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Background: In the current COVID-19 pandemic caused by the SARS-Coronavirus-2 (SARS-CoV-2) it is important to understand if breast milk may be a vehicle of infection. The possible transmission of the virus via breastfeeding is still largely unexplored. Methods: This is a prospective collaborative observational study where samples of human milk from 12 breastfeeding mothers positive for SARS-Coronavirus 2 were collected. Search for the viral RNA in breast milk samples was performed by real-time PCR methodology. All the newborns underwent a clinical follow up for the first month of life or until the finding of two sequential negative swabs. Findings: In eleven cases the search for SARS-CoV-2 RNA in milk samples resulted negative and in one case it was positive. Eleven of the twelve newborns were exclusively breastfed in the first month of life and closely monitored. Clinical outcome was uneventful. Four newborns tested positive for SARS-CoV-2 and were all detected in the first 48 hours of life, after the onset of maternal symptoms. Also the clinical course of these 4 infants, including the one who received mother’s milk positive for SARS-CoV-2, was uneventful, and all of them became SARS-CoV-2 negative within 6 weeks of life. Interpretations: Our study supports the view that SARS-CoV-2 positive mothers do not expose their newborns to additional risk of infection by breastfeeding. This is an important message that should be given to mothers and healthcare providers in this moment of uncertainty due to the COVID-19 pandemic. Clearly, the recommended hygiene measures for direct breastfeeding, as well as for milk expression when a mother and her infant need to be separated, must be carefully followed. Funding: This Study was supported by University of Turin (grant RILO2019 to EB and DL). Declaration of Interests: The authors declare no conflict of interest. Ethics Approval Statement: The study was approved by the local Ethical Committee (protocol number 0039684), and informed consent to participate in the study was obtained from each mother.

Background Lactoferrin is the major antimicrobial protein in human milk. In our randomized controlled trial (RCT) of bovine lactoferrin (BLF) supplementation in preterm neonates, BLF reduced late-onset sepsis (LOS). Mother's own milk (MM) contains higher concentrations of lactoferrin than donor milk or formula, but whether BLF is more effective in infants who receive formula or donor milk is uncertain. Aim To evaluate the incidence of LOS in preterm infants fed MM and in those fed formula and/or donor milk. Study Design This is a (A) post hoc subgroup analysis, in our RCT of BLF, of its effects in preterm infants fed MM, with or without formula, versus those fed formula and/or donor milk (no-MM) and (B) post hoc meta-analysis, in our RCT of BLF and in the ELFIN (Enteral Lactoferrin in Neonates) RCT, of the effect of BLF in subgroups not exclusively fed MM. Results (A) Of 472 infants in our RCT, 168 were randomized to placebo and 304 were randomized to BLF. Among MM infants, LOS occurred in 22/133 (16.5%) infants randomized to placebo and in 14/250 (5.6%) randomized to BLF (relative risk or risk ratio (RR): 0.34; relative risk reduction (RRR): 0.66; 95% confidence interval (95% CI) for RR: 0.18–0.64; p Conclusion Adequately powered studies should address the hypothesis that BLF is more effective in infants fed formula or donor milk than those fed MM. Such studies should evaluate whether a specific threshold of total lactoferrin intake can be identified to protect such patients from LOS.

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.

Summary We report the case of a 31-week gestational age neonate with Candida albicans sepsis and a hepatic abscess. Diagnosis relied on clinical and radiological signs of sepsis, liver function impairment and culture isolation of Candida spp. from sterile sites. Liver ultrasound documented the presence of a multiloculated abscess. Treatment with micafungin (3 mg/kg/day) resulted in normalization of liver function and inflammatory laboratory values and improvement of clinical condition. After 30 days of treatment, the liver abscess resolved and at the 8-month follow up the infant is doing well. Prompt diagnosis and antifungal treatment avoided surgical drainage and liver surgery in this high-risk neonate.

Invasive disseminated neonatal aspergillosis is an uncommon disease, with only scattered reports in literature in the last few years. Here we report on a 25-week gestational age, 730 g at birth preterm female infant who developed on day-of-life 10 multiple cutaneous exhulcerative lesions in her right arm, trunk and abdomen. Early recognition and diagnosis of these lesions as a due to cutaneous initial symptom of cutaneous disseminated aspergillosis, as well as prompt treatment with Liposomal amphotericin B + Itraconazole, secured successful recovery from the systemic infection. Skin lesions healed without any surgical treatment. The infant was discharged in good health. Long-term follow-up at three years of age revealed normality of all neurodevelopmental and cognitive parameters. To our knowledge, this is one of the very few cases of survival, free from sequelae, for a preterm infant affected by neonatal cutaneous disseminated aspergillosis.

