Weeks Of Postnatal Life Research Articles

Effects of a Human Milk-Derived Human Milk Fortifier on the Antibacterial Actions of Human Milk

To compare the effects of a human breastmilk-derived fortifier on the antibacterial activity of milk obtained from lactating mothers delivering prematurely with the effects of a powdered fortifier on the same milk. Human milk samples were obtained after the first week of postnatal life from 10 lactating mothers, who had delivered prematurely. A bovine milk-based powdered fortifier and a human breastmilk-based frozen fortifier were evaluated. All mothers were healthy and they were not on any medications, although they were taking prenatal vitamins during lactation. The effects of each fortifier on the antimicrobial activity of milk toward Enterobacter sakazaki (ES), Escherichia coli, Clostridium difficile (CD), and Shigella soneii (SS) were evaluated by both the filter paper method and the growth inhibition method. Human milk inhibited the growth of all of the test organisms. This antibacterial activity was almost totally inhibited by the addition of the bovine protein-based human milk fortifier, while it remained unaffected by the addition of the human breastmilk-based fortifier. Breastmilk from women who have delivered preterm has antibacterial activity that can be affected by the addition of bovine-based fortifier, but not by the addition of a human breastmilk-based fortifier.

Both postnatal and postmenstrual age contribute to the interindividual variability in tramadol glucuronidation in neonates

Introduction Although of pharmacokinetic and -dynamic relevance, data on ontogeny of UDP-glucuronosyltransferase (UGT) activity in neonates are scant. We therefore wanted to assess the impact of both postnatal and postmenstrual age (PNA/PMA) on the interindividual variability of glucuronidation to overall tramadol urinary elimination in neonates. Methods O-demethyl tramadol (M1) and M1-glucuronide (M1G) were determined in 24 hour urine collections during continuous intravenous tramadol administration in neonates. Glucuronidation fraction (%) was calculated by the ratio of M1G to the sum of M1G and M1 free (M1total). Fractions (%) in early (< day 8) or late neonatal life (day 8–28) were compared (Mann–Whitney U) and forward multiple regression was applied to assess the impact of various covariates. Results Urine collections were available in 59 neonates with a PNA of 6 (1–28) days and a PMA of 38 (SD 4) weeks. Mean M1G/M1total was 27 (SD 15) % and was significantly lower in early compared to late neonatal life (22 versus 32%, p = 0.0001). In a forward multiple regression model, both PMA and early versus late neonatal life remained independent variables to explain the interindividual variability in M1G/M1total. Conclusions Besides PMA, there is an additional, independent impact of PNA since phenotypic glucuronidation activity is significantly lower in the first week of postnatal life. These findings should be taken into account in the assessment of compounds for whom glucuronidation is of pharmacokinetic, pharmacodynamic or toxicological relevance.

Functional Development of the Ovarian Noradrenergic Innervation

A substantial fraction of the noradrenergic innervation targeting the mammalian ovary is provided by neurons of the celiac ganglion. Although studies in the rat have shown that noradrenergic nerves reach the ovary near the time of birth, it is unknown how the functional capacity of this innervation unfolds during postnatal ovarian development. To address this issue, we assessed the ability of the developing ovary to incorporate and release (3)H-norepinephrine. Incorporation of (3)H-norepinephrine was low during the first 3 wk of postnatal life, but pharmacological inhibition of norepinephrine (NE) neuronal uptake with cocaine showed that an intact transport mechanism for NE into nerve terminals is already in place by the first week after birth. Consistent with this functional assessment, the mRNA encoding the NE transporter was also expressed in the celiac ganglion at this time. During neonatal-infantile development [postnatal (PN) d 5-20], the spontaneous, vesicle-independent outflow of recently taken up NE was high, but the NE output in response to K(+)-induced depolarization was low. After PN d 20, spontaneous outflow decreased and the response to K(+) increased markedly, reaching maximal values by the time of puberty. Tyramine-mediated displacement of NE stored in vesicles, which displace vesicular NE, showed that vesicle-dependent NE storage becomes functional by PN d 12 and that vesicular release increases during the juvenile-peripubertal phases of sexual development. These results indicate that vesicular release of NE from ovarian noradrenergic nerves begins to operate by the third week of postnatal life, becoming fully functional near the time of puberty.

