Fabio Mosca

Prevalence of the Congenital Long-QT Syndrome

Background— The prevalence of genetic arrhythmogenic diseases is unknown. For the long-QT syndrome (LQTS), figures ranging from 1:20 000 to 1:5000 were published, but none was based on actual data. Our objective was to define the prevalence of LQTS. Methods and Results— In 18 maternity hospitals, an ECG was performed in 44 596 infants 15 to 25 days old (43 080 whites). In infants with a corrected QT interval (QTc) >450 ms, the ECG was repeated within 1 to 2 weeks. Genetic analysis, by screening 7 LQTS genes, was performed in 28 of 31 (90%) and in 14 of 28 infants (50%) with, respectively, a QTc >470 ms or between 461 and 470 ms. A QTc of 451 to 460, 461 to 470, and >470 ms was observed in 177 (0.41%), 28 (0.06%), and 31 infants (0.07%). Among genotyped infants, disease-causing mutations were found in 12 of 28 (43%) with a QTc >470 ms and in 4 of 14 (29%) with a QTc of 461 to 470 ms. One genotype-negative infant (QTc 482 ms) was diagnosed as affected by LQTS on clinical grounds. Among family members of genotype-positive infants, 51% were found to carry disease-causing mutations. In total, 17 of 43 080 white infants were affected by LQTS, demonstrating a prevalence of at least 1:2534 apparently healthy live births (95% confidence interval, 1:1583 to 1:4350). Conclusions— This study provides the first data-based estimate of the prevalence of LQTS among whites. On the basis of the nongenotyped infants with QTc between 451 and 470 ms, we advance the hypothesis that this prevalence might be close to 1:2000. ECG-guided molecular screening can identify most infants affected by LQTS and unmask affected relatives, thus allowing effective preventive measures.

Bovine Lactoferrin Supplementation for Prevention of Late-Onset Sepsis in Very Low-Birth-Weight Neonates: A Randomized Trial

CONTEXT Sepsis is a common and severe complication in premature neonates, particularly those with very low birth weight (VLBW) (<1500 g). Whether lactoferrin, a mammalian milk glycoprotein involved in innate immune host defenses, can reduce the incidence of sepsis is unknown. In animal models, the probiotic Lactobacillus rhamnosus GG (LGG) enhances the activity of lactoferrin but has not been studied in human infants. OBJECTIVE To establish whether bovine lactoferrin (BLF), alone or in combination with LGG, reduces the incidence of late-onset sepsis in VLBW neonates. DESIGN, SETTING, AND PATIENTS Prospective, multicenter, double-blind, placebo-controlled, randomized trial conducted in 11 Italian tertiary neonatal intensive care units. Patients were 472 VLBW infants enrolled from October 1, 2007, through July 31, 2008, and assessed until discharge for development of sepsis. INTERVENTION Infants were randomly assigned to receive orally administered BLF (100 mg/d) alone (n = 153), BLF plus LGG (6 x 10(9) colony-forming units/d) (n = 151), or placebo (n = 168) from birth until day 30 of life (day 45 for neonates <1000 g at birth). MAIN OUTCOME MEASURE First episode of late-onset sepsis, ie, sepsis occurring more than 72 hours after birth with isolation of any pathogen from blood or from peritoneal or cerebrospinal fluid. RESULTS Demographic, clinical, and management characteristics of the 3 groups were similar, including type of feeding and intake of maternal milk. Incidence of late-onset sepsis was significantly lower in the BLF and BLF plus LGG groups (9/153 [5.9%] and 7/151 [4.6%], respectively) than in the control group receiving placebo (29/168 [17.3%]) (risk ratio, 0.34; 95% confidence interval, 0.17-0.70; P = .002 for BLF vs control and risk ratio, 0.27; 95% confidence interval, 0.12-0.60; P < .001 for BLF plus LGG vs control). The decrease occurred for both bacterial and fungal sepsis. No adverse effects or intolerances to treatment occurred. CONCLUSION Compared with placebo, BLF supplementation alone or in combination with LGG reduced the incidence of a first episode of late-onset sepsis in VLBW neonates. TRIAL REGISTRATION isrctn.org Identifier: ISRCTN53107700.

