Publications by authors named "Francesca Garofoli"

34 Publications

Oral melatonin as a new tool for neuroprotection in preterm newborns: study protocol for a randomized controlled trial.

Trials 2021 Jan 22;22(1):82. Epub 2021 Jan 22.

Child Neurology and Psychiatry Unit, Department of Brain and Behavioral Sciences, University of Pavia, 27100, Pavia, Italy.

Background: Prevention of neurodevelopmental impairment due to preterm birth is a major health challenge. Despite advanced obstetric and neonatal care, to date there are few neuroprotective molecules available. Melatonin has been shown to have anti-oxidant/anti-inflammatory effects and to reduce brain damage, mainly after hypoxic ischemic encephalopathy. The planned study will be the first aiming to evaluate the capacity of melatonin to mitigate brain impairment due to premature birth.

Method: In our planned prospective, multicenter, double-blind, randomized vs placebo study, we will recruit, within 96 h of birth, 60 preterm newborns with a gestational age ≤ 29 weeks + 6 days; these infants will be randomly allocated to oral melatonin, 3 mg/kg/day, or placebo for 15 days. After the administration period, we will measure plasma levels of malondialdehyde, a lipid peroxidation product considered an early biological marker of melatonin treatment efficacy (primary outcome). At term-equivalent age, we will evaluate neurological status (through cerebral ultrasound, cerebral magnetic resonance imaging, vision and hearing evaluations, clinical neurological assessment, and screening for retinopathy of prematurity) as well as the incidence of bronchodysplasia and sepsis. We will also monitor neurodevelopmental outcome during the first 24 months of corrected age (using the modified Fagan Test of Infant Intelligence at 4-6 months and standardized neurological and developmental assessments at 24 months).

Discussion: Preterm birth survivors often present long-term neurodevelopmental sequelae, such as motor, learning, social-behavioral, and communication problems. We aim to assess the role of melatonin as a neuroprotectant during the first weeks of extrauterine life, when preterm infants are unable to produce it spontaneously. This approach is based on the supposition that its anti-oxidant mechanism could be useful in preventing neurodevelopmental impairment. Considering the short- and long-term morbidities related to preterm birth, and the financial and social costs of the care of preterm infants, both at birth and over time, we suggest that melatonin administration could lead to considerable saving of resources. This would be the first study addressing the role of melatonin in very low birth weight preterm newborns, and it could provide a basis for further studies on melatonin as a neuroprotection strategy in this vulnerable population.

Trial Registration: ClinicalTrials.gov NCT04235673 . Prospectively registered on 22 January 2020.
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http://dx.doi.org/10.1186/s13063-021-05034-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820522PMC
January 2021

Cytomegalovirus-Specific T Cell Epitope Recognition in Congenital Cytomegalovirus Mother-Infant Pairs.

Front Immunol 2020 24;11:568217. Epub 2020 Nov 24.

University of Massachusetts Medical School, Worcester, MA, United States.

Congenital cytomegalovirus (cCMV) infection is the most common infection acquired before birth and from which about 20% of infants develop permanent neurodevelopmental effects regardless of presence or absence of symptoms at birth. Viral escape from host immune control may be a mechanism of CMV transmission and infant disease severity. We sought to identify and compare CMV epitopes recognized by mother-infant pairs. We also hypothesized that if immune escape were occurring, then one pattern of longitudinal CD8 T cell responses restricted by shared HLA alleles would be maternal loss (by viral escape) and infant gain (by viral reversion to wildtype) of CMV epitope recognition. The study population consisted of 6 women with primary CMV infection during pregnancy and their infants with cCMV infection. CMV UL83 and UL123 peptides with known or predicted restriction by maternal MHC class I alleles were identified, and a subset was selected for testing based on several criteria. Maternal or infant cells were stimulated with CMV peptides in the IFN-γ ELISpot assay. Overall, 14 of 25 (56%; 8 UL83 and 6 UL123) peptides recognized by mother-infant pairs were not previously reported as CD8 T cell epitopes. Of three pairs with longitudinal samples, one showed maternal loss and infant gain of responses to a CMV epitope restricted by a shared HLA allele. CD8 T cell responses to multiple novel CMV epitopes were identified, particularly in infants. Moreover, the hypothesized pattern of CMV immune escape was observed in one mother-infant pair. These findings emphasize that knowledge of paired CMV epitope recognition allows exploration of viral immune escape that may operate within the maternal-fetal system. Our work provides rationale for future studies of this potential mechanism of CMV transmission during pregnancy or clinical outcomes of infants with cCMV infection.
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http://dx.doi.org/10.3389/fimmu.2020.568217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732427PMC
November 2020

The dynamical interplay of perinatal leptin with birthweight and 3-month weight, in full-term, preterm, IUGR mother-infant dyads.

J Matern Fetal Neonatal Med 2020 Nov 8:1-7. Epub 2020 Nov 8.

Neonatal Unit and Neonatal Intensive Care Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italia.

Objective: To evaluate the dynamical interplay between perinatal leptin concentrations and neonatal weight evolution until 3 months of age.

Methods: In a prospective observational study, maternal, cord blood and neonatal plasma leptin concentrations were correlated to birthweight and 3-month weight in 26 full-term, 20 preterm, and 17 intrauterine growth restriction (IUGR) mother-neonate couples.

Results: The median of maternal, cord blood, neonatal leptin concentrations were significantly different among the three groups ( = 0.010; <0.001; =0.041 correspondingly). In the respect of the full-term group, higher concentrations were reported in preterm and IUGR mothers and lower concentrations in cord blood and neonatal plasma. The post-hoc comparisons showed that maternal concentrations were significantly higher in the IUGR group ( = 0.005 vs full-term), cord blood concentrations resulted always significantly lower (preterm, IUGR vs full-term  < 0.001) and neonatal concentrations were significantly lower in the preterm group ( = 0.018 vs full-term). Neonatal birthweight and 3-month weight were always significantly different among groups ( < 0.001), even if preterm and IUGR still had lower weight than full-term, the percent increasing of weight between birth and 3-month demonstrated that preterm and IUGR infants have grown significantly faster, (preterm, IUGR vs full-term  < 0.001). The univariable analysis showed a maternal leptin association with offspring' birthweight ( = -38%,  = 0.006) and with 3-month weight ( = -43%,  = 0.002). Accounting for confounders, these associations lost significance. Cord blood leptin concentrations positively correlated with birthweight and with 3-month weight (both,  < 0.001). The latter correlation, when adjusting for birthweight became negative ( = -43%  < 0.001).