Altered expression of cyclooxygenase-2, presenilins and oxygen radical scavenging enzymes in a rat model of global perinatal asphyxia

Cyclooxygenase-2 (COX-2) and presenilin (PSEN) 1 and 2 genes are regulated during development as well as in pathological conditions associated to hypoxia. In this study, we investigated their patterns of expression during the first 2 weeks of postnatal life in a rat model of moderate global perinatal asphyxia that we have previously reported to be characterized by early oxidative stress and delayed behavioral alterations. In the hippocampus, global perinatal asphyxia induced an early up-regulation COX-2 mRNA (postnatal day, pnd, 1), which preceded those of PSEN 1 and 2 genes, observed at pnd 4. At pnd 11, the expression of all three genes was decreased compared to control animals. In addition, we analyzed the expression of the scavenging enzymes catalase, copper/zinc- and manganese-superoxide dismutase. As for COX-2, the three enzymes were up-regulated in the hippocampus at pnd 1 and returned at or below baseline by pnd 4. In the cortex, only PSEN 1 and 2 showed a moderate up-regulation at pnd 1 followed by a down-regulation at pnd 11. These findings suggest that moderate perinatal hypoxic episodes are associated with a dysregulation of the several genes involved in brain development and anti-oxidant defenses, which follows a rapid and transient oxidative stress. Such alterations are particularly evident in the hippocampus and could represent an adaptive response to the hypoxic condition. The delayed down-regulation of the scavenging enzymes could set the ground for brain damage and delayed behavioral alterations and further support the potential benefit of early anti-oxidant treatments in a short therapeutic window soon after birth.

The cell lineage of neuronal subtypes in the mammalian cerebral cortex.

We have studied the lineage relationships of pyramidal and nonpyramidal neurons, the principal neuronal types in the cerebral cortex, using a recombinant retrovirus that carries the gene encoding Escherichia coli beta-galactosidase as a lineage marker. The phenotype of every cell of clones of beta-galactosidase-labelled neurons generated by intraventricular injection of recombinant retrovirus in rat embryos at different stages of cortical neurogenesis was identified using light and electron microscopy as well as immunohistochemistry for known markers of neuronal subtypes. We found that clonally related neurons in adult rats showed the same morphological and neurotransmitter phenotypes, suggesting that lineages of pyramidal and nonpyramidal neurons are specified as early as E14, the time of onset of neurogenesis. However, when we followed the development of cortical cell lineages, we noted that a significant number of neuronal clones showed a mixed pyramidal/nonpyramidal cell composition during the first three weeks of life. We suggest that the change in the composition of neuronal clones between the third week of postnatal life and adulthood may either be due to changes in the phenotype of some developing neurons or, more likely, to selective cell death.

Characterization of a cerebellar granule progenitor cell line, E tC.1, and its responsiveness to 17-β-estradiol

Mouse cerebellar development occurs at late embryonic stages and through the first few weeks of postnatal life. Hormones such as 17-β-estradiol (E2) have been implicated in cerebellar development, through the expression of E2 receptors (ER). However, the role of E2 in the development and function of cerebellar neurons has yet to be fully elucidated. To gain insight into E2's actions on the developing cerebellum, we characterized a cloned neuronal cell line, E tC.1, derived from late embryonic cerebellum for its neural properties and responsiveness to E2. Our results revealed that E tC.1 cells express markers characteristic of neural progenitor cells such as Nestin, Musashi, and Doublecortin (DCX), and of the granule cell lineage such as Math1 and Zipro1. The ER alpha and beta (ERα and ERβ) were also identified in this cell line. Functionality of ERs was verified using an Estrogen Response Element (ERE)-Luciferase reporter plasmid. E2 modulated ERα, FMRP, and IL-6, which were expressed in these cells. However, E2 did not induce changes in neural proteins nor induce maturation of E tC.1 cells. CREB and ERK 1/2 protein kinases were not modulated by E2 either. Interestingly, E tC.1 expressed active p450 Aromatase (P450arom), which was confirmed by the aromatization of androstenedione (AD) to E2 and other estrogen metabolites. Collectively, our results show that the E tC.1 cell line may serve as a model to study early development of cerebellar progenitor granule cells, and their responsiveness to E2.