Fungal colonisation by Candida spp. affects a high proportion of VLBW neonates in NICU. However, few data are available on the clinical characteristics of colonisation in preterm infants who are colonised at baseline via vertical transmission, compared to preterms who become colonised during their stay in NICU via horizontal transmission.We reviewed the database of a multicentre, randomised trial of prophylactic fluconazole in VLBW neonates conducted in 8 Italian NICUs in the years 2004 and 2005 (Manzoni et al., NEJM 2007;356(24):2483-95). Per the protocol, all enrolled infants underwent weekly surveillance cultures from birth till discharge. We investigated the frequency of the two different modalities of Candida colonisation in this population, as well as the clinical and outcome characteristics possibly related to them.Overall, Candida colonisation affected 54 of 336 infants (16.1%). Baseline (i.e., detected3(rd) day of life) colonisation affected 16 (4.7%), and acquired 38 (11.4%), of the 54 colonised preterms. Infants with baseline colonisation had significantly higher birth weight (1229 ± 28 g vs. 1047 g ± 29, p = 0.01) and gestational age (30.2 wks ± 2.7 vs. 28.5 wks ± 2.6, p = 0.01), and were significantly more likely to limit progression from colonisation to invasive Candida infection when fluconazole prophylaxis was instituted (21.6% vs. 42.7%, p = 0.009). Isolation of C. parapsilosis was significantly more frequent in infants with acquired colonisation.Infants with baseline and acquired colonisation differ for demographics characteristics and for their response to fluconazole prophylaxis. This information may be useful for targeting more accurate management strategies for these two different groups of colonised preterms in NICU.

As the incidence rates of neonatal systemic fungal infections (SFI) have been increasing over the last years, research efforts have been addressed towards identifying both effective preventative strategies, and efficacious and well-tolerated antifungal drugs. Historically, the first options in treatment of neonatal SFI have been#x2013; and currently are#x2013; fluconazole and amphotericin B. However, these two drugs carry limitations both in efficacy and in putative toxicity. Recently, new therapeutic alternatives have drawn the neonatologists' attention. Echinocandins are a new class of antifungal drugs with characteristics that might better meet the needs of this particular population of patients. Caspofungin (CSP), micafungin (MICA), and anidulafungin have inherent good activities both against biofilms, and against natively fluconazole-resistant strains of Candida spp, thus overcoming two of the major weaknesses of the commonly used antifungal drugs in nurseries. CSP and MICA have been recently studied in neonatal populations. The kinetics and appropriate dosing of this agent in premature and term infants have been described, but ongoing further studies are needed to better address this area. Case-report series show clinical efficacy and tolerability in critical neonatal patients given CSP and MICA. In addition, extrapolation of data from randomized trials conducted in pediatric and adult patients showed through a subgroup analysis that both CSP and MICA are effective and well tolerated also in neonates. Further studies properly designed for neonatal populations will better address long-term safety and ecological issues related to echinocandin use in neonates.

Preterm neonates in neonatal intensive care units (NICU) are at high risk of invasive fungal infection (IFI), mostly by Candida spp. IFI in such patients is increasingly leading to high morbidity and mortality and frequent neurodevelopmental disabilities in the survivors. Most conditions and risk factors associated with neonatal IFI are unavoidable, being intrinsic to prematurity or related to the aggressive nature of the care these patients require. Neonatal IFI is difficult to diagnose, as candidaemia may be transient and difficult to eradicate due to the high rates of end-organ dissemination. The best option to decrease the burden of disease is thus to prevent it. Fluconazole administration is a suitable strategy and proved effective in many retrospective, single-centre studies and in four randomised, prospective clinical trials. Nevertheless, the use of this azole in high-risk preterm neonates in NICU is not yet a standard of care. This article summarises current evidence on the use of fluconazole in preterm neonates and discusses the concerns surrounding its use in nurseries.