Conclusion: Our results showed that maternal leptin levels lost their influence on neonatal weight when considering confounders. At 3-month, once birthweight adjusted, the percent increasing of weight was statistically larger in preterm and IUGR than the full-term group and the correlation between cord blood leptin and weight turned negative, from positive at birth. These data may be a clue for further investigation on the relationship between perinatal leptin concentrations and catch-up growth.
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http://dx.doi.org/10.1080/14767058.2020.1839750DOI Listing
November 2020

Onset of valganciclovir resistance in two infants with congenital cytomegalovirus infection.

Int J Infect Dis 2020 Sep 29;98:150-152. Epub 2020 Jun 29.

Molecular Virology Unit, Microbiology and Virology Department, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Department of Clinical, Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Italy.

Ganciclovir and its prodrug valganciclovir are elective treatments for cCMV. Neonates with important symptoms undergo 6 months of therapy to ameliorate/prevent symptoms and late sequelae, but evidence of resistance is emerging. Over the last 5 years, we took care of 59 cCMV infants and experienced two cases of resistance among nine cCMV infants receiving long-term valganciclovir therapy. In the first case, valganciclovir therapy was prolonged beyond 6 months due to severity of symptoms, control of viral load, and absence of adverse events. Resistance was detected in the 8th month of therapy. In the second case, after a significant reduction following valganciclovir administration and no adverse events, CMV viral load suddenly increased in the 6th month of therapy due to resistance. Both events were associated with UL97 gene mutation. The cCMV infants, affected by severe symptoms, remained in a steady state during treatment, and their later neurological development was coherent with initial seriousness of diagnosis. Prolonged therapeutic exposure may therefore be a risk for resistance, suggesting that constant dosage/weight adjustments, monthly surveillance of viral load, and therapeutic drug monitoring could be proposed to monitor resistance onset and optimize the therapy regime. The risk-benefit ratio for long-term therapy, including the possibility of resistance onset, alongside SNHL and neurodevelopmental improvement, should also be evaluated.
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http://dx.doi.org/10.1016/j.ijid.2020.06.087DOI Listing
September 2020

Oral vitamin A supplementation for ROP prevention in VLBW preterm infants.

Ital J Pediatr 2020 Jun 3;46(1):77. Epub 2020 Jun 3.

Neonatal Unit and Neonatal Intensive Care Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.

Vitamin A administration may decrease any stage of retinopathy of prematurity (ROP) in preterm infants. To evaluate whether vitamin A oral supplementation could be preventive in ROP incidence and severity in VLBW infants, we compared results from 31 preterm infants, (< 1500 g or < 32 weeks) who, during a previous investigation, prospectively received 3000 UI/kg/die oral retinol palmitate drops, for 28 days, with 31 matching preterm newborns hospitalized in our NICU the same period, as control group. Although ROP incidence was similar, in the supplemented group, we had 9 cases of ROP grade 1, no ROP grade ≥ 2, in the un-supplemented group, 4 cases of ROP grade 1 and 6 ROP grade ≥ 2 (p = 0.018). The percentage of babies requiring treatment for ROP was 0 in treated and 16.6 in the un-treated group (p = 0.020). Moreover, Vitamin A administration showed a protective effect with an 88% risk reduction of developing severe ROP. Since vitamin A parenteral/IM administration presents some awareness, the results of this investigation may be important to plan further trials to confirm the usefulness of oral administration in mitigating the ROP severity of VLBW infants.ClinicalTrials.gov NCT02102711; may 03/06/2014.
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http://dx.doi.org/10.1186/s13052-020-00837-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268228PMC
June 2020

Prenatal and postnatal determinants in shaping offspring's microbiome in the first 1000 days: study protocol and preliminary results at one month of life.

Ital J Pediatr 2020 Apr 15;46(1):45. Epub 2020 Apr 15.

Dietetics and Clinical Nutrition Laboratory - Department of Public Health, Experimental and Forensic Medicine, University of Pavia, via Bassi 21, 27100, Pavia, Italy.

Background: Fetal programming during in utero life defines the set point of physiological and metabolic responses that lead into adulthood; events happening in "the first 1,000 days" (from conception to 2-years of age), play a role in the development of non-communicable diseases (NCDs). The infant gut microbiome is a highly dynamic organ, which is sensitive to maternal and environmental factors and is one of the elements driving intergenerational NCDs' transmission. The A.MA.MI (Alimentazione MAmma e bambino nei primi MIlle giorni) project aims at investigating the correlation between several factors, from conception to the first year of life, and infant gut microbiome composition. We described the study design of the A.MA.MI study and presented some preliminary results.

Methods: A.MA.MI is a longitudinal, prospective, observational study conducted on a group of mother-infant pairs (n = 60) attending the Neonatal Unit, Fondazione IRCCS Policlinico San Matteo, Pavia (Italy). The study was planned to provide data collected at T0, T1, T2 and T3, respectively before discharge, 1,6 and 12 months after birth. Maternal and infant anthropometric measurements were assessed at each time. Other variables evaluated were: pre-pregnancy/gestational weight status (T0), maternal dietary habits/physical activity (T1-T3); infant medical history, type of feeding, antibiotics/probiotics/supplements use, environment exposures (e.g cigarette smoking, pets, environmental temperature) (T1-T3). Infant stool samples were planned to be collected at each time and analyzed using metagenomics 16S ribosomal RNA gene sequence-based methods.

Results: Birth mode (cesarean section vs. vaginal delivery) and maternal pre pregnancy BMI (BMI < 25 Kg/m vs. BMI ≥ 25 Kg/m), significant differences were found at genera and species levels (T0). Concerning type of feeding (breastfed vs. formula-fed), gut microbiota composition differed significantly at genus and species level (T1).

