N-acetylcysteine treatment ameliorates the skeletal phenotype of a mouse model of diastrophic dysplasia.

Diastrophic dysplasia (DTD) is a recessive chondrodysplasia caused by mutations in SLC26A2, a cell membrane sulfate-chloride antiporter. Sulfate uptake impairment results in low cytosolic sulfate, leading to cartilage proteoglycan (PG) undersulfation. In this work, we used the dtd mouse model to study the role of N-acetyl-l-cysteine (NAC), a well-known drug with antioxidant properties, as an intracellular sulfate source for macromolecular sulfation. Because of the important pre-natal phase of skeletal development and growth, we administered 30 g/l NAC in the drinking water to pregnant mice to explore a possible transplacental effect on the fetuses. When cartilage PG sulfation was evaluated by high-performance liquid chromatography disaccharide analysis in dtd newborn mice, a marked increase in PG sulfation was observed in newborns from NAC-treated pregnancies when compared with the placebo group. Morphometric studies of the femur, tibia and ilium after skeletal staining with alcian blue and alizarin red indicated a partial rescue of abnormal bone morphology in dtd newborns from treated females, compared with pups from untreated females. The beneficial effect of increased macromolecular sulfation was confirmed by chondrocyte proliferation studies in cryosections of the tibial epiphysis by proliferating cell nuclear antigen immunohistochemistry: the percentage of proliferating cells, significantly reduced in the placebo group, reached normal values in dtd newborns from NAC-treated females. In conclusion, NAC is a useful source of sulfate for macromolecular sulfation in vivo when extracellular sulfate supply is reduced, confirming the potential of therapeutic approaches with thiol compounds to improve skeletal deformity and short stature in human DTD and related disorders.

Pregnancy outcome after TNF-α inhibitor therapy during the first trimester: a prospective multicentre cohort study.

AIMS: TNF-α inhibitors are considered relatively safe in pregnancy but experience is still limited. The aim of this study was to evaluate the risk of major birth defects, spontaneous abortion, preterm birth and reduced birth weight after first trimester exposure to TNF-α inhibitors. METHODS: Pregnancy outcomes of women on adalimumab, infliximab, etanercept, certolizumab pegol or golimumab were evaluated in a prospective observational cohort study and compared with outcomes of a non-exposed random sample. The samples were drawn from pregnancies identified by institutes collaborating in the European Network of Teratology Information Services. RESULTS: In total, 495 exposed and 1532 comparison pregnancies were contributed from nine countries. The risk of major birth defects was increased in the exposed (5.0%) compared with the non-exposed group (1.5%; adjusted odds ratio (ORadj ) 2.2, 95% CI 1.0, 4.8). The risk of preterm birth was increased (17.6%; ORadj 1.69, 95% CI 1.1, 2.5), but not the risk of spontaneous abortion (16.2%; adjusted hazard ratio [HRadj ] 1.06, 95% CI 0.7, 1.7). Birth weights adjusted for gestational age and sex were significantly lower in the exposed group compared to the non-exposed cohort (P = 0.02). As a diseased comparison group was not possible to ascertain, the influence of disease and treatment on birth weight and preterm birth could not be differentiated. CONCLUSIONS: TNF-α inhibitors may carry a risk of adverse pregnancy outcome of moderate clinical relevance. Considering the impact of insufficiently controlled autoimmune disease on the mother and the unborn child, TNF-α inhibitors may nevertheless be a treatment option in women with severe disease refractory to established immunomodulatory drugs.

Estimation of reference curves for the urinary steroid metabolome in the first year of life in healthy children : Tracing the complexity of human postnatal steroidogenesis.

