Group B streptococcus late-onset disease,contaminated breast milk and mothers persistently GBS negative: Report of 3cases

Background: Human milk is fundamental for its nutritional properties and to protect newborns, but it is not sterile and can sometime transmit bacteria. Few anecdotal cases suggest that breast milk could be a possible source of group B Streptococcus (GBS) late onset disease, although the pathogenesis is not entirely understood. Case presentation: We report 3 cases of GBS late onset disease in full-term newborns. Fresh breast milk cultures yielded GBS, but mothers of neonates had no signs of mastitis and remained persistently GBS negative at rectovaginal site. Conclusions: Breast milk containing group B Streptococcus can be a risk factor for late onset disease. The persistent negative maternal GBS status supports the assumption that newborns, colonised in the throat, could be the initial source of GBS, while the mammary gland could act as a GBS replication site. It is unclear whether a low bacterial load may represent only contamination rather than true milk infection

Neurophysiological monitoring in neonatal abstinence syndrome from cocaine

Introduction. Neonatal abstinence syndrome (NAS) in a newborn is a result of the sudden discontinuation of exposure to psychotropic drugs abused by the mother during pregnancy. Since forty decades, the standardized Finnegan Neonatal Abstinence Scoring Tool (FNAST) documents the infant withdrawal, and initiate the appropriate treatment regimen, when elevated scored are reported. Whereas FNAST is successfully applied for opioids NAS, in case of other psychotropic drugs and especially cocaine, the tool is not always efficacious or predictive. Methods. Continuous v-Electroencephalography (vEEG) provides particularly useful information about brain cortical functioning and evaluation of background activity in normal newborns. vEEG allows to properly study and identify clinical manifestations as physiological motor paroxysms, that disappear from birth to infant age in correlation with the neurological development. Due to its feature to be a non-invasive tool continuous vEEG monitoring could be used to describe some clinical manifestations and assess if they can be correlated to possible injuries in critical neonates as those exposed in utero to psychoactive drugs presenting NAS. Results. An example for the potential use of such methodology is discussed in a case of NAS due to prenatal exposure to cocaine as a complementary tool for the evaluation of behavioural state and clinical and neurological signs in newborns in utero exposed to psychoactive drugs, excluding epileptic phenomena. Discussion. Video-EEG recording could be considered an important and objective tool that allows the evaluation of behavioural state and clinical and neurological signs in newborns in utero exposed to psychoactive drugs and the neurophysiological definition of signs and symptoms, which cannot be evaluated by FNAST such as startles and its variability during subsequent days after birth, subclinical seizures or brain injuries

Group b streptococcus late-onset disease: 2003-2010

BACKGROUND: There is insufficient population-based data on group B streptococcus (GBS) late-onset disease (LOD). Risk factors and routes of GBS transmission are poorly understood. METHODS: A prospective, cohort study was conducted to collect incidence data on LOD and evaluate GBS infections over an 8-year period (2003-2010). Starting from January 2007, maternal rectovaginal and breast milk cultures were routinely collected on confirmation of the LOD diagnosis to assess maternal GBS culture status. RESULTS: The incidence rate of LOD was 0.32 per 1000 live births (1.4 and 0.24 per 1000 live births for preterm and term newborns, respectively). The registered cases of LOD (n = 100) were classified as sepsis (n = 57), meningitis (n = 36), or focal infection (n = 7). Thirty neonates were preterm (2 had recurrent infection); 68 were term. Four infants died (3 early preterm, 1 term). At the time the LOD diagnosis was confirmed, 3 (6%) of 53 mothers had GBS mastitis, and 30 (64%) of 47 carried GBS at the rectovaginal site. Early (7-30 days) LOD presentation was associated with neonatal brain lesions or death (odds ratio: 0.96 [95% confidence interval: 0.93-0.99]). Intrapartum antibiotic exposure was significantly associated with mild (12 of 22) rather than severe (11 of 45; P = .03) LOD. CONCLUSIONS: Preterm neonates had the highest rates of LOD and mortality. Most mothers carried GBS at the time of the LOD diagnosis, whereas 6% had mastitis. Intrapartum antibiotics were associated both with delayed presentation of symptoms and milder LOD. Pediatrics 2013;131:e361-e368Early neonatal mortality has remained high and unchanged for many years in Tanzania, a resource-limited country. Helping Babies Breathe (HBB), a novel educational program using basic interventions to enhance delivery room stabilization/resuscitation, has been developed to reduce the number of these deaths. METHODS: Master trainers from the 3 major referral hospitals, 4 associated regional hospitals, and 1 district hospital were trained in the HBB program to serve as trainers for national dissemination. A before (n = 8124) and after (n = 78 500) design was used for implementation. The primary outcomes were a reduction in early neonatal deaths within 24 hours and rates of fresh stillbirths (FSB). RESULTS: Implementation was associated with a significant reduction in neonatal deaths (relative risk [RR] with training 0.53; 95% confidence interval [CI] 0.43-0.65; P ≤.0001) and rates of FSB (RR with training 0.76; 95% CI 0.64-0.90; P = .001). The use of stimulation increased from 47% to 88% (RR 1.87; 95% CI 1.82-1.90; P ≤.0001) and suctioning from 15% to 22% (RR 1.40; 95% CI 1.33-1.46; P ≤.0001) whereas face mask ventilation decreased from 8.2% to 5.2% (RR 0.65; 95% CI 0.60- 0.72; P ≤ .0001). Copyright © 2013 by the American Academy of Pediatrics