Conclusion: These preliminary and explorative results confirmed that pre-pregnancy, mode of delivery and infant factors likely impact infant microbiota composition at different levels.

Trial Registration: ClinicalTrials.gov identifier: NCT04122612.
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http://dx.doi.org/10.1186/s13052-020-0794-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7158098PMC
April 2020

Rapid detection of bacteria in bloodstream infections using a molecular method: a pilot study with a neonatal diagnostic kit.

Mol Biol Rep 2020 Jan 22;47(1):363-368. Epub 2019 Oct 22.

UOC Neonatology and Neonatal Intensive Care Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.

Neonatal sepsis is a life-threatening condition and its early diagnosis is crucial for infant survival. Identifying responsible pathogens is a key step. Blood culture (BC) is the gold standard, but more rapid and specific diagnostic methods are needed. We evaluated the reliability and utility of 3 h turnaround time diagnostic molecular kit, "EuSepScreen lattanti "CE IVD marked, (EuSepScreen lattanti, Eurospital Spa Trieste, Italy) specifically targeted to detect 4 pathogens in neonatal sepsis: Klebsiella pneumoniae (KP), Escherichia coli (EC), Streptococcus agalactiae (GBS), and Lysteria monocytogenes. We evaluated 69 neonates, 40 full term and 29 preterm infants, with suspected bloodstream infection, who, overall the routine clinical procedures, were tested using the molecular kit. Kit results were compared to BC outcomes. Nineteen cases for early onset sepsis (EOS) were evaluated, 2 of them resulted positive to a molecular kit and to BC (both for GBS and EC). In the 50 cases of suspected late onset sepsis (LOS), 7 infants reported positive and coincident results to both the methods, in 3 further cases the molecular kit identified pathogens (EC) in neonates with negative BC result; in 10 cases BC revealed etiological pathogens exceeding the molecular kit possibility of identification. In case of EOS, results of the molecular kit were coincident to these of BC, but available in 3 h turnaround time, which is an advantage, so the kit may actually be an "add-on tool" for EOS, with reference to EC and GBS, but a larger study with a greater number of EOS cases are needed to validate its usefulness in the NICU. Regarding LOS the restricted panel of identifiable microorganisms failed to provide timely information for sepsis diagnosis, highlighting the need of enlarged number microorganisms for the diagnosis of LOS.Trial registration number: NCT03884894.
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http://dx.doi.org/10.1007/s11033-019-05138-2DOI Listing
January 2020

The role of immature platelet fraction (IPF%) in full-term and preterm infants: Italian data of a promising clinical biomarker in neonates.

Int J Lab Hematol 2020 02 12;42(1):e10-e13. Epub 2019 Jul 12.

Neonatal Unit and Neonatal Intensive Care Unit, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy.

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http://dx.doi.org/10.1111/ijlh.13071DOI Listing
February 2020

Levels and effectiveness of oral retinol supplementation in VLBW preterm infants.

Int J Immunopathol Pharmacol 2018 Mar-Dec;32:2058738418820484

1 Neonatal Immunology Laboratory, UOC Neonatology and Neonatal Intensive Care Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.

Retinol palmitate oral administration is convenient, but it is difficult to assess/monitor its nutritional status in preterm infants and literature is controversial about the administration route and the effectiveness of vitamin A supplementation. We primarily evaluated retinol plasma levels to assess the vitamin A nutritional status in preterm infants (<1500 g; 32 weeks) after 28 days of oral supplementation (3000 IU/kg/day, retinol palmitate drops), in addition to vitamin A standard amount as suggested by European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) guidelines. We then observed the rate of typical preterm pathologies in the supplemented group (31 newborns) and in 10 matching preterm infants, hospitalized in neonatal intensive care unit (NICU) in the same period, who received neither vitamin A supplementation nor parents allowed plasma sampling. Oral integration resulted in constant retinol plasma concentration around the desired level of 200 ng/mL, but without statistical increase during the study period. Due to the complexity of vitamin A metabolism and the immaturity of preterm infant's organs, retinol supplementation may had first saturated other needy tissues; therefore, plasmatic measures may not be consistent with improved global vitamin A body distribution. Therefore, achieving a constant retinol concentration is a valuable result and supportive for oral administration: decreasing levels, even after parenteral/enteral supplementation, were reported in the literature. In spite of favourable trend and no adverse events, we did not report statistical difference in co-morbidities. This investigation confirms the necessity to perform further trials in preterm newborns, to find an index reflecting the complex nutritional retinol status after oral administration of vitamin A, highlighting its effectiveness/tolerability in correlated preterm infant's pathologies.
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http://dx.doi.org/10.1177/2058738418820484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6311539PMC
July 2019

Neonatal HCMV-related polymicrogyria in seroimmune women: What is the optimal pregnancy management?

J Clin Virol 2018 11 2;108:141-146. Epub 2018 Oct 2.

Molecular Virology Unit, Microbiology and Virology Department, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Section of Microbiology, Department of Clinical, Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy. Electronic address:

Background: Human cytomegalovirus (HCMV) infection is the most common congenital infection in developed countries. Recent studies highlighted similar percentages of symptoms in HCMV congenitally-infected infants following either primary or non-primary maternal infections.

Objectives: To highlight correlation between neonatal brain abnormalities, detected by ultrasounds and magnetic resonance image in HCMV congenitally-infected infants, and maternal virological parameters during pregnancy, especially in seroimmune mothers.

Study Design: We considered the 36 HCMV congenitally-infected infants (26 asymptomatic and 10 symptomatic) referred to our center over 4 consecutive years. Maternal serologic data during pregnancy were available for all cases. Neonatal cranial ultrasound and magnetic resonance images were related to maternal virological findings during pregnancy.

Results: Polymicrogyria was observed in 6/10 (60.0%) symptomatic and 0/26 (0%) asymptomatic newborns (p < 0.001). The 6 infants with polymicrogyria were all born to mothers who were HCMV IgG reactive with negative specific IgM, in the first trimester of pregnancy (range: 8-14 weeks). For these six women, pre-conceptional HCMV serologic information were absent and they all were considered immune for HCMV during pregnancy, therefore no further serologic investigation or specific educational and hygienic information were recommended during gestation.