CONTEXT: Complex steroid disorders such as P450 oxidoreductase deficiency or apparent cortisone reductase deficiency may be recognized by steroid profiling using chromatographic mass spectrometric methods. These methods are highly specific and sensitive, and provide a complete spectrum of steroid metabolites in a single measurement of one sample which makes them superior to immunoassays. The steroid metabolome during the fetal-neonatal transition is characterized by (a) the metabolites of the fetal-placental unit at birth, (b) the fetal adrenal androgens until its involution 3-6 months postnatally, and (c) the steroid metabolites produced by the developing endocrine organs. All these developmental events change the steroid metabolome in an age- and sex-dependent manner during the first year of life. OBJECTIVE: The aim of this study was to provide normative values for the urinary steroid metabolome of healthy newborns at short time intervals in the first year of life. METHODS: We conducted a prospective, longitudinal study to measure 67 urinary steroid metabolites in 21 male and 22 female term healthy newborn infants at 13 time-points from week 1 to week 49 of life. Urine samples were collected from newborn infants before discharge from hospital and from healthy infants at home. Steroid metabolites were measured by gas chromatography-mass spectrometry (GC-MS) and steroid concentrations corrected for urinary creatinine excretion were calculated. RESULTS: 61 steroids showed age and 15 steroids sex specificity. Highest urinary steroid concentrations were found in both sexes for progesterone derivatives, in particular 20α-DH-5α-DH-progesterone, and for highly polar 6α-hydroxylated glucocorticoids. The steroids peaked at week 3 and decreased by ∼80% at week 25 in both sexes. The decline of progestins, androgens and estrogens was more pronounced than of glucocorticoids whereas the excretion of corticosterone and its metabolites and of mineralocorticoids remained constant during the first year of life. CONCLUSION: The urinary steroid profile changes dramatically during the first year of life and correlates with the physiologic developmental changes during the fetal-neonatal transition. Thus detailed normative data during this time period permit the use of steroid profiling as a powerful diagnostic tool.

Comparison of Griffiths-II and Bayley-II tests for the developmental assessment of high-risk infants.

INTRODUCTION: Two important risk factors for abnormal neurodevelopment are preterm birth and neonatal hypoxic ischemic encephalopathy. The new revisions of Griffiths Mental Development Scale (Griffiths-II, [1996]) and the Bayley Scales of Infant Development (BSID-II, [1993]) are two of the most frequently used developmental diagnostics tests. The Griffiths-II is divided into five subscales and a global development quotient (QD), and the BSID-II is divided into two scales, the Mental scale (MDI) and the Psychomotor scale (PDI). The main objective of this research was to establish the extent to which developmental diagnoses obtained using the new revisions of these two tests are comparable for a given child. MATERIAL AND METHODS: Retrospective study of 18-months-old high-risk children examined with both tests in the follow-up Unit of the Clinic of Neonatology of our tertiary care university Hospital between 2011 and 2012. To determine the concurrent validity of the two tests paired t-tests and Pearson product-moment correlation coefficients were computed. Using the BSID-II as a gold standard, the performance of the Griffiths-II was analyzed with receiver operating curves. RESULTS: 61 patients (80.3% preterm, 14.7% neonatal asphyxia) were examined. For the BSID-II the MDI mean was 96.21 (range 67-133) and the PDI mean was 87.72 (range 49-114). For the Griffiths-II, the QD mean was 96.95 (range 60-124), the locomotors subscale mean was 92.57 (range 49-119). The score of the Griffiths locomotors subscale was significantly higher than the PDI (p<0.001). Between the Griffiths-II QD and the BSID-II MDI no significant difference was found, and the area under the curve was 0.93, showing good validity. All correlations were high and significant with a Pearson product-moment correlation coefficient >0.8. CONCLUSIONS: The meaning of the results for a given child was the same for the two tests. Two scores were interchangeable, the Griffiths-II QD and the BSID-II MDI.

Expressive writing intervention for mothers following the birth of their premature baby.

The birth of a preterm infant is in most cases unexpected and can be a distressing experience for parents. Parents of premature babies report more stress, experience more adjustment difficulties and need for support during the first year after delivery compared to parents of infants born at term. It has been documented that parents may experience posttraumatic stress reactions, anxiety and depression following the premature birth of their baby, which subsequently may impact on the mother-baby-interactions, their attachment relationship and the cognitive, social and behavioural development of the baby. In this pilot study, we offered an expressive writing intervention to women who recently had a premature baby to alleviate their psychological distress and to improve their physical health. During the expressive writing intervention, women were asked to write down their deepest thoughts and feelings about the most traumatic aspect of their experience of having a premature baby for 15 min over three consecutive days. The aims of the study were as follows: (1) To evaluate the effect of expressive writing on psychological and physical health in women who recently had a premature baby. (2) To evaluate the effect of expressive writing on the use of healthcare services and medication in this population. (3) To evaluate the acceptability and feasibility of this intervention for this population. Forty participants were randomly allocated to either the expressive writing intervention group or a wait list control group. Pre- and post questionnaires to evaluate the effectiveness of the expressive writing intervention, as well as their acceptability and feasibility were completed. The intervention took place when the baby was 3 months of corrected age. Post-measures were completed at 1 and 3 months following the intervention. Results and their clinical implications will be discussed with regards to the implementation of this safe and cost-effective method as a preventative measure in the routine care of women who recently gave birth to a premature baby

Presence of air in the hepatic portal system in association with umbilical venous catheter malposition

The authors report a case of umbilical venous catheter malposition with air in the portal venous system in a preterm neonate. Initially, the hypothesis of necrotizing enterocolitis was considered, but the newborn progressed with no finding of disease and the air disappeared at follow-up radiography. The differential diagnosis of such a finding can avoid unnecessary clinical treatments.