Comparative evaluation of the effects of indomethacin and ibuprofen on cerebral perfusion and oxygenation in preterm infants with patent ductus arteriosus

OBJECTIVE To compare the effects on cerebral perfusion and oxygenation of intravenous ibuprofen and indomethacin as treatment for patent ductus arteriosus in preterm infants. STUDY DESIGN Sixteen infants receiving mechanical ventilation (< 31 weeks gestation) with patent ductus arteriosus received either 0.2 mg/kg indomethacin (n = 8) or 10 mg/kg ibuprofen (n = 8) infused over 1 minute. Near-infrared spectroscopy was used to measure changes in cerebral blood volume and in oxidized cytochrome oxidase concentration. Cerebral blood flow velocity in the pericallosal artery was measured using Doppler ultrasonography. RESULTS Indomethacin caused a significant reduction of CBV (maximal changes in cerebral blood volume: -320 +/- 171 microL/100 gm) and, in four of eight patients, a fall in oxidized cytochrome oxidase concentration (maximal change in oxidized cytochrome oxidase concentration in the eight patients: -0.68 +/- 0.98 mumol/L, NS). Cerebral blood flow velocity fell significantly. Ibuprofen caused no significant reduction of cerebral blood volume, oxidized cytochrome oxidase concentration, or cerebral blood flow velocity, whereas a significant increase of cerebral blood volume (+207 +/- 200 microL/100 gm) was observed after 60 minutes. Ductus closure was seen in six of eight infants after the first dose of indomethacin and in five of eight infants after the first dose of ibuprofen. The therapeutic cycle involved administration of a second and third dose, provided no side effects occurred. Treatment was effective in all infants. CONCLUSION Compared with indomethacin, treatment with ibuprofen does not significantly reduce cerebral perfusion and oxygen availability; the observed increase in cerebral blood volume requires further investigation.

Galacto-oligosaccharides and long-chain fructo-oligosaccharides as prebiotics in infant formulas: A review

The present review summarizes clinical and experimental data concerning the possible effects of a prebiotic mixture of short-chain galacto-oligosaccharides and long-chain fructo-oligosaccharides. The results from several studies, made up of over 400 preterm and term infants, clearly demonstrate that the prebiotic mixture under examination specifically stimulates the growth of bifidobacteria and lactobacilli and reduces the growth of pathogens. As a consequence of the changed intestinal flora by the dietary galacto-oligosaccharides and fructo-oligosaccharides, the faecal pH values and the short-chain fatty acid pattern were similar to those found in breastfed infants. In addition, the stool consistency was the same as in breastfed infants. In vitro experiments have demonstrated that the specific short-chain fatty acid pattern, at a pH similar to that found in faecal samples of breastfed infants, reduces the growth of pathogens in a dose-dependent manner but does not influence the growth of bifidobacteria and lactobacilli. In an animal vaccination model, the prebiotic mixture improved the response to vaccination. In an allergy model (sensitization by ovalbumin), the allergic reaction was reduced by the prebiotic mixture. The data obtained from animal experiments are in agreement with preliminary data from clinical trials which indicate a reduced allergic response (reduced plasma IgE/IgG4 ratio) and reduced episodes of upper airway infection during the first year of life. Conclusion: Experimental evidence demonstrates that the prebiotic mixture employed in these studies modulates the intestinal flora and modulates the immune system as human milk does. There are sufficient experimental data to put forward the hypothesis that substances like the prebiotic mixture under study will substantially contribute to the improvement of the protective properties of infant formulas.

Increase of faecal bifidobacteria due to dietary oligosaccharides induces a reduction of clinically relevant pathogen germs in the faeces of formula-fed preterm infants

UNLABELLED In a previous study on formula-fed preterm infants, we were able to demonstrate that dietary oligosaccharides (a mixture of 90% galacto-oligosaccharides and 10% fructo-oligosaccharides in a concentration of 1 g/dl) stimulate the growth of faecal bifidobacteria. In the present explorative analysis of this study, we focus on the effect of the dominance of bifidobacteria on the presence of clinically relevant pathogens (Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus haemolyticus, Pseudomonas aeruginosa, Enterobacter, Klebsiella, Proteus, Streptococcus group B, Clostridium difficile, Bacillus subtilis and Acinetobacter). CONCLUSION The data demonstrate that stimulation of bifidobacteria by prebiotic oligosaccharides reduces the presence of clinically relevant pathogens in the faecal flora, indicating that prebiotic substances might have the capacity to protect against enteral infections.