Conclusion: These data highlight the elevated frequency of polymicrogyria in HCMV congenitally-infected infants born to mothers defined as seroimmune in the early stage of pregnancy and having no pre-existing serologic information. The paper stresses the potential utility of pre-conceptional screening to define maternal infection reliably (primary vs non-primary), and allow evidence-based counseling in women with positive serology, suggesting also preventive hygienic measures during pregnancy.
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http://dx.doi.org/10.1016/j.jcv.2018.10.001DOI Listing
November 2018

Congenital Cytomegalovirus: A European Expert Consensus Statement on Diagnosis and Management.

Pediatr Infect Dis J 2017 12;36(12):1205-1213

From the *Paediatric Infectious Diseases Research Group, St George's University, London, United Kingdom; †Centre for Virology, University College Medical School, London; ‡Kingston Hospital NHS Foundation Trust, London, United Kingdom; §The Hague Medical Center (HMC), Department of Pediatrics and Sophia Children's hospital, Erasmus Medical Center Rotterdam Department of Pediatric Infectious Diseases; ¶Pediatric Infectious Diseases Unit, Hospital Universitario 12 de Octubre, Universidad Complutense, Instituto de Investigación Hospital 12 de Octubre, Madrid, Spain; ∥Center for Chronic Immunodeficiency and Center for Pediatrics and Adolescent Medicine, Medical Center and Faculty of Medicine, University of Freiburg, Germany; **Our Lady's Children's Hospital Crumlin, UCD School of Medicine and Health Sciences, Dublin, Ireland; ††Department of Obstetrical, Gynaecological and Paediatric Sciences, Operative Unit of Neonatology, Polyclinic St. Orsola-Malpighi, University of Bologna, Bologna, Italy; ‡‡Pediatric Infectious Diseases, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain; §§Department of Paediatrics, The University of Melbourne & Murdoch Children's Research Institute, Royal Children's Hospital Melbourne, Parkville, Australia; ¶¶NICU and Neonatal Unit, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy; ∥∥Infectious Diseases Unit, 3rd Department of Pediatrics, Faculty of Medicine, Aristotle University School of Health Sciences, Thessaloniki, Greece; ***Great Ormond Street Children's Hospital, London, and the Institute of Child Health, UCL, London, United Kingdom; †††NICU and Neonatal Unit, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy; ‡‡‡Imperial College NHS Healthcare, London, United Kingdom; §§Pediatric Infectious Diseases, Children's Hospital, University of Helsinki and Helsinki University Hospital, Finland; ¶¶¶Department of Pediatric Infectious Diseases, Emma Children's Hospital, Academic Medical Center, Amsterdam, The Netherlands; ∥∥∥National and Kapodistrian University of Athens, Greece; ****Children's Hospital of Geneva, University Hospitals of Geneva, Switzerland; ††††Pediatric Infectious Diseases Unit, Gregorio Marañón Hospital, Madrid, Spain; and ‡‡‡‡Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands.

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http://dx.doi.org/10.1097/INF.0000000000001763DOI Listing
December 2017

An Italian Prospective Experience on the Association Between Congenital Cytomegalovirus Infection and Autistic Spectrum Disorder.

J Autism Dev Disord 2017 May;47(5):1490-1495

Neonatal Immunology Laboratory, Neonatal Intensive Care Unit, Fondazione IRCCS Policlinico San Matteo, 27100, Pavia, Italy.

The aim of this retrospective study, with prospective data collection, was to correlate congenital cytomegalovirus (CMV) infection with autism spectrum disorder (ASD) and to define its prevalence. Seventy proven congenitally-infected infants, born between 2007 and 2012, were referred to our centre for CMV diagnosis and follow-up, which consisted of a consolidated protocol allowing an early evaluation of autism. We considered four children 2-year old, two of whom, at the age of 3, were diagnosed with ASD demonstrating a 2-3 fold higher prevalence (2.86%), than that in general Italian population (0.66-1.36%).Our protocol enabled us to make the earliest diagnosis and highlight the role of the virus among other causes of autism, which may be a long term sequela of congenital CMV.
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http://dx.doi.org/10.1007/s10803-017-3050-3DOI Listing
May 2017

Impact of Early Postnatal Nutrition on the NMR Urinary Metabolic Profile of Infant.

J Proteome Res 2016 10 28;15(10):3712-3723. Epub 2016 Sep 28.

Neonatal Unit and Neonatal Intensive Care Unit, Fondazione IRCCS Policlinico San Matteo , 27100 Pavia, Italy.

NMR-based metabolomics was used to compare the metabolic urinary profiles of exclusively breast-fed term infants (n = 11) with those of a double-blinded controlled trial with 49 formula-fed term newborns randomized to receive either an infant formula enriched by functional ingredients (n = 24) or a standard formula (n = 25). Anthropometric measurements and urine samples were taken at enrollment (within the first month of life), at around 60 days of life, and at the end of study period (average age of 130 days). The metabolic profiles were examined in relation to time and diet strategy. A common age-dependent modification of the urine metabolome was observed for the three types of nutrition, mainly characterized by similar temporal trends of choline, betaine, myoinositol, taurine, and citrate. Contrariwise, differences in the metabolic profiles were identified according to the type of diet (human versus formula milk), while no significant difference was observed between the two formulas. These modifications are discussed mainly in terms of the different milk compositions. Despite the low number of enrolled infants (n = 60), these findings pointed out the potential of the metabolomics approach for neonatal nutritional science, in particular to provide important contributions to the optimization of formula milk.
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http://dx.doi.org/10.1021/acs.jproteome.6b00537DOI Listing
October 2016

Safety, growth, and support to healthy gut microbiota by an infant formula enriched with functional compounds.

Clin Nutr 2017 02 27;36(1):238-245. Epub 2015 Nov 27.

Neonatal Unit and Neonatal Intensive Care Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Neonatal Immunology Laboratory, Neonatal Unit and Neonatal Intensive Care Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.

Background & Aims: Safety and growth adequacy of infant formulae enriched by functional ingredients need stringent evaluation by means of randomized controlled trials (RCTs), therefore we performed a double-blind RCT to evaluate an infant formula enriched with galacto-oligosaccharides, beta-palmitate, and acidified milk vs. a standard infant formula.