High expression levels of macrophage migration inhibitory factor sustain the innate immune responses of neonates.

The vulnerability to infection of newborns is associated with a limited ability to mount efficient immune responses. High concentrations of adenosine and prostaglandins in the fetal and neonatal circulation hamper the antimicrobial responses of newborn immune cells. However, the existence of mechanisms counterbalancing neonatal immunosuppression has not been investigated. Remarkably, circulating levels of macrophage migration inhibitory factor (MIF), a proinflammatory immunoregulatory cytokine expressed constitutively, were 10-fold higher in newborns than in children and adults. Newborn monocytes expressed high levels of MIF and released MIF upon stimulation with Escherichia coli and group B Streptococcus, the leading pathogens of early-onset neonatal sepsis. Inhibition of MIF activity or MIF expression reduced microbial product-induced phosphorylation of p38 and ERK1/2 mitogen-activated protein kinases and secretion of cytokines. Recombinant MIF used at newborn, but not adult, concentrations counterregulated adenosine and prostaglandin E2-mediated inhibition of ERK1/2 activation and TNF production in newborn monocytes exposed to E. coli. In agreement with the concept that once infection is established high levels of MIF are detrimental to the host, treatment with a small molecule inhibitor of MIF reduced systemic inflammatory response, bacterial proliferation, and mortality of septic newborn mice. Altogether, these data provide a mechanistic explanation for how newborns may cope with an immunosuppressive environment to maintain a certain threshold of innate defenses. However, the same defense mechanisms may be at the expense of the host in conditions of severe infection, suggesting that MIF could represent a potential attractive target for immune-modulating adjunctive therapies for neonatal sepsis.

Mixed subtype of congenital mesoblastic nephroma with poor evolution: a case report and literature review

Abstract A male child born at 27 weeks, weighting 1305 g and presenting with a right-sided abdominal tumor. Computed tomography scan demonstrated the presence of a solid mass compressing the right kidney. Puncture biopsy revealed congenital mesoblastic nephroma. The patient underwent total right nephroureterectomy, and died on the second day after surgery.

Neuroprotection by selective neuronal deletion of Atg7 in neonatal brain injury.

Perinatal asphyxia induces neuronal cell death and brain injury, and is often associated with irreversible neurological deficits in children. There is an urgent need to elucidate the neuronal death mechanisms occurring after neonatal hypoxia-ischemia (HI). We here investigated the selective neuronal deletion of the Atg7 (autophagy related 7) gene on neuronal cell death and brain injury in a mouse model of severe neonatal hypoxia-ischemia. Neuronal deletion of Atg7 prevented HI-induced autophagy, resulted in 42% decrease of tissue loss compared to wild-type mice after the insult, and reduced cell death in multiple brain regions, including apoptosis, as shown by decreased caspase-dependent and -independent cell death. Moreover, we investigated the lentiform nucleus of human newborns who died after severe perinatal asphyxia and found increased neuronal autophagy after severe hypoxic-ischemic encephalopathy compared to control uninjured brains, as indicated by the numbers of MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3)-, LAMP1 (lysosomal-associated membrane protein 1)-, and CTSD (cathepsin D)-positive cells. These findings reveal that selective neuronal deletion of Atg7 is strongly protective against neuronal death and overall brain injury occurring after HI and suggest that inhibition of HI-enhanced autophagy should be considered as a potential therapeutic target for the treatment of human newborns developing severe hypoxic-ischemic encephalopathy.