Changes in thymus size, cellularity and relation between thymocyte subpopulations in young adult rats induced by Somatostatin-14

The role of somatostatin on inhibition of both normal and tumor cell cycle, secretion of endocrine and exocrine cells, as well as induction apoptosis is well documented. However, its effect on T cell development and thymic structure is not fully clarified. In order to investigate the influence of somatostatin in vivo on the thymus structure and T cell development, the young adult Albino Oxford male rats were intracerebroventriculary treated with somatostatin-14. We examined the thymus compartments and its cellularity, through assessment of morphometric parameters by stereological method, and the relation between thymocytes subpopulations, over expression of CD4, CD8 and T-cell receptor (TCR) alpha beta by flow cytometry. Additionally, we also determined the body and thymus weight of the rats, during the first three months of life, to define the time of SRIH-14 application. A decrease of relative thymus weight from the fourth weeks of postnatal life, and an unchanged relative thymus weight obtained in treated group indicates that SRIH-14 in young adult rats inhibits growth of whole organism, not only thymus. The changes in the absolute number and numerical density of cortical thymocytes indicate that SRIH-14 alters the true lymphoid tissue. SRIH-14 changes relation between thymocyte subsets, increase number of CD4(-)CD8(-)TCR alpha beta(-) and CD4(-)CD8(+)TCR alpha beta(hi) thymocyte subsets as well as the CD4(-)CD8(-)TCR alpha beta(low/hi) thymocytes, while decrease number of CD4(+)CD8(+) TCR alpha beta(-/low/hi) thymocyte subsets. These results indicate that somatostatin-14 is not involved in the control of the physiologic involution of the thymus, although induces thymic weight loss through the reduction of true lymphoid tissue. In addition, changes in frequency of thymocyte subpopulations, especially immature cells, indicate that SRIH-14 modulates thymocytes development and maturation.

Predictability of vancomycin pharmacokinetics in neonates

Dear Editor, We read with great interest the paper of Cunha et al. on the cost-ineffectiveness of measuring serum vancomycin trough concentrations in adult hospitalized patients receiving parenteral vancomycin. Based on a retrospective analysis of observations collected in 351 patients, the authors illustrated that vancomycin dosed by creatinine clearance estimations, based on serum creatinine values, was acceptably accurate [1]. We would like to add to the discussion that the conclusions formulated by Cunha et al. in adults might be extrapolated to neonatal populations in whom vancomycin dosed by creatinine clearance estimations is acceptable once serum creatinine values reflect renal function. Since glycopeptides are almost exclusively eliminated according to the glomerular filtration rate (GFR), developmental changes in renal clearing capacity in the neonate have to be taken into account. We therefore would like to report here our recently published data on vancomycin clearance in the first month of life in 214 neonates and compare them with the findings of Cunha et al. [1, 2]. Size explained 49.8%, postmenstrual age 18.2%, and renal function (serum creatinine values) 14.1% of vancomycin clearance variability, resulting in over 80% of explained variability in vancomycin clearance in the first 4 weeks of postnatal life [2]. In children and adults, serum creatinine values serve as a useful and reliable marker of renal clearance. In neonates, however, serum creatinine values at birth mainly reflect the maternal renal function and only turn into a reliable marker of renal clearance after the first week of life [3]. The overall high predictability of vancomycin clearance in this cohort of neonates therefore mainly relates to the fact that this drug is only very rarely administered in the very first days of life when creatinaemia does not yet reflect neonatal GFR and is in contrast to the limited predictability of renal drug clearance at birth [4]. The bactericidal activity of glycopeptide antibiotics is based on the inhibition of bacterial cell-wall synthesis. Glycopeptide antibiotics are the drugs of choice for methicillin-resistant staphylococcal infections and are widely used as empiric treatment for infections related to the central venous line in neonates. These infections are often caused by coagulase-negative staphylococci. Taking these epidemiological factors into account, vancomycin is only rarely administered in the first days of life but is a frequently administered drug in neonates for the abovementioned pathogens [5]. We therefore suggest extrapolating the conclusions formulated by Cunha et al. in adults to all populations in whom vancomycin dosed by creatinine clearance estimations is acceptably accurate hereby excluding the first days of postnatal life in addition to other specific conditions such as extracorporeal membrane oxygenation. Eur J Clin Microbiol Infect Dis (2007) 26:847–848 DOI 10.1007/s10096-007-0367-4

Expression of insulin‐like growth factor system genes during the early postnatal neurogenesis in the mouse hippocampus