Methods: Weight, length, head circumference and fecal bacteria (Bifidobacteria, BIF/Clostridia, CLO) were measured in healthy full term infants, at baseline - as before 21 days of life - at 60 and 135 days thereafter. A group of 51 neonates received the enriched formula (ENR), 59 the standard one (ST). Parents were trained to daily register gastrointestinal diseases.

Results: All the infants grew homogeneously increasing the anthropometric parameters and complying with WHO and Italian standards: the mean (SD) difference in daily weight between ENR and ST groups was -0.74 (1.13) g/day, corresponding to a 90% CI of -2.62 to 1.13 g/day, well within the postulated interval of equivalence of -3.9 to +3.9 g/day. A statistical improvement in BIF concentration in the microbiota of infants fed by ENR was recorded. There was no between-group change in logCLO, but logBIF increase was higher at T2 vs. T0 in ENR (treatment × time interaction = 0.71, 95% CI 0.08-1.34, p = 0.028) than in ST neonates. This corresponds to estimated mean (95% CI) values of 8.37 (8.04-8.69) log-units for ENR vs. 8.08 (7.77-8.39) log-units for ST neonates. Gastrointestinal effects were mild and similar, with no statistical difference between two groups.

Conclusion: Safety and growth ability of the enriched formula has been confirmed. A positive effect on neonatal gut microbiota, consisting of increased fecal BIF counts at T2 vs. baseline has been shown too. Nonetheless, larger RCTs are needed to estimate with greater precision the effective potential attributable to the enriched formula on neonatal microbiota, with particular reference to the mode of delivery.
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http://dx.doi.org/10.1016/j.clnu.2015.11.006DOI Listing
February 2017

Maternal and neonatal outcomes in pregnant women with autoimmune diseases in Pavia, Italy.

BMC Pediatr 2015 Dec 18;15:217. Epub 2015 Dec 18.

Neonatal Unit and Neonatal Intensive Care Unit, IRCCS San Matteo Hospital Foundation, Pavia, Italy.

Background: The increased number of childbearing women with autoimmune diseases leads to a growing interest in studying relationship among maternal disease, therapy, pregnancy and off-spring. The aim of this study was to determine the impact of autoimmune disease on pregnancy and on neonatal outcome, taking into account the maternal treatment and the transplacental autoantibodies passage.

Methods: We studied 70 infants born to 70 pregnant women with autoimmune disease attended in Fondazione IRCCS Policlinico San Matteo, Pavia, Italy from June 2005 to June 2012. Maternal and neonatal characteristics were collected and relevant clinical, laboratory, therapeutics, sonographic and electrocardiographic investigations were recorded and analyzed.

Results: We observed a high rate of spontaneous abortions in medical history, 29 %, and 18.6 % of preterm births and 22.9 % of low birth weight (< 2500 g). Transplacental autoantibodies passage wasn't related to maternal or obstetrical complication, but anti-Ro/SSA positive pregnancies correlated with abnormal fetal heart rate (P = 0.01). Pregnant women on therapy showed an higher incidence of maternal (p = 0.002), obstetric (p = 0.007) complications and an increased rate of intrauterine growth restriction (p = 0.01) than the untreated ones.

Conclusions: Autoimmune diseases in pregnancy require to be carefully monitored to ensure the best possible management of mothers, fetuses and newborns due to the high rate of morbidity specially in case of maternal polytherapy and/or anti-Ro/SSA positivity.
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http://dx.doi.org/10.1186/s12887-015-0532-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4683757PMC
December 2015

Expression and function of toll-like receptors in human circulating endothelial colony forming cells.

Immunol Lett 2015 Nov 8;168(1):98-104. Epub 2015 Oct 8.

Laboratory of Neonatal Immunology, Fondazione IRCCS Policlinico "San Matteo", Pavia, Italy; Neonatal Intensive Care Unit, Fondazione IRCCS Policlinico "San Matteo", Pavia, Italy.

Mature endothelial cells are known to sense microbial products through toll-like receptors (TLRs), a family of membrane proteins which serve as pathogen recognition and signaling elements; however, there are limited data in the literature about the expression and function of TLRs in human circulating endothelial colony forming cells (ECFCs), which are considered the most likely endothelial precursors. We expanded and differentiated in vitro umbilical cord blood (UCB) and adult peripheral blood (PB) ECFCs and studied the expression of TLR1 to TLR10 mRNA by qPCR analysis, and we further characterized TLR function in ECFCs through functional assays including in vitro ECFC growth and differentiation, assessment of cytokine production, and measurement of intracellular Ca(2+) signals. Both UCB- and PB-ECFCs had detectable mRNA levels of all the TLRs from 1 to 10; TLR4, a sensor of Gram-negative bacterial lipopolysaccharide (LPS), had a higher level compared to other TLRs. Exposure to LPS induced cytokine production, although with less efficiency compared to PB-mononuclear cells. However, no effect of LPS was seen on ECFC growth and differentiation, and no increase in intracellular Ca(2+) concentrations, which is essential for ECFC proliferation, was observed after exposure to increasing amounts of LPS. Our data show that all TLRs from 1 to 10 are constitutively expressed in ECFCs, and suggest that TLR4 is functional in ECFCs, but its activation through its ligand LPS does not affect ECFC growth and differentiation.
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http://dx.doi.org/10.1016/j.imlet.2015.09.014DOI Listing
November 2015

Complexity of parental prenatal attachment during pregnancy at risk for preterm delivery.

J Matern Fetal Neonatal Med 2016 Mar 9;29(5):771-6. Epub 2015 Mar 9.

a Neonatal Intensive Care Unit, IRCCS Foundation Policlinico San Matteo , Pavia , Italy .

Objective: To clarify the links between parents' prenatal attachment and psychosocial perinatal factors such as maternal depression, anxiety and social support.

Methods: Cross-sectional study including 43 couples with high-risk pregnancy (RP) and 37 with physiologic pregnancy (PP). Self-report measures (depression, anxiety, social support and prenatal attachment) are completed by mothers, prenatal attachment questionnaire by fathers.