Cytotoxic Effect of Progesterone, Tamoxifen and Their Combination in Experimental Cell Models of Human Adrenocortical Cancer

Progesterone (Pg) and estrogen (E) receptors (PgRs and ERs) are expressed in normal and neoplastic adrenal cortex, but their role is not fully understood. In literature, Pg demonstrated cytotoxic activity on AdrenoCortical Carcinoma (ACC) cells, while tamoxifen is cytotoxic in NCI-H295R cells. Here, we demonstrated that in ACC cell models, ERs were expressed in NCI-H295R cells with a prevalence of ER-β over the ER-α.Metastasis-derived MUC-1 and ACC115m cells displayed a very weak ER-α/β signal, while PgR cells were expressed, although at low level. Accordingly, these latter were resistant to the SERM tamoxifen and scarcely sensitive to Pg, as we observed a lower potency compared to NCI-H295R cells in cytotoxicity (IC50: MUC-1 cells: 67.58 µM (95%CI: 63.22-73.04), ACC115m cells: 51.76 µM (95%CI: 46.45-57.67) and cell proliferation rate. Exposure of NCI-H295R cells to tamoxifen induced cytotoxicity (IC50: 5.43 µM (95%CI: 5.18-5.69 µM) mainly involving ER-β, as their nuclear localization increased after tamoxifen: Δ A.U. treated vs untreated: 12 h: +27.04% (p < 0.01); 24 h: +36.46% (p < 0.0001). This effect involved the SF-1 protein reduction: Pg: -36.34 ± 9.26%; tamoxifen: -46.25 ± 15.68% (p < 0.01). Finally, in a cohort of 36 ACC samples, immunohistochemistry showed undetectable/low level of ERs, while PgR demonstrated a higher expression. In conclusion, ACC experimental cell models expressed PgR and low levels of ER in line with data obtained in patient tissues, thus limiting the possibility of a clinical approach targeting ER. Interestingly, Pg exerted cytotoxicity also in metastatic ACC cells, although with low potency. Keywords: ACC cell lines; ACC primary cells; adrenocortical carcinoma; estrogen receptors; progesterone receptors; tamoxifen

Children with special health care needs attending emergency department in Italy: analysis of 3479 cases

Background: Although children with special health care needs (CSHCN) represent a minority of the population, they go through more hospitalizations, more admissions to the Emergency Department (ED), and receive a major number of medical prescriptions, in comparison to general pediatric population. Objectives of the study were to determine the reasons for admission to the ED in Italian CSHCN, and to describe the association between patient's demographic data, clinical history, and health services requirements. Methods: Ad hoc web site was created to collect retrospective data of 3479 visits of CSHCN to the ED in 58 Italian Hospitals. Results: Seventy-two percent of patients admitted to ED were affected by a previously defined medical condition. Most of the ED admissions were children with syndromic conditions (54%). 44.2% of the ED admissions were registered during the night-time and/or at the weekends. The hospitalization rate was of 45.6% among patients admitted to the ED. The most common reason for admission to the ED was the presence of respiratory symptoms (26.6%), followed by gastrointestinal problems (21.3%) and neurological disorders (18.2%). 51.4% of the access were classified as 'urgent', with a red/yellow triage code. Considering the type of ED, 61.9% of the visits were conducted at the Pediatric EDs (PedEDs), 33.5% at the Functional EDs (FunEDs) and 4.6% at the Dedicated EDs (DedEDs). Patients with more complex clinical presentation were more likely to be evaluated at the PedEDs. CSHCN underwent to a higher number of medical procedures at the PedEDs, more in comparison to other EDs. Children with medical devices were directed to a PedED quite exclusively when in need for medical attention. Subjects under multiple anti-epileptic drug therapy attended to PedEDs or FunEDs generally. Patients affected by metabolic diseases were more likely to look for medical attention at FunEDs. Syndromic patients mostly required medical attention at the DedEDs. Conclusions: Access of CSHCN to an ED is not infrequent. For this reason, it is fundamental for pediatricians working in any kind of ED to increase their general knowledge about CHSCN and to gain expertise in the management of such patients and their related medical complexity