AIMS Cytoplasmic accumulation of the nuclear protein transactive response DNA-binding protein 43 (TDP-43) is an early determinant of motor neuron degeneration in most amyotrophic lateral sclerosis (ALS) cases. We previously disclosed this accumulation in circulating lymphomonocytes (CLM) of ALS patients with mutant TARDBP, the TDP-43-coding gene, as well as of a healthy individual carrying the parental TARDBP mutation. Here, we investigate TDP-43 subcellular localization in CLM and in the constituent cells, lymphocytes and monocytes, of patients with various ALS-linked mutant genes. METHODS TDP-43 subcellular localization was analysed with western immunoblotting and immunocytofluorescence in CLM of healthy controls (n = 10), patients with mutant TARDBP (n = 4, 1 homozygous), valosin-containing protein (VCP; n = 2), fused in sarcoma/translocated in liposarcoma (FUS; n = 2), Cu/Zn superoxide dismutase 1 (SOD1; n = 6), chromosome 9 open reading frame 72 (C9ORF72; n = 4), without mutations (n = 5) and neurologically unaffected subjects with mutant TARDBP (n = 2). RESULTS TDP-43 cytoplasmic accumulation was found (P < 0.05 vs. controls) in CLM of patients with mutant TARDBP or VCP, but not FUS, in line with TDP-43 subcellular localization described for motor neurons of corresponding groups. Accumulation also characterized CLM of the healthy individuals with mutant TARDBP and of some patients with mutant SOD1 or C9ORF72. In 5 patients, belonging to categories described to carry TDP-43 mislocalization in motor neurons (3 C9ORF72, 1 TARDBP and 1 without mutations), TDP-43 cytoplasmic accumulation was not detected in CLM or in lymphocytes but was in monocytes. CONCLUSIONS In ALS forms characterized by TDP-43 mislocalization in motor neurons, monocytes display this alteration, even when not manifest in CLM. Monocytes may be used to support diagnosis, as well as to identify subjects at risk, of ALS and to develop/monitor targeted treatments.

Background Clinical assessment is the gold standard for diagnosis of bronchiolitis. To date, only one study found LUS (Lung Ultrasound) to be a valuable tool in the diagnosis of bronchiolitis. Aim of this study is to evaluate the accuracy of lung ultrasonography in the diagnosis and management of bronchiolitis in infants. Methods This was an observational cohort study of infants admitted to our Pediatric Unit with suspected bronchiolitis. A physical examination and lung ultrasound scans were performed on each patient. Diagnosis and grading of bronchiolitis was assessed according to a clinical and a ultrasound score. An exploratory analysis was used to assess correspondence between the lung ultrasound findings and the clinical evaluation and to evaluate the inter-observer concordance between the two different sonographs. Results One hundred six infants were studied (average age 71 days). According to our clinical score, 74 infants had mild bronchiolitis, 30 had moderate bronchiolitis and two had severe bronchiolitis. 25 infants composed the control group. Agreement between the clinical and sonographic diagnosis was good (90.6 %) with a statistically significant inter-observer ultrasound diagnosis concordance (89.6 %). Lung ultrasound permits the identification of infants who are in need of supplementary oxygen with a specificity of 98.7 %, a sensitivity of 96.6 %, a positive predictive value of 96.6 % and a negative predictive value of 98.7 %. An aberrant ultrasound lung pattern in posterior chest area was collected in 86 % of infants with bronchiolitis. In all patients clinical improvement at discharge was associated with disappearance of the previous LUS findings. Subpleural lung consolidation of 1 cm or more in the posterior area scan and a quantitative classification of interstitial syndrome based on intercostal spaces involved bilaterally, good correlate with bronchiolitis severity and oxygen use. Conclusions The lung ultrasound findings strictly correlate with the clinical evaluations in infants with bronchiolitis and permit the identification of infants who are in need of supplementary oxygen with high specificity. Scans of the posterior area are more indicative in ascertaining the severity of bronchiolitis. Trial registration Clinical Trial Registration NCT01993797

Invasive fungal infections in preterm neonates in the neonatal intensive care unit are predominantly caused by Candida spp, and have a high burden of morbidity and mortality. Effective prophylactic strategies have recently become available, but the identification of the best possible strategies to manage high-risk infants is still a priority. Choice and use of appropriate antifungal drugs needs careful assessment of neonatal characteristics, the epidemiology and drug pharmacokinetics. Ideally, antifungal drugs for preterm neonates should target fungal bio-films, prevent or effectively treat end-organ localisations, be active against fluconazole-resistant Candida species, and have reliable safety and tolerability profiles. The paper reviews the state-of-the-art in the area of neonatal fungal infections, and addresses some open questions related to the best possible prophylactic and therapeutic strategies to be implemented in such unique patients.