Late effects of cancer at a young age: Registry-based studies of the health of cancer patients and their off-spring

Modern cancer therapy has resulted in increased survival among patients diagnosed with cancer at a young age. These improvements have led to the investigation of late morbidity and mortality associated with cancer and its treatments. The aim of this study was to evaluate late effects of cancer treated at a young age on the health of patients and their offspring. Utilising the nationwide population-based registries in Finland, we evaluated the risk of hypothyroidism and the probability of parenthood in cancer survivors as well as preterm birth, neonatal outcomes, and the risk of cancer among offspring of patients. The survivor cohort, identified from the Finnish Cancer Registry, consisted of 25,784 cancer patients diag-nosed between ages 0 and 34 in 1953–2004. By linkage to the population register, siblings of these patients were identified for comparison. The prevalence of hypothyroidism was higher among former childhood cancer (aged 0–16) patients than in the general population. The probability of parenthood following early onset cancer was overall significantly reduced compared to siblings. Offspring of female cancer survivors were at an increased risk of preterm birth, this risk being highest among patients diagnosed in childhood and early adulthood (aged 20–34 years). The offspring were not, however, at a significantly increased risk of neonatal death or stillbirth, though they were more likely to need monitoring or intensive care in the neonatal period. The risk of sporadic cancer among offspring of male and female cancer survivors was not elevated in comparison to the general population. The study showed that former cancer patients are at risk of certain adverse endocrine and reproductive health outcomes and should be followed for timely intervention. The offspring of cancer survivors do not appear to be at risk for adverse health outcomes.

Cognitive Development of Very Low Birth Weight Children from Infancy to Pre-school Age

The survival of preterm born infants has increased but the prevalence of long-term morbidities has still remained high. Preterm born children are at an increased risk for various developmental impairments including both severe neurological deficits as well as deficits in cognitive development. According to the literature the developmental outcome perspective differs between countries, centers, and eras. Definitions of preterm infant vary between studies, and the follow-up has been carried out with diverse methods making the comparison less reliable. It is essential to offer parents upto-date information about the outcome of preterm infants born in the same area. A centralized follow-up of children at risk makes it possible to monitor the consequences of changes in the treatment practices of hospitals on developmental outcome. This thesis is part of a larger regional, prospective multidisciplinary follow-up project entitled “Development and Functioning of Very Low Birth Weight Infants from Infancy to School Age” (PIeniPAinoisten RIskilasten käyttäytyminen ja toimintakyky imeväisiästä kouluikään, PIPARI). The thesis consists of four original studies that present data of very low birth weight (VLBW) infants born between 2001 and 2006, who are followed up from the neonatal period until the age of five years. The main outcome measure was cognitive development and secondary outcomes were significant neurological deficits (cerebral palsy, CP, deafness, and blindness). In Study I, the early crying and fussing behavior of preterm infants was studied using parental diaries, and the relation of crying behavior and cognitive and motor development at the age of two years was assessed. In Study II, the developmental outcome (cognitive, CP, deafness, and blindness) at the age of two years was studied in relation to demographic, antenatal, neonatal, and brain imaging data. Development was studied in relationship to a full-term born control group born in the same hospital. In Study III, the stability of cognitive development was studied in VLBW and full-term groups by comparing the outcomes at the ages of two and five years. Finally, in Study IV the precursors of reading skills (phonological processing, rapid automatized naming, and letter knowledge) were assessed for VLBW and full-term children at the age of five years. Pre-reading skills were studied in relation to demographic, antenatal, neonatal, and brain imaging data. The main findings of the thesis were that VLBW infants who fussed or cried more in the infancy were not at greater risk for problems in their cognitive development. However, crying was associated with poorer motor development. The developmental outcome of the present population was better that has been reported earlier and this improvement covered also cognitive development. However, the difference to fullterm born peers was still significant. Major brain pathology and intestinal perforation were independent significant risk factors for adverse outcome, also when several individual risk factors were controlled for. Cognitive development at the age of two years was strongly related with development at the age of five years, stressing the importance of the early assessment, and the possibility for early interventions. Finally, VLBW children had poorer pre-reading skills compared with their full-term born peers, but the IQ was an important mediator even when children with mental retardation were excluded from the analysis. The findings suggest that counseling parents about the developmental perspectives of their preterm infant should be based on data covering the same birth hospital. Neonatal brain imaging data and neonatal morbidity are important predictors for developmental outcome. The findings of the present study stress the importance of both short-term (two years) and long-term (five years) follow-ups for the individual, and for improving the quality of care.

Hérnia de bochdalek em adulto

Bochdalek´s hernia is a congenital malformation of the posterolateral diaphragm region. It is more common on the left and more frequently seen in newborns and rare in adults, with over a few 100 reported cases. We present a case of Bochdalek´s hernia in a 49-year-old patient with long term dyspeptic symptoms. The upper endoscopy showed a gastric fundus herniation sliding into the chest through the diaphragmatic defect. The patient also presented with a rare pulmonary malformation diagnosed during surgery. It was corrected through thoracic approach with no other complications.