Results: Depression (p < 0.001) and state anxiety (p < 0.001) are higher in RP. Both, maternal and paternal antenatal attachment is significantly lower in RP (p < 0.001; p < 0.005) but not related to depression or anxiety. Paternal antenatal attachment is strictly related to the maternal attachment scale in both groups (PP: r < 0.034; RP: r < 0.004) and paternal antenatal scores in RP have a negative significant correlation with mothers' depression (r < 0.095).

Conclusion: Hospitalized expecting parents at risk of preterm delivery develop less attachment to the fetus and higher levels of anxiety and depression compared to the physiologic pregnancy group. Maternal antenatal attachment is an independent variable related to the diagnosis of a possible preterm delivery. The promotion of prenatal psychological well-being and attachment for future mothers and fathers may serve to improve maternal health practices, perinatal health and neonatal outcome.
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http://dx.doi.org/10.3109/14767058.2015.1017813DOI Listing
March 2016

Risk and protective factors in maternal-fetal attachment development.

Early Hum Dev 2014 Sep;90 Suppl 2:S45-6

Neonatal Intensive Care Unit, IRCCS Foundation Policlinico San Matteo, Pavia, Italy.

Prenatal attachment can be described as the parents' emotions, perceptions and behaviors that are related to the fetus. This relationship has been described as the most basic form of the human intimacy and represents the earlier internalized representation of the fetus that both parents typically acquire and elaborate during pregnancy. The quality of the relationship between an infant and his or her parent is an important factor influencing the child's later development, both cognitive and emotional. There is evidence - even though yet unclear - that demographic, perinatal and psychological variables may correlate with attachment. In this perspective, it is essential to recognize the factors influencing attachment of parents towards their fetus and to planning psychosocial interventions in antepartum units or in obstetric clinics, in order to preserve a positive physical and emotional development of the infant and to provide family-centered prenatal care. Particular attention should be paid to women hospitalized for a high-risk pregnancy, since this condition involves a high distress that often results in feelings of anxiety and depression, that can hinder an adequate mother-fetus attachment.
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http://dx.doi.org/10.1016/S0378-3782(14)50012-6DOI Listing
September 2014

Urinary (1)H-NMR and GC-MS metabolomics predicts early and late onset neonatal sepsis.

Early Hum Dev 2014 Mar;90 Suppl 1:S78-83

Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.

The purpose of this article is to study one of the most significant causes of neonatal morbidity and mortality: neonatal sepsis. This pathology is due to a bacterial or fungal infection acquired during the perinatal period. Neonatal sepsis has been categorized into two groups: early onset if it occurs within 3-6 days and late onset after 4-7 days. Due to the not-specific clinical signs, along with the inaccuracy of available biomarkers, the diagnosis is still a major challenge. In this regard, the use of a combined approach based on both nuclear magnetic resonance ((1)H-NMR) and gas-chromatography-mass spectrometry (GC-MS) techniques, coupled with a multivariate statistical analysis, may help to uncover features of the disease that are still hidden. The objective of our study was to evaluate the capability of the metabolomics approach to identify a potential metabolic profile related to the neonatal septic condition. The study population included 25 neonates (15 males and 10 females): 9 (6 males and 3 females) patients had a diagnosis of sepsis and 16 were healthy controls (9 males and 7 females). This study showed a unique metabolic profile of the patients affected by sepsis compared to non-affected ones with a statistically significant difference between the two groups (p = 0.05).
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http://dx.doi.org/10.1016/S0378-3782(14)70024-6DOI Listing
March 2014

Enteral nutrition and infections: the role of human milk.

Early Hum Dev 2014 Mar;90 Suppl 1:S57-9

Neonatal Unit and Neonatal Intensive Care Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Neonatal Immunology Laboratory, Neonatal Intensive Care Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.

Human milk (HM) is known as the best nutrition for newborns and support the optimal growth of infants, providing essential substances, nutrients, bioactive and immunologic constituents. HM also grants a favorable microbial colonization with attendant priming/maturation of the gut. The bioactive and immunologic elements of HM demonstrated to protect offspring against infection and inflammation and contribute to immune maturation. Some of these elements are being investigated in order to be used to ameliorate formula milk. A formula milk similar to breast milk may help neonatal gut to build a microbiota near to the one of the breast fed infants, improving the neonate's protection against pathogens. The aim of this review is to summarize the most significant bioactive constituents of HM that own natural anti-infectious properties and contribute to neonatal immune defense.
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http://dx.doi.org/10.1016/S0378-3782(14)70019-2DOI Listing
March 2014

The early administration of Lactobacillus reuteri DSM 17938 controls regurgitation episodes in full-term breastfed infants.

Int J Food Sci Nutr 2014 Aug 17;65(5):646-8. Epub 2014 Mar 17.

Neonatal Immunology Laboratory, Neonatal Unit and Neonatal Intensive Care Unit, Fondazione IRCCS Policlinico San Matteo , Pavia , Italy .

Forty breastfed full-term infants were randomly, double blind assigned to receive orally Lactobacillus reuteri (L. reuteri) DSM 17938, 5 drops/daily (10(8) colony-forming units), for 4 weeks (n = 20) or an identical placebo (n = 20), starting before third day of life. They underwent basal and final visit to monitor growth parameters and gastrointestinal (GI) disease. Parents registered daily: crying minutes, stool frequency and consistency, numbers of regurgitations, adverse events. Secretory IgA (sIgA) has been measured in saliva on 28th day. Treated infants demonstrated a reduction in daily regurgitations at the end of treatment (p = 0.02), three neonates in the placebo group only needed simethicone for GI pain, sIgA level was similar in both groups. Random casualty produced an unbalanced gender distribution in the groups, but this bias did not affect the results. Therefore, early administration of L. reuteri DSM 17938 resulted beneficial in preventing regurgitation episodes during the first month of life.
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http://dx.doi.org/10.3109/09637486.2014.898251DOI Listing
August 2014

The red cell distribution width (RDW): value and role in preterm, IUGR (intrauterine growth restricted), full-term infants.

Hematology 2014 Sep 13;19(6):365-9. Epub 2013 Nov 13.