OBJECTIVE. Colonization by Candida spp is a major risk factor for development of fungal sepsis, but little is known about the variables associated with progression to invasive disease in already colonized neonates. We investigated such variables in a large number of colonized preterm neonates in an NICU.SETTING. This study was conducted in the Department of Neonatology and the NICU at Sant'Anna Hospital in Torino, Italy.DESIGN AND PATIENTS A database search of clinical charts and weekly surveillance cultures was used to identify all neonates with birth weights RESULTS. Colonization occurred in 201 infants (32.1% of very low birth weight admitted neonates), and invasive fungal infection occurred in 51 (8.1%) of them, with an overall progression rate of 0.25. At univariate analysis, 10 factors (namely low birth weight, low gestational age, use of third-generation cephalosporins, endotracheal intubation, duration of stay in the NICU, bacterial sepsis, colonization of central venous catheter, of endotracheal tube, of gastric aspirate, or in ≥3 [multiple] sites) were associated with an increased risk of progression, whereas prophylaxis with fluconazole was associated to a decreased risk. After logistic regression, only colonization of central venous catheter and colonization in multiple sites remained significantly associated with invasive fungal infection. Fluconazole prophylaxis remained an independent protective factor.CONCLUSIONS. Central venous catheter colonization and multiple-site colonization are independent risk factors and predictors of progression to fungal sepsis in preterm very low birth weight neonates colonized by Candida spp during their stay in the NICU. Fluconazole prophylaxis is an independent protective factor. These findings can be used to improve the surveillance, prophylaxis, or preemptive measures in neonates at high risk.

BACKGROUND Colonization by Candida species is the most important predictor of the development of invasive fungal disease in preterm neonates, and the enteric reservoir is a major site of colonization. We evaluated the effectiveness of an orally supplemented probiotic (Lactobacillus casei subspecies rhamnosus; Dicoflor [Dicofarm spa]; 6 x 10(9) cfu/day) in the prevention of gastrointestinal colonization by Candida species in preterm, very low birth weight (i.e., < 1500-g) neonates during their stay in a neonatal intensive care unit. METHODS Over a 12-month period, a prospective, randomized, blind, clinical trial that involved 80 preterm neonates with a very low birth weight was conducted in a large tertiary neonatal intensive care unit. During the first 3 days of life, the neonates were randomly assigned to receive either an oral probiotic added to human (maternal or pooled donors') milk (group A) or human milk alone (group B) for 6 weeks or until discharge from the NICU, if the neonate was discharged before 6 weeks. On a weekly basis, specimens obtained from various sites (i.e., oropharyngeal, stool, gastric aspirate, and rectal specimens) were collected from all patients for surveillance culture, to assess the occurrence and intensity of fungal colonization in the gastrointestinal tract. RESULTS The incidence of fungal enteric colonization (with colonization defined as at least 1 positive culture result for specimens obtained from at least 1 site) was significantly lower in group A than in group B (23.1% vs. 48.8%; relative risk, 0.315 [95% confidence interval, 0.120-0.826]; P = .01). The numbers of fungal isolates obtained from each neonate (P = .005) and from each colonized patient (P = .005) were also lower in group A than in group B. L. casei subspecies rhamnosus was more effective in the subgroup of neonates with a birth weight of 1001-1500 g. There were no changes in the relative proportions of the different Candida strains. No adverse effects potentially associated with the probiotic were recorded. CONCLUSIONS Orally administered L. casei subspecies rhamnosus significantly reduces the incidence and the intensity of enteric colonization by Candida species among very low birth weight neonates.

To determine whether an association exists between either fungal or bacterial sepsis and retinopathy of prematurity (ROP). Retrospective cohort study on all neonates with birth weight

Summary Near infrared spectroscopy (NIRS) monitoring is a new challenge for clinicians who deal with early detection of dangerous hypoperfusion in the brain, as well as in splanchnic and renal districts in critically ill preterm infants. Previous studies performed on infants and children with congenital heart disease, demonstrated the efficacy of this non-invasive method in managing hypoperfusive states pre, post and during cardiac surgery. Its use has improved post surgery outcome. NIRS monitoring has been used also to assess therapeutic intervention utility. Early identification of silent hypoperfusion has made NIRS use in preterm infants very interesting for neonatologists, especially where other techniques have failed. In this work, literature on this topic has been carefully examined, particularly the “two site NIRS” use in preterm infants, to evaluate how regional splanchnic oxygen saturation changes, both in physiological events, such as enteral feeding and in hemodynamic disorders, that occur in patients with significant patent ductus and in hypoperfusive states that lead to necrotizing enterocolitis.