Insulin-like growth factor-1 (IGF-1) is essential to hippocampal neurogenesis and the neuronal response to hypoxia/ischemia injury. IGF (IGF-1 and -2) signaling is mediated primarily by the type 1 IGF receptor (IGF-1R) and modulated by six high-affinity binding proteins (IGFBP) and the type 2 IGF receptor (IGF-2R), collectively termed IGF system proteins. Defining the precise cells that express each is essential to understanding their roles. With the exception of IGFBP-1, we found that mouse hippocampus expresses mRNA for each of these proteins during the first 2 weeks of postnatal life. Compared to postnatal day 14 (P14), mRNA abundance at P5 was higher for IGF-1, IGFBP-2, -3, and -5 (by 71%, 108%, 100%, and 98%, respectively), lower for IGF-2, IGF-2R, and IGFBP-6 (by 65%, 78%, and 44%, respectively), and unchanged for IGF-1R and IGFBP-4. Using laser capture microdissection (LCM), we found that granule neurons and pyramidal neurons exhibited identical patterns of expression of IGF-1, IGF-1R, IGF-2R, IGFBP-2, and -4, but did not express other IGF system genes. We then compared IGF system expression in mature granule neurons and their progenitors. Progenitors exhibited higher mRNA levels of IGF-1 and IGF-1R (by 130% and 86%, respectively), lower levels of IGF-2R (by 72%), and similar levels of IGFBP-4. Our data support a role for IGF in hippocampal neurogenesis and provide evidence that IGF actions are regulated within a defined in vivo milieu.

MEF2C Transcription Factor Controls Chondrocyte Hypertrophy and Bone Development

Chondrocyte hypertrophy is essential for endochondral bone development. Unexpectedly, we discovered that MEF2C, a transcription factor that regulates muscle and cardiovascular development, controls bone development by activating the gene program for chondrocyte hypertrophy. Genetic deletion of Mef2c or expression of a dominant-negative MEF2C mutant in endochondral cartilage impairs hypertrophy, cartilage angiogenesis, ossification, and longitudinal bone growth in mice. Conversely, a superactivating form of MEF2C causes precocious chondrocyte hypertrophy, ossification of growth plates, and dwarfism. Endochondral bone formation is exquisitely sensitive to the balance between MEF2C and the corepressor histone deacetylase 4 (HDAC4), such that bone deficiency of Mef2c mutant mice can be rescued by an Hdac4 mutation, and ectopic ossification in Hdac4 null mice can be diminished by a heterozygous Mef2c mutation. These findings reveal unexpected commonalities in the mechanisms governing muscle, cardiovascular, and bone development with respect to their regulation by MEF2 and class II HDACs.

Rat behavioral thermoregulation integrates with nonshivering thermogenesis during postnatal development.

Rat pups are capable of behavioral thermoregulation, both in the nest and on a thermocline, as early as the 1st week of postnatal life, and these pups can also produce heat metabolically without shivering. The rat pup's primary source of nonshivering thermogenesis is the sympathetically mediated metabolism of brown adipose tissue (BAT). BAT is well formed in newborns and functions shortly after birth. While infant behavioral thermoregulation and BAT thermogenesis have been extensively studied, little is known about the extent to which thermoregulatory behavior can be influenced by BAT thermogenesis. In the present study, 2-, 7-, and 14-day-old pups were observed on a thermal gradient following pharmacological stimulation or inhibition of BAT thermogenesis, and their thermal preferences were quantified. The authors found that 7- and 14-day-old pups treated with norepinephrine (NE), which increases BAT thermogenesis, preferred cooler portions of the gradient than saline-treated controls, whereas 2-day-olds failed to show a similar NE-induced behavioral adjustment. These findings indicate that the ability to adjust thermoregulatory behavior to compensate for enhanced metabolic thermogenesis develops during the 1st week of postnatal life.