Obstetric outcomes in the second birth of women with a previous caesarean delivery: a retrospective cohort study from Peru

PURPOSE: To examine obstetric outcomes in the second birth of women who had undergone a previous cesarean delivery. METHODS: This was a large hospital-based retrospective cohort study. We included pregnant women who had a previous delivery (vaginal or cesarean) attending their second birth from 2001 to 2009. Main inclusion criteria were singleton pregnancies and delivery between a gestation of 24 and 41 weeks. Two cohorts were selected, being women with a previous cesarean delivery (n=7,215) and those with a vaginal one (n=23,720). Both groups were compared and logistic regression was performed to adjust for confounding variables. The obstetric outcomes included uterine rupture, placenta previa, and placental-related complications such as placental abruption, preeclampsia, and spontaneous preterm delivery. RESULTS: Women with previous cesarean delivery were more likely to have adverse outcomes such as uterine rupture (OR=12.4, 95%CI 6.8-22.3), placental abruption (OR=1.4, 95%CI 1.1-2.1), preeclampsia (OR=1.4, 95%CI 1.2-1.6), and spontaneous preterm delivery (OR=1.4, 95%CI 1.1-1.7). CONCLUSIONS: Individuals with previous cesarean section have adverse obstetric outcomes in the subsequent pregnancy, including uterine rupture, and placental-related disorders such as preeclampsia, spontaneous preterm delivery, and placental abruption.

Uterine Doppler velocimetry of the uterine arteries in the second and third trimesters for the prediction of gestational outcome

PURPOSE: The aim of this longitudinal study was to investigate the value of uterine artery Doppler sonography during the second and third trimesters in the prediction of adverse pregnancy outcome in low-risk women. METHODS: From July 2011 to August 2012, a total of 205 singleton pregnant women presenting at our antenatal clinic were enrolled in this prospective study and were assessed for baseline demographic and obstetric data. They underwent ultrasound evaluation at the time of second and third trimesters, both included Doppler assessment of bilateral uterine arteries to determine the values of the pulsatility index (PI) and resistance index (RI) and presence of early diastolic notch. The endpoint of this study was assessing the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of Doppler ultrasonography of the uterine artery, for the prediction of adverse pregnancy outcomes including preeclampsia, stillbirth, placental abruption and preterm labor. RESULTS: The mean age of cases was 26.4±5.11. The uterine artery PI and RI values for both second (PI: 1.1±0.42 versus 1.53±0.59, p=0.002; RI: 0.55±0.09 versus 0.72±0.13, p=0.000 respectively) and third-trimester (PI: 0.77±0.31 versus 1.09±0.46, p=0.000; RI: 0.46±0.10 versus 0.60±0.14, p=0.010 respectively) evaluations were significantly higher in patients with adverse pregnancy outcome than in normal women. Combination of PI and RI >95th percentile and presence of bilateral notch in second trimester get sensitivity and specificity of 36.1 and 97% respectively, while these measures were 57.5 and 98.2% in third trimester. CONCLUSIONS: According to our study, it seems that uterine artery Doppler may be a valuable tool for the prediction of a variety of adverse outcomes in second and third trimesters.

Maternal age and adverse perinatal outcomes in a birth cohort (BRISA) from a Northeastern Brazilian city

PURPOSE:To verify the existence of associations between different maternal ages and the perinatal outcomes of preterm birth and intrauterine growth restriction in the city of São Luís, Maranhão, Northeastern Brazil.METHODS:A cross-sectional study using a sample of 5,063 hospital births was conducted in São Luís, from January to December 2010. The participants comprise the birth cohort for the study "Etiological factors of preterm birth and consequences of perinatal factors for infant health: birth cohorts from two Brazilian cities" (BRISA). Frequencies and 95% confidence intervals were used to describe the results. Multiple logistic regression models were applied to assess the adjusted odds ratio (OR) of maternal age associated with the following outcomes: preterm birth and intrauterine growth restriction.RESULTS:The percentage of early teenage pregnancy (12–15 years old) was 2.2%, and of late (16–19 years old) was 16.4%, while pregnancy at an advanced maternal age (>35 years) was 5.9%. Multivariate analyses showed a statistically significant increase in preterm births among females aged 12–15 years old (OR=1.6; p=0.04) compared with those aged 20–35 years. There was also a higher rate in preterm births among females aged 16–19 years old (OR=1.3; p=0.01). Among those with advanced maternal age (>35 years old), the increase in the prevalence of preterm birth had only borderline statistical significance (OR=1.4; p=0.05). There was no statistically significant association between maternal age and increased prevalence of intrauterine growth restriction.