Biallelic mutations in DYNC2LI1 are a rare cause of Ellis-van Creveld syndrome

Ellis van Creveld syndrome (EvC) is a chondral and ectodermal dysplasia caused by biallelic mutations in the EVC, EVC2 and WDR35 genes. A proportion of cases with clinical diagnosis of EvC, however, do not carry mutations in these genes. To identify the genetic cause of EvC in a cohort of mutation-negative patients, exome sequencing was undertaken in a family with three affected members, and mutation scanning of a panel of clinically and functionally relevant genes was performed in 24 additional subjects with features fitting/overlapping EvC. Compound heterozygosity for the c.2T&gt;C (p.Met1?) and c.662C&gt;T (p.Thr221Ile) variants in DYNC2LI1, which encodes a component of the intraflagellar transport-related dynein-2 complex previously found mutated in other short-rib thoracic dysplasias, was identified in the three affected members of the first family. Targeted resequencing detected compound heterozygosity for the same missense variant and a frameshift change (p.Val141*) in two siblings with EvC from a second family, while a newborn with a more severe phenotype carried two DYNC2LI1 truncating variants. Our findings indicate that DYNC2LI1 mutations are associated with a wider clinical spectrum than previously appreciated, including EvC, with the severity of the phenotype likely depending on the extent of defective DYNC2LI1 function

Intersociety policy statement on the use of whole-exome sequencing in the critically ill newborn infant

The rapid advancement of next-generation sequencing (NGS) technology and the decrease in costs for whole-exome sequencing (WES) and whole-genome sequening (WGS), has prompted its clinical application in several fields of medicine. Currently, there are no specific guidelines for the use of NGS in the field of neonatal medicine and in the diagnosis of genetic diseases in critically ill newborn infants. As a consequence, NGS may be underused with reduced diagnostic success rate, or overused, with increased costs for the healthcare system. Most genetic diseases may be already expressed during the neonatal age, but their identification may be complicated by nonspecific presentation, especially in the setting of critical clinical conditions. The differential diagnosis process in the neonatal intensive care unit (NICU) may be time-consuming, uncomfortable for the patient due to repeated sampling, and ineffective in reaching a molecular diagnosis during NICU stay. Serial gene sequencing (Sanger sequencing) may be successful only for conditions for which the clinical phenotype strongly suggests a diagnostic hypothesis and for genetically homogeneous diseases. Newborn screenings with Guthrie cards, which vary from country to country, are designed to only test for a few dozen genetic diseases out of the more than 6000 diseases for which a genetic characterization is available. The use of WES in selected cases in the NICU may overcome these issues. We present an intersociety document that aims to define the best indications for the use of WES in different clinical scenarios in the NICU. We propose that WES is used in the NICU for critically ill newborn infants when an early diagnosis is desirable to guide the clinical management during NICU stay, when a strong hypothesis cannot be formulated based on the clinical phenotype or the disease is genetically heterogeneous, and when specific non-genetic laboratory tests are not available. The use of WES may reduce the time for diagnosis in infants during NICU stay and may eventually result in cost-effectiveness

Exposure to Gastric Acid Inhibitors Increases the Risk of Infection in Preterm Very Low Birth Weight Infants but Concomitant Administration of Lactoferrin Counteracts This Effect

Objective: To investigate whether exposure to inhibitors of gastric acidity, such as H2 blockers or proton pump inhibitors, can independently increase the risk of infections in very low birth weight (VLBW) preterm infants in the neonatal intensive care unit. Study design: This is a secondary analysis of prospectively collected data from a multicenter, randomized controlled trial of bovine lactoferrin (BLF) supplementation (with or without the probiotic Lactobacillus rhamnosus GG) vs placebo in prevention of late-onset sepsis (LOS) and necrotizing enterocolitis (NEC) in preterm infants. Inhibitors of gastric acidity were used at the recommended dosages/schedules based on the clinical judgment of attending physicians. The distribution of days of inhibitors of gastric acidity exposure between infants with and without LOS/NEC was assessed. The mutually adjusted effects of birth weight, gestational age, duration of inhibitors of gastric acidity treatment, and exposure to BLF were controlled through multivariable logistic regression. Interaction between inhibitors of gastric acidity and BLF was tested; the effects of any day of inhibitors of gastric acidity exposure were then computed for BLF-treated vs -untreated infants. Results: Two hundred thirty-five of 743 infants underwent treatment with inhibitors of gastric acidity, and 86 LOS episodes occurred. After multivariate analysis, exposure to inhibitors of gastric acidity remained significantly and independently associated with LOS (OR, 1.03; 95% CI, 1.008-1.067; P = .01); each day of inhibitors of gastric acidity exposure conferred an additional 3.7% odds of developing LOS. Risk was significant for Gram-negative (P < .001) and fungal (P = .001) pathogens, but not for Gram-positive pathogens (P = .97). On the test for interaction, 1 additional day of exposure to inhibitors of gastric acidity conferred an additional 7.7% risk for LOS (P = .003) in BLF-untreated infants, compared with 1.2% (P = .58) in BLF-treated infants. Conclusion: Exposure to inhibitors of gastric acidity is significantly associated with the occurrence of LOS in preterm VLBW infants. Concomitant administration of BLF counteracts this selective disadvantage. Trial registration: isrctn.org: ISRCTN53107700