Huddling by rat pups: Ontogeny of individual and group behavior

A full account of behavioral development in rats must include the ontogeny of both individual and group behavior. Most of our accumulated knowledge, however, pertains to individual ontogenesis. Group behavior and its development are readily seen in the huddling behavior of rat pups. A rat huddle is an entity with characteristics and capabilities distinct from those of the individuals that comprise it. The huddle is a natural context for acquiring olfactory preferences for species odors. Olfactory learning in a huddle involves thermal and tactile stimulation from the mother's body but, surprisingly, not the rewards of suckling or of milk transfer. Although there is complete developmental continuity of huddling behavior, the sensory controls of huddling change dramatically during the first 2 weeks of postnatal life. Huddling behavior is initially controlled by thermal cues ("physiological huddling") and then becomes dominated by olfactory stimuli ("filial huddling"). The complex group behavior of huddling was modeled successfully with computational methods. Group behavior emerges from individual interactions, guided entirely by rules of individual behavior (no rules for group behavior). Three simple rules of autonomous activity/inactivity can spawn the patterns of aggregon formation displayed by groups of 7-day-old pups, but not by 10-day-olds. The developmental change evident by Day 10 requires adding a rule by which each individual is affected by the activity state of adjacent pups. Group behavior responded to manipulations of central oxytocin on Day 10, but not on Day 7.

The emergence of the cortisol circadian rhythm in monozygotic and dizygotic twin infants: the twin‐pair synchrony

ObjectiveStudies on the influence of genetic factors on the ontogeny of cortisol circadian rhythm in infants are lacking. This study evaluated the influence of twinning and the heritability on the age of emergence of salivary cortisol rhythm.Design and subjectsA longitudinal study was performed using salivary samples obtained during morning and night, at 2, 4, 8, 12, 16, 20 and 24 weeks of postnatal life in 34 infants, 10 monozygotic (MZ) and 7 dizygotic (DZ) twin pairs. Salivary cortisol was determined by radioimmunoassay (RIA). Zigosity was verified by DNA analysis of at least 13 short tandem repeat polymorphisms. Difference of the emergence of cortisol circadian rhythm, within each twin pair, the intraclass correlation coefficient and the heritability index (h2) were calculated.ResultsThe mean (± SEM) age of emergence of salivary cortisol circadian rhythm was similar in MZ and DZ (7·8 ± 1·0 vs 7·4 ± 1·3 weeks). Seven pairs showed coincidence of the emergence of cortisol rhythm. Ten pairs were not coincident; among them the within-pair difference of emergence of salivary circadian rhythm was similar in both MZ and DZ groups. The intraclass correlation coefficients were rMZ = 0·60, P = 0·02; and rDZ = 0·65, P = 0·03, respectively. The heritability index (h2) was 0·21 (ns).ConclusionsSalivary circadian rhythm appeared at the same postnatal age in MZ and DZ twin infants. Although several physiological aspects might be involved, the heritability index, obtained in the present study, suggests less genetic than environmental impact on the age of the onset of the cortisol circadian rhythm. Our data also indicated that each twin-pair show synchrony because they probably shared prenatal and postnatal environmental synchronizers.

Age-Related Changes in Pro-Inflammatory Cytokines, Acute Phase Proteins and Cortisol Concentrations in Neonatal Piglets

Age-related changes have been described in the resting levels of cortisol and acute phase proteins in the neonatal pig. This study evaluated the plasma concentrations of the pro-inflammatory cytokines tumour necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β), the acute phase proteins C-reactive protein (CRP), serum amyloid A (SAA) and haptoglobin (Hp), as well as cortisol during the first week of postnatal life in piglets. The influence of invasive managerial practices such as teeth clipping, ear notching and tail docking on possible age-related changes in the production of these inflammatory mediators was also assessed. A total of 96 piglets were selected from 24 litters at birth, and were randomly assigned to one of four sampling times over the first week of life and one of two treatments. Blood samples were taken at 1, 3, 5 or 7 days of age. Piglets were ear notched, teeth clipped and tail docked (NCD), or were left untreated (CON). Significant effects of age were found in plasma concentrations of TNF-α, SAA, Hp and cortisol (p < 0.001). Concentrations of TNF-α and Hp increased with age, and peak concentrations were found on day 5. SAA and cortisol levels were highest on day 1, decreasing gradually with age. NCD piglets tended to have higher levels of plasma Hp than CON animals (p = 0.066). However, no differences between NCD and CON piglets were found in any other parameter measured. Furthermore, age effects were not affected by these husbandry practices. These results indicate that age-related changes exist in several inflammatory mediators, and suggest that these managerial practices do not result in systemic inflammation in early postnatal life of piglets.