Effects of a dietary and environmental prevention programme on the incidence of allergic symptoms in high atopic risk infants: Three years follow-up

ABSTRACT A prospective case‐control study is presented to assess an allergy prevention programme in children up to 36 months of age. Infants born at three maternity hospitals were followed from birth: 279 infants with high atopic risk (intervention group) were compared with 80 infants with similar atopic risk but no intervention (non‐intervention group). The intervention programme included dietary measures (exclusive and prolonged milk feeding diet followed by a hypoantigenic weaning diet) and environmental measures (avoidance of parental smoking in the presence of the babies, day care >2 years of life). Mothers in this group who had insufficient breast milk were randomly assigned to one of two coded formulas: either a hydrolysed milk formula (Nidina HA, Nestlé) or a conventional adapted formula (Nan, Nestlé). Other environmental measures remained the same as for the breastfeeding mothers. The non‐intervention group were either breastfed or received the usual Italian milk feeding and weaning diet, without environmental advice. The main outcome measures were anthropometric measurements and allergic disease manifestations. Normal anthropometric data were observed both in the intervention group and in the nonintervention group. The incidence of allergic manifestations was much lower in the intervention group than in the nonintervention group at 1 year (11.5 versus 54.4%, respectively) and at 2 years (14.9 versus 65.6%) and 3 years (20.6 versus 74.1 %). Atopic dermatitis and recurrent wheezing were found in both the intervention group and the non‐intervention group from birth up to the second year of life, while urticaria and gastrointestinal disorders were only present in the non‐intervention group in the first year of life. Conjunctivitis and rhinitis were present after the second year in both the intervention group and the non‐intervention group. Relapse of the same allergic symptom was less in the intervention group (13.0%) than in the non‐intervention group (36.9%). In comparison to the non‐intervention group, there were fewer intervention group cases with two or more different allergic symptoms (8.7 versus 32.6%), and they were more likely to avoid steroid treatment (0 versus 10.8%) and hospital admission (0 versus 6.5%). Babies in the non‐intervention group fed with adapted formula were more likely to develop allergies than breastfed babies in the same group. In the intervention group the breastfed infants had the lowest incidence of allergic symptoms, followed by the infants fed the hydrolysed formula (ns). Infants in the intervention group fed the adapted formula had significantly more allergies than the breastfed and hydrolysed milk fed infants, although less than their counterparts in the non‐intervention group. Of the affected subjects in the intervention group, 80.4% were RAST and/or Prick positive to food or inhalant allergens. Total serum IgE values detected at birth in the intervention group were not predictive, but at 1 and 2 years of age, IgE values more than 2 SD above the mean in asymptomatic babies were found to predictive for later allergy. In breastfed babies the total IgE level at 1 and 2 years of age was lower than in the other two feeding groups. Of the various factors tested in the non‐intervention group, the following were the most important in the pathogenesis of allergic symptoms: (i) formula implementation begun in the first week of life; (ii) early weaning (< 4 months); (iii) feeding beef (< 6 months); (iv) early introduction of cows milk (< 6 months); and (v) parental smoking in the presence of the babies and early day care admission (< 2 years of life). All the preventive measures used in this study (exclusive breastfeeding and/or hydrolysed milk feeding, delayed and selective introduction of solid foods, and environmental advice) were effective at the third year of follow‐up, greatly reducing allergic manifestations in high atopic risk babies in comparison with those not receiving these interventions.

Probabilistic diffusion tractography of the optic radiations and visual function in preterm infants at term equivalent age

Children born prematurely have a high incidence of visual disorders which cannot always be explained by focal retinal or brain lesions. The aim of this study was to test the hypothesis that visual function in preterm infants is related to the microstructural development of white matter in the optic radiations. We used diffusion tensor imaging (DTI) with probabilistic diffusion tractography to delineate the optic radiations at term equivalent age and compared the fractional anisotropy (FA) to a contemporaneous evaluation of visual function. Thirty-seven preterm infants (19 male) born at median (range) 28(+4) (24(+1)-32(+3)) weeks gestational age, were examined at a post-menstrual age of 42 (39(+6)-43) weeks. MRI and DTI were acquired on a 3 Tesla MR system with DTI obtained in 15 non-collinear directions with a b value of 750 s/mm(2). Tracts were generated from a seed mask placed in the white matter lateral to the lateral geniculate nucleus and mean FA values of these tracts were determined. Visual assessment was performed using a battery of nine items assessing different aspects of visual abilities. Ten infants had evidence of cerebral lesions on conventional MRI. Multiple regression analysis demonstrated that the visual assessment score was independently correlated with FA values, but not gestational age at birth, post-menstrual age at scan or the presence of lesions on conventional MRI. The occurrence of mild retinopathy of prematurity did not affect the FA measures or visual scores. We then performed a secondary analysis using tract-based spatial statistics to determine whether global brain white matter development was related to visual function and found that only FA in the optic radiations was correlated with visual assessment score. Our results suggest that in preterm infants at term equivalent age visual function is directly related to the development of white matter in the optic radiations.