Inter-society consensus document on treatment and prevention of bronchiolitis in newborns and infants

Acute bronchiolitis is the leading cause of lower respiratory tract infection and hospitalization in children less than 1 year of age worldwide. It is usually a mild disease, but some children may develop severe symptoms, requiring hospital admission and ventilatory support in the ICU. Infants with pre-existing risk factors (prematurity, bronchopulmonary dysplasia, congenital heart diseases and immunodeficiency) may be predisposed to a severe form of the disease. Clinical diagnosis of bronchiolitis is manly based on medical history and physical examination (rhinorrhea, cough, crackles, wheezing and signs of respiratory distress). Etiological diagnosis, with antigen or genome detection to identify viruses involved, may have a role in reducing hospital transmission of the infection. Criteria for hospitalization include low oxygen saturation (<90-92%), moderate-to-severe respiratory distress, dehydration and presence of apnea. Children with pre-existing risk factors should be carefully assessed. To date, there is no specific treatment for viral bronchiolitis, and the mainstay of therapy is supportive care. This consists of nasal suctioning and nebulized 3% hypertonic saline, assisted feeding and hydration, humidified O2 delivery. The possible role of any pharmacological approach is still debated, and till now there is no evidence to support the use of bronchodilators, corticosteroids, chest physiotherapy, antibiotics or antivirals. Nebulized adrenaline may be sometimes useful in the emergency room. Nebulized adrenaline can be useful in the hospital setting for treatment as needed. Lacking a specific etiological treatment, prophylaxis and prevention, especially in children at high risk of severe infection, have a fundamental role. Environmental preventive measures minimize viral transmission in hospital, in the outpatient setting and at home. Pharmacological prophylaxis with palivizumab for RSV bronchiolitis is indicated in specific categories of children at risk during the epidemic period. Viral bronchiolitis, especially in the case of severe form, may correlate with an increased incidence of recurrent wheezing in pre-schooled children and with asthma at school age. The aim of this document is to provide a multidisciplinary update on the current recommendations for the management and prevention of bronchiolitis, in order to share useful indications, identify gaps in knowledge and drive future research

Human iPSC modelling of a familial form of atrial fibrillation reveals a gain of function of I-f and I-CaL in patient-derived cardiomyocytes

Aims: Atrial fibrillation (AF) is the most common type of cardiac arrhythmias, whose incidence is likely to increase with the aging of the population. It is considered a progressive condition, frequently observed as a complication of other cardiovascular disorders. However, recent genetic studies revealed the presence of several mutations and variants linked to AF, findings that define AF as a multifactorial disease. Due to the complex genetics and paucity of models, molecular mechanisms underlying the initiation of AF are still poorly understood. Here we investigate the pathophysiological mechanisms of a familial form of AF, with particular attention to the identification of putative triggering cellular mechanisms, using patient's derived cardiomyocytes (CMs) differentiated from induced pluripotent stem cells (iPSCs). Methods and results: Here we report the clinical case of three siblings with untreatable persistent AF whose whole-exome sequence analysis revealed several mutated genes. To understand the pathophysiology of this multifactorial form of AF we generated three iPSC clones from two of these patients and differentiated these cells towards the cardiac lineage. Electrophysiological characterization of patient-derived CMs (AF-CMs) revealed that they have higher beating rates compared to control (CTRL)-CMs. The analysis showed an increased contribution of the If and ICaL currents. No differences were observed in the repolarizing current IKr and in the sarcoplasmic reticulum calcium handling. Paced AF-CMs presented significantly prolonged action potentials and, under stressful conditions, generated both delayed after-depolarizations of bigger amplitude and more ectopic beats than CTRL cells. Conclusions: Our results demonstrate that the common genetic background of the patients induces functional alterations of If and ICaL currents leading to a cardiac substrate more prone to develop arrhythmias under demanding conditions. To our knowledge this is the first report that, using patient-derived CMs differentiated from iPSC, suggests a plausible cellular mechanism underlying this complex familial form of AF