The postnatal development of the optic nerve of a reptile (Vipera aspis): a quantitative ultrastructural study

The number of axons in the optic nerve of the ovoviviparous reptile Vipera aspis was estimated from electron micrographs taken during the first 5 weeks of postnatal life. One to two days after birth, the optic nerve contains about 170,000 fibres, of which about 9% are myelinated. At the end of the fifth postnatal week, the number of optic fibres has fallen to about 100,000, of which about 42% are myelinated. This fibre loss continues after the fifth postnatal week, since in the adult viper the nerve contains about 60,000 fibres, of which 85% are myelinated; overall, about 65% of the optic nerve fibres present at birth disappear before the number of axons stabilises at the adult level. This study shows, for the first time, that the mode of development of the visual axons of reptiles is not that of anamniote vertebrates but similar to that of birds and mammals.

Systemic and renal hemodynamic effects of the AT1 receptor antagonist, ZD 7155, and the AT2 receptor antagonist, PD 123319, in conscious lambs

Experiments were carried out to investigate age- and dose-dependent effects of the selective AT(1) receptor antagonist, ZD 7155, and the selective AT(2) receptor antagonist, PD 123319, on systemic and renal hemodynamics in conscious, chronically instrumented lambs aged approximately 1 and approximately 6 weeks of postnatal life. Mean arterial pressure (MAP), mean venous pressure (MVP), and renal blood flow (RBF) were measured for 10 min before and for 120 min after ZD 7155, PD 123319, or vehicle. In both age groups, administration of ZD 7155 decreased renal vascular resistance (RVR) and increased RBF within 5 min. These responses lasted less than 90 min but were not dose-dependent. MAP decreased by 30 min after administration of ZD 7155 in both age groups at doses >/=400 microg kg(-1); the remaining decreased for up to 120 min, depending upon the dose. Pressor responses to angiotensin II (ANG II) were abolished within 5 min of administration of all doses of ZD 7155, at both 1- and 6 weeks. PD 123319 had no detectable effects on systemic or renal hemodynamics or on the pressor responses to ANG II. Therefore, under physiological conditions in conscious newborn animals, ANG II modulates both resting blood pressure and RVR through activation of AT(1) but not AT(2) receptors.

Effects of human milk fortifier on the antimicrobial properties of human milk

To evaluate the effects of addition of human milk (HM) fortifier and iron on the anti-infective properties of HM. HM samples were collected from 28 lactating mothers who delivered prematurely, within the first week of post-natal life. HM fortifier Eoprotin was used. The effects of this fortifier against Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa and Candida albicans were evaluated using a filter paper method. The measurements were repeated with pure HM, fortified HM and iron-added HM. HM inhibited the growth of S. aureus, E. coli, P. aeruginosa and Candida. Addition of HM fortifier did not result in any significant difference on this effect. The addition of iron to HM reduced antimicrobial effect against all three bacteria and the Candida. Premature HM has strong antimicrobial activity and addition of the milk fortifier Eoprotin does not change this effect, but addition of iron reduces this antimicrobial activity.

Free Carnitine Levels in Respiratory Distress Syndrome during the First Week of Life

Antenatal carnitine administration has been shown to induce fetal lung maturity by increasing pulmonary surfactant in animal and human studies. The aim of this study was to investigate serum free carnitine (FC) levels in preterm infants with respiratory distress syndrome (RDS) and controls during the first week of postnatal life. The study groups consisted of 76 preterm infants with gestational ages ranging from 28 to 36 weeks, and birthweights ranging from 1046 to 2352 g. Serum FC levels were measured in preterm infants (group A, 37 with RDS; group B, 39 controls without RDS) within the first 6 hours after birth, on days 3 and 7. For specific analyses, serum FC levels were determined for gestational ages 28 to 31 weeks and 32 to 36 weeks in both groups. Initial FC levels were decreased insignificantly in group A (22.5 +/- 7.3 micromol/L) compared with group B (23.5 +/- 6.8 micromol/L; P > 0.05). On days 3 and 7 of life, serum FC levels were significantly lower in group A (18.3 +/- 6.1 and 10.2 +/- 3.3 micromol/L, respectively) than in group B (23.4 +/- 7.1 and 22.8 +/- 3.7 micromol/L, respectively; P < 0.05 and P < 0.05, respectively) on days 3 and 7 of life, respectively. Serum FC level remained stable in the non-RDS group ( P > 0.05), but it decreased significantly in the RDS group during the first week of postnatal life ( P < 0.05). No differences were seen between the corresponding gestational age groups. Serum FC levels in RDS infants decreased from days 1 to 7. Decreased neonatal serum carnitine levels in preterm infants with RDS during the first week of life might be caused by increasing consumption of carnitine in lung tissue for surfactant synthesis.

