpes simplex virus-thymidine kinase), τ-eGFP and lacZ reporters] localized in PP neurons and their intermediate progenitor neuroblasts. The volume, area and thickness of the pallium were measured in an E12-P4 (postnatal age 4) longitudinal study with comparisons between ablated (HSV-TK(+/0)) and control (HSV-TK(0/0)) littermates. The extent of ablations was also systematically varied, and the effect on physical growth was assessed in an E18 cross-sectional study. The morphological evidence obtained in the present study supports the conclusion that genetically targeted ablations delay the settlement of the principal PP neurons of the dorsal pallium. This leads to progressive and substantial reductions of growth, despite compensatory responses that rapidly replace the ablated cells. These growth defects originate from inductive cellular interactions in the proliferative matrix of the ventricular zone of the pallium, but are amplified by subsequent morphogenic and trophic cellular interactions. The defects persist during the course of prenatal and postnatal development to demonstrate a constrained dose-response relationship with the extent of specific killing of GPT neurons. The defects propagate simultaneously in both the horizontal and vertical cytoarchitectural dimensions of the developing pallium, an outcome that produces a localized shortfall of volume in the telencephalic vesicles.

Color doppler evaluation of the influence of type of delivery, sex, postnatal age and time post feeding on full term healthy newborns cerebral blood flow / Doppler colorido na avaliação da influência do tipo de parto, sexo, idade pós-natal e tempo pós-mamada no fluxo sanguíneo cerebral em recém-nascidos a termo e saudáveis

OBJECTIVE: The purpose of this study was to evaluate with Color Doppler the influence of type of delivery, sex, postnatal age and time post feeding on full term healthy newborns cerebral blood flow. METHOD: 50 newborns were studied. The Doppler parameters, peak-systolic velocity, end-diastolic velocity, mean velocity, pulsatility index and resistance index, were measured in the anterior cerebral artery, middle cerebral artery, posterior cerebral artery, and basilar artery. The data were compared and analyzed by statistical tests. Informed consent was obtained from all parents, and the study was approved by institutional ethical committee and review board. RESULTS: We observed not statistically significant differences on cerebral blood flow Doppler parameters in relation to type of delivery, sex, postnatal age and feeding in full term healthy newborns. CONCLUSION: We believe that the knowledge of these cerebral hemodynamic profile of newborns in the first days of life can contribute in an accurate interpretation of cranial Doppler abnormal findings when pathologic flow velocities are analyzed.

OBJETIVO: O objetivo deste estudo foi avaliar com Doppler colorido a influência do tipo de parto, sexo, idade pós-natal e tempo pós-mamada no fluxo sanguíneo cerebral de recém-nascidos a termo e saudáveis. MÉTODO: Foram estudados 50 recém-nascidos. A Dopplervelocimetria foi obtida nas artérias cerebral anterior, cerebral média, cerebral posterior e basilar. Os parâmetros foram comparados e analisados pelos testes estatísticos Esta pesquisa foi aprovada pela comissão ética e de pós-graduação das instituições e o consentimento informado dos pais foi obtido em todos os casos. RESULTADOS: Não observamos diferenças estatísticamente significativas na Dopplervelocimetria do fluxo sanguíneo cerebral em relação ao tipo de parto, sexo, idade pós-natal e tempo pós-mamada dos recém-nascidos normais e saudáveis estudados. CONCLUSÃO: Acreditamos que o conhecimento deste perfil hemodinâmico do fluxo sanguíneo cerebral de recém-nascidos nos primeiros dias de vida possa contribuir para uma acurada interpretação dos achados do Doppler cerebral quando alterações patológicas de velocidade do fluxo sanguíneo forem analisadas.