Short-term, long-term and paracrine effect of human umbilical cord-derived stem cells in lung injury prevention and repair in experimental bronchopulmonary dysplasia

Background Bronchopulmonary dysplasia (BPD) remains a main complication of extreme prematurity and currently lacks efficient treatment. Rat bone marrow-derived mesenchymal stem cells (MSC) prevent lung injury in an oxygen-induced model of BPD. Human cord is an advantageous source of stem cells that is especially appealing for the treatment of neonatal diseases. The therapeutic benefit after established lung injury and long-term safety of cord-derived stem cells is unknown. Methods Human cord-derived perivascular cells (PCs) or cord blood-derived MSCs were delivered prophylactically or after established alveolar injury into the airways of newborn rats exposed to hyperoxia, a well-established BPD model. Results Rat pups exposed to hyperoxia showed the characteristic arrest in alveolar growth with air space enlargement and loss of lung capillaries. PCs and MSCs partially prevented and rescued lung function and structure. Despite therapeutic benefit, cell engraftment was low, suggesting that PCs and MSCs act via a paracrine effect. Accordingly, cell free-derived conditioned media from PCs and MSCs also exerted therapeutic benefit when used either prophylactically or therapeutically. Finally, long-term (6 months) assessment of stem cell or conditioned media therapy showed no adverse lung effects of either strategy, with persistent improvement in exercise capacity and lung structure. Conclusions Human umbilical cord-derived PCs and MSCs exert short- and long-term therapeutic benefit without adverse lung effects in this experimental model and offer new therapeutic options for lung diseases characterised by alveolar damage.

Bovine Lactoferrin Prevents Invasive Fungal Infections in Very Low Birth Weight Infants: A Randomized Controlled Trial

Background: Lactoferrin is a mammalian milk glycoprotein involved in innate immunity. Recent data show that bovine lactoferrin (bLF) prevents late-onset sepsis in preterm very low birth weight (VLBW) neonates. Methods: This is a secondary analysis of data from a multicenter randomized controlled trial where preterm VLBW neonates randomly received bLF (100 mg/day; group A1), bLF + Lactobacillus rhamnosus GG (106 colony-forming units per day; group A2), or placebo (group B) for 6 weeks. Here we analyze the incidence rates of fungal colonization, invasive fungal infection (IFI), and rate of progression from colonization to infection in all groups. Results: This study included 472 neonates whose clinical, nutritional, and demographical characteristics were similar. Overall, the incidence of fungal colonization was comparable (17.6%, 16.6%, and 18.5% in A1, A2, and B, respectively; P = .89 [A1] and .77 [A2]). In contrast, IFIs were significantly decreased in A1 and A2 (0.7% and 2.0%, respectively) compared with B (7.7%; P = .002 [A1] and .02 [A2]), and this was significantly true both in <1000 g (0.9% [A1] and 5.6% [A2], vs 15.0%) and in 1001 to 1500 g infants (0% and 0% vs 3.7%). The progression rate colonization-infection was significantly lower in the bLF groups: 3.7% (A1) and 12% (A2), vs 41.9%; P < .001 (A1) and P = .02 (A2). No IFI-attributable deaths occurred in the treatment groups, versus 2 in placebo. No adverse effects or intolerances occurred. Conclusions: Prophylactic oral administration of bLF reduces the incidence of IFI in preterm VLBW neonates. No effect is seen on colonization. The protective effect on IFI is likely due to limitation of ability of fungal colonies to progress toward invasion and systemic disease in colonized infants.

Effects of a new mixture of prebiotics on faecal flora and stools in term infants.

A double‐blind, randomized, controlled study was performed in 90 full term infants to evaluate dose‐related bifidogenic effects of a new synergistic mixture of galacto‐oligosaccharides (GOS) and fructo‐oligosacharides (FOS). The GOS/FOS mixture showed a dose‐dependent stimulatory effect on the intestinal growth of bifidobacteria. Also stool consistency and faecal pH were positively affected.