Vitamin D and calcium deficiency initiated in pregnancy and maintained after weaning accelerate auditory dysfunction in the offspring in BALB/cJ mice

The objective of this study was to examine the effect of vitamin D and calcium deficiency initiated in pregnancy and maintained through 10 weeks of postnatal life in BALB/cJ mice on auditory thresholds measured at 5 test frequencies using auditory brainstem response procedures. The BALB/cJ strain has a genetic defect resulting in a progressive sensorineural (inner ear) hearing loss similar to that experienced by individuals of advanced age. Beginning at 14 days of pregnancy and throughout lactation, mice were fed one of the following diets: adequate in both vitamin D and calcium (0.5% Ca by weight); deficient in vitamin D and calcium (0.2% Ca); or deficient in vitamin D and calcium (0.1% Ca). Offspring were fed the same diet as the mother for 10 weeks postweaning. At weaning, auditory brainstem response thresholds at 32 kHz were significantly higher (worse) in the offspring of the vitamin D–deficient and 0.1% calcium dams as compared to those of the other 2 diet groups. At 1 week postweaning, differences in hearing sensitivity began to emerge at 4, 8, 24, and increased at 32 kHz. Four weeks after weaning, the mice fed the adequate diet had significantly better hearing than the vitamin D–deficient and 0.1% calcium group at 4, 24, and 32 kHz ( P ≤ .05). That is, the more severe the diet the greater the hearing loss. These results suggest that exposure to vitamin D and calcium deficiency early in life may accelerate hearing impairment in susceptible individuals.

Non-lethal fetal toxicity of the angiotensin receptor blocker candesartan

Angiotensin receptor blockers are potent antihypertensive drugs with very few side effects [1, 2]. No association has been documented between use of angiotensin receptor blockers during the first trimester of gestation and congenital defects. However, there are several reports of malformations and physiologic disturbances, mostly with lethal outcome, in infants exposed to these drugs during the second and third trimesters, as recently reviewed [3, 4]. We report the adverse long-term sequelae noted in an infant following maternal treatment with an angiotensin receptor blocker. A 39-year old woman on treatment with candesartan cilexetil 16 mg once a day [5] for mild essential hypertension became pregnant but the drug was not discontinued. At 31 weeks a male boy weighing 1.65 kg was delivered by cesarian section. The physical examination disclosed climb contractures, skull hypoplasia with microcephaly (head circumference 0.265 m) and moderately underdeveloped calvarial bones. The child developed immediate respiratory distress (treated with oxygen, exogenous surfactant and mechanical respiratory support), arterial hypotension (treated with dopamine and epinephrine), and moderate oliguria (creatinine up to 281 μmol/l, urea up to 15.6 mmol/l and a pathologically increased urinary protein to creatinine ratio of 739 mg/mmol; upper reference 50). His conditions improved during the second week of postnatal life. However, a tendency towards arterial hypertension (mean blood pressure 75–80 mm Hg; upper reference 68) was noted, requiring treatment with the calcium channel blocker amlodipine once a day during 6 weeks. Routine chromosome analysis revealed a normal male karyotype. The boy is currently 34 months of age. Body weight is 11.1 kg (−2.8 SDS), length 0.901 m (−1.5 SDS), head circumference 0.481 m (−2 SDS) and blood pressure slightly elevated (approximately 110/70 mm Hg; upper reference 106/66) and the calvarial bones normally developed. His cognitive and especially his linguistic development are moderately retarded. The physical examination is otherwise normal. Plasma creatinine (36 μmol/l) and urea (6.0 mmol/l) are normal. The urinary protein to creatinine ratio is slightly increased (29 mg/mmol, upper reference 20). Renal ultrasound study demonstrates rather small hyperechogenic kidneys and loss of corticomedullary differentiation. In conclusion during pregnancy the use of drugs that block the renin–angiotensin–aldosterone system, namely angiotensin receptor blockers [3, 4] and converting enzyme inhibitors [4, 6], is strongly cautioned against. Infants surviving the exposition to these agents during the second and third trimesters tend to a chronic kidney disease and a developmental delay. A corresponding long-term follow up is warranted. Giacomo D. Simonetti is currently supported by a scholarship of the Ettore e Valeria Rossi Foundation.