Objective: To measure the red cell distribution width (RDW) ranges at birth and to evaluate potential association with typical neonatal diseases: patent of the ductus arteriousus (PDA), bronchopulmonary dysplasia (BPD), and late-onset sepsis (LOS) mortality.

Methods: Forty-six full-term, 41 preterm, and 35 intrauterine growth restricted (IUGR) infants participated in this retrospective, observational study. RDW was measured before 3 days of life (T0) in all infants, and at first month of life (T1) in preterm/IURG patients.

Results: RDW% mean (standard deviation) at T0 was: 15.65 (1.18) in full-term newborns; 17.7 (2.06) in preterm; 17.45 (1.81) in IUGR. A negative correlation (r = -0.51; P < 0.001) between RDW and gestational age was found. RDW at T1 was: 17.25 (2.19) in the preterm group; 17.37 (2.56) in IUGR group. Fourteen preterm infants reported: 12 PDA, 5 LOS, 4 BPD, and 3 died; 10 IUGR infants had: 4 PDA, 6 LOS, 3 BPD, and 1 died. RDW of IUGR infants suffering from those pathologies was not statistically different compared with unaffected infants, while preterm newborns with pathologies reported higher RDW: PDA vs. PDA absent: P = 0.008 at T0; P < 0.002 at T1. BPD vs. BPD absent: P < 0.005 at T1. LOS vs. LOS absent: P < 0.005 at T0. RDW in preterm/IUGR population was associated with early mortality, T0: dead 21.2 (2.7) vs. alive 16.7 (1.7), P < 0.0001.

Conclusion: RDW and gestational age at birth were negatively correlated. High RDW resulted to be an indication of risk for critical newborns. This parameter can be inexpensively and routinely verified and further studies are required to confirm its prognostic role in neonatal pathologies.
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http://dx.doi.org/10.1179/1607845413Y.0000000141DOI Listing
September 2014

Microorganisms in human milk: lights and shadows.

J Matern Fetal Neonatal Med 2013 Oct;26 Suppl 2:30-4

Neonatal Unit and Neonatal Intensive Care Unit, Maternal-Infant Department, Fondazione IRCCS Policlinico San Matteo , Pavia , Italy .

Human milk has been traditionally considered germ free, however, recent studies have shown that it represents a continuous supply of commensal and potentially probiotic bacteria to the infant gut. Mammary microbioma may exercise anti-infective, anti-inflammatory, immunomodulatory and metabolic properties. Moreover human milk may be a source of pathogenic microorganism during maternal infection, if contaminated during expression or in case of vaccination of the mother. The non-sterility of breast milk can, thus, be seen as a protective factor, or rarely, as a risk factor for the newborn.
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http://dx.doi.org/10.3109/14767058.2013.829693DOI Listing
October 2013

Diagnostic performance of triggering receptor expressed on myeloid cells-1 and CD64 index as markers of sepsis in preterm newborns.

Pediatr Crit Care Med 2013 Feb;14(2):178-82

Laboratory of Neonatal Immunology, Neonatal Intensive Care Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.

Objective: CD64 index and triggering receptor expressed on myeloid cells-1 are biomarkers on neutrophil polymorphonuclear cells with crucial role in sepsis. The study aim is to assess diagnostic performance, individually and combined, of CD64 index and triggering receptor expressed on myeloid cells-1 (surface marker/soluble form), in late-onset sepsis of preterm infants.

Design: Observational study.

Setting: Neonatal ICU.

Patients: Sixteen septic and 16 control preterm infants, gestational age younger than 32 weeks and/or birth weigh less than 1500 g.

Measurement And Main Results: Seventy preterm infants, free of sepsis were enrolled into the study. CD64 index and triggering receptor expressed on myeloid cells-1 were measured once between day 5 and 15 of life (T0) and once between day 16 and 25 (T1). At T1, 16 infants were assigned to septic group because of reported signs of sepsis and positive blood culture. From the remaining 54 infants, 16 of them who always remained free of sepsis had a blood sample at T1 and constituted the control group (n = 16). Comparing T1 vs T0, triggering receptor expressed on myeloid cells-1 polymorphonuclear cells percentage was significantly lower (p = 0.002) in septic group but not in control group; soluble triggering receptor expressed on myeloid cells-1 concentration did not show significant differences in both groups; CD64 index significantly increased (p = 0.0004) in septic group, while no difference was found in control group. Comparing septic with control group at T0, no differences were found in any markers. At T1, triggering receptor expressed on myeloid cells-1 polymorphonuclear cells percentage was significantly lower (p = 0.003) and CD64 index was higher (p = 0.00019) in septic infants. Triggering receptor expressed on myeloid cells-1 polymorphonuclear cells receiver operating characteristic curve indicated cutoff 62.12%, sensitivity 56.2%, specificity 93.5%, and area under the curve 0.8. CD64 index receiver operating characteristic curve indicated cutoff 2.85, sensitivity 87.5%, specificity 100%, and area under the curve 0.95. Combination of the two indexes was not useful in increasing individual diagnostic power.

Conclusions: Despite limited sample size, CD64 index demonstrated to be a promising biomarker, with high specificity, to diagnose late-onset sepsis. Further investigations are needed to substantiate these findings. Triggering receptor expressed on myeloid cells-1 showed less valuable diagnostic role.
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http://dx.doi.org/10.1097/PCC.0b013e31826e726dDOI Listing
February 2013

Breast milk-acquired cytomegalovirus infection in very low birth weight infants.

J Matern Fetal Neonatal Med 2012 Oct;25 Suppl 3:57-62

Neonatal Unit and Neonatal Intensive Care Unit, Maternal-Infant Department, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.

Perinatal transmission of human cytomegalovirus (HCMV) infection in very low birth weight (VLBW) premature infants can lead to serious clinical symptoms and it has ben increasingly recognized that breast milk is the most frequent route of transmission. Breast milk is considered ideal food for newborns because of its nutritional value and anti-infectious components, but it can also be vehicle for viral and bacterial infection. The majority of HCMV seropositive mothers shed the virus into their breast milk and can transmit infection to their offspring. Perinatally acquired infections in full-term neonates are usually asymptomatic without sequelae due to protective maternal HCMV-specific antibodies received during pregnancy. In contrast, VLBW preterm infants are at risk of symptomatic infection with neutropaenia, thrombocytopaenia, sepsis-like syndrome and, less frequently, pneumonia and enteric infection. Postnatally acquired infection seems to spontaneously resolve without altering the clinical outcome. Ganciclovir treatment is restricted to severe symptomatic infections. Preterm infants with a gestational age <30 weeks, or with a birth weight <1000 g, are at greater risk of severe postnatal symptomatic HCMV infection, transmitted via maternal milk. The pasteurization of breast milk entirely eliminates infectivity and prevents virus transmission but alters nutritional and immunological milk properties, and freezing reduces, but does not eradicate, infectivity. Most authors encourage fresh maternal breastfeeding because its beneficial effects outweigh the risk of a transient infection, sequelae-free. Nevertheless, an individual decision based on the condition of health of the infant is important.
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http://dx.doi.org/10.3109/14767058.2012.712345DOI Listing
October 2012

Pharmacokinetics, pharmacodynamics and clinical use of valganciclovir in newborns with symptomatic congenital cytomegalovirus infection.

Curr Drug Metab 2013 Feb;14(2):208-15

Neonatal Immunology Laboratory, Neonatal Intensive Care Unit, Fondazione IRCCS Policlinico San Matteo, Pavia Piazzale Golgi 19, 27100 Pavia, Italy.

Congenital cytomegalovirus infection is the most common cause of nonhereditary sensorineural hearing loss and an important cause of psychomotor retardation. Newborns suffering from symptomatic congenital cytomegalovirus infection have been typically treated with i.v. ganciclovir (GCV). Nowadays valganciclovir (V-GCV), a mono-valyl ester pro-drug of GCV, is available as an oral syrup. The existing literature demonstrated that V-GCV is well absorbed from the gastrointestinal tract and is rapidly converted into GCV in the intestinal wall and liver. The mechanism of antiviral action is the same that has been described for GCV. All these characteristics make this formulation particularly suitable for the symptomatic congenitally infected newborns. In neonates, V-GCV oral formulation proved stable and constant GVC plasma concentrations, in the suggested therapeutic range. The syrup demonstrated to be clinically effective and well tolerated and to be appropriate for a prolonged post-discharge therapy avoiding the discomfort of hospitalization, reducing the risk for nosocomial infections and decreasing the cost for the National Health Service. This article reviews all the available literature about V-GCV syrup in the treatment of newborns and infants with congenital CMV infection with the regard to pharmacokinetics, pharmacodynamic properties and clinical use, focussing on new data and on our experience.
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February 2013

Nutritional needs of premature infants.

J Matern Fetal Neonatal Med 2011 Oct 16;24 Suppl 1:27-9. Epub 2011 Sep 16.

Neonatal Intensive Care Unit and Neonatal Immunology Laboratory, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.

Preterm birth is the leading cause of perinatal morbidity and mortality in developed countries. Many innovation in neonatology have raised survival rates in the two past decades, but despite progress in neonatal intensive care, nutrition and growth of preterm infants are still critical points for neonatologists around the world and extrauterine growth restriction remains a common problem. Since growth is recognized as a major problem, in 2010, the European Society of Pediatric Gastroenterology and Nutrition published recommendations on enteral nutrition for preterm infants. The aim of this review is to revise nutritional needs of premature infants, taking into consideration the recommendations of ESPGHAN and the recent international literature.
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http://dx.doi.org/10.3109/14767058.2011.607568DOI Listing
October 2011

A novel LAMA3 mutation in a newborn with junctional epidermolysis bullosa herlitz type.

Neonatology 2011 25;99(3):188-91. Epub 2010 Sep 25.

Department of Internal Medicine and Therapeutics, Clinical Pharmacology Unit, University of Pavia, Pavia, Italy.

The case of a male neonate of 41 weeks' gestation who developed blistering of the skin immediately after birth is described. His parents were consanguineous Tunisians. Electron microscopy of a cutaneous biopsy showed skin cleavage within the lamina lucida and immunoepitope mapping revealed a complete absence of laminin 332 expression. These findings referred to the diagnosis of junctional epidermolysis bullosa (JEB) Herlitz type. The neonate died at 3 months of age due to sepsis. Molecular analysis of laminin 332 chain genes LAMA3, LAMB3 and LAMC2 disclosed a novel homozygous nonsense mutation in LAMA3 (p.Y955X). Clinical and laboratory analyses are essential for the diagnosis of JEB subtypes, and molecular analysis screening is crucial to manage a new pregnancy in families with suspected cases of JEB.
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http://dx.doi.org/10.1159/000314076DOI Listing
August 2011

Congenital cytomegalovirus infection: treatment, sequelae and follow-up.

J Matern Fetal Neonatal Med 2010 Oct;23 Suppl 3:45-8

Neonatology and Neonatal Intensive Care Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.

Cytomegalovirus (CMV) is the most common cause of congenital infection affecting about 1% of all the live births worldwide. Its prevalence in the developed world seems to be slightly lower, ranging between 0.6 and 0.7%. Symptoms can be detected at birth in 10-15% of the congenitally infected of which 50-90% will develop sequelae, the most frequent being sensorineural hearing loss (SNHL), visual defect, psychomotor impairment, mental retardation, cerebral palsy and seizures. Eighty-five to 90% of the infected newborns are asymptomatic but 10-15% of them are equally at risk for sensorineural sequelae, like 20-30% of all the infected children. Therefore it is important a time prolonged and closer follow-up of infected children that we propose should be until 6 years of age. This should lead to an early intervention, better management and eventually even control the long-term sequelae. Infants born with symptomatic congenital infection have a worse prognosis than those with no evidence of clinical disease, and ganciclovir (GCV) intravenous 6 mg/kg every 12 h for 6 weeks is the most used therapy for symptomatic newborns. Valganciclovir (V-GCV) syrup is a pro-drug of GCV and presents high oral bioavailability. To date, it is possible to administer this drug at home, and the tolerability profile may allow for wider indications and longer treatments.
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http://dx.doi.org/10.3109/14767058.2010.506753DOI Listing
October 2010