Pyruvate dehydrogenase (PDH) has low activity in the circulating lymphocytes (CL) of obese adolescents and adults. In vitro, it is unresponsive to insulin at 5 micro-units/ml and is activated at 50 micro-units/ml, in contrast with activation and inhibition respectively at these concentrations in CL from controls. These changes are seen as being indicative of a molecular disorder underlying insulin resistance. The aims of the present study were to determine whether a substantial enhancement of blood insulin levels restores the PDH activity in CL from obese adolescents and abolishes the in vitro alterations, and whether PDH activity and indices of insulin resistance are correlated. Six obese adolescents and six normal-weight controls underwent a 4 h frequently sampled intravenous glucose test with minimal model analysis, to bring about a sharp rise in blood insulin and provide a reliable index of insulin sensitivity (S(I)). PDH activity was evaluated in CL obtained from blood samples at set times before and after their exposure to insulin in vitro. Insulin levels rose in all subjects in the first 10 min, although to a much greater extent in the obese group, and then decreased until the end of the test (240 min; t(240)). PDH activity in CL paralleled the insulin pattern in the control subjects, whereas in the obese subjects it was below normal 3 min before the start of the test (t(-3)), but rose significantly throughout the test. PDH responses in vitro to insulin in CL taken from the control subjects at t(-3) and t(240) and in CL taken from the obese subjects at t(-3) were as reported above, but were normal (i.e. the same as in control CL) in CL taken from the obese subjects at t(240). Baseline PDH activity was inversely correlated with body mass index and with fasting insulin, and directly correlated with S(I). These results show that a brief and sharp enhancement of blood insulin overcomes derangements in PDH that reflect systemic insulin resistance in obese adolescents.

Background Proteasomes constitute the degradative machinery of the ubiquitin/adenosine triphosphate-dependent proteolytic pathway, which is involved in many cell functions, including immune response and apoptosis, and in HIV maturation and infectivity. Objective To examine whether proteasomes are targeted by antiretroviral agents. Methods Chymotrypsin-like, trypsin-like and peptidyl-glutamyl-peptide hydrolysing activities of purified human 26S and 20S proteasomes, the latter depleted or enriched in 11S regulator, were assayed after incubation with indinavir, lamivudine and zidovudine at 1-80 microM alone and in combination. To assess the drug effects on cellular functions regulated by proteasomes, the accumulation of ubiquitin-tagged proteins, the processing of the nuclear factor kappa B precursor p105, and the degradation of the inhibitor of nuclear factor kappa B, isoform alpha (IkappaBalpha) were evaluated by Western immunoblotting in Jurkat cells after incubation for 6 h with the drugs above. Results Trypsin-like and mostly chymotrypsin-like activities of purified 26S proteasome were inhibited by each drug from 10 to 80 microM, more by double combinations and mostly by the triple combination. The peptidyl-glutamyl-peptide hydrolysing activity of the 26S proteasome and the three peptidase activities of the 20S proteasome, depleted or enriched in 11S regulator, were unaffected. The accumulation of ubiquitin-tagged proteins, reduced IkappaBalpha degradation and p105 processing were appreciable in intact cells with the triple drug combination. Conclusion The human 26S proteasome is a target of antiretroviral agents. This suggests that the antiviral action and some clinical and immunological benefits of combined antiretroviral therapy rely not only on its known effects on viral enzymes, but also on host cell components.

Sepsis-related morbidity and mortality are major problems in NICU. Preterm neonates display clinical characteristics that make them prone to infections. Due to the high frequency of severe neurodevelopmental sequelae in survivors, the best possible strategy to manage sepsis in NICU is to prevent them. Hygiene, cohorting, stewardship on use of H2-blockers, steroids and broad-spectrum antibiotic are mandatory, as well as proper management of central venous accesses and surgical devices. In addition, clinical research offers the opportunity of adopting pharmacological preventative strategies such as use of palivizumab to prevent RSV infection, use of fluconazole to prevent fungal sepsis, use of probiotics and lactoferrin to enhance the innate immunity, and use of pagibaximab to prevent staphylococcal sepsis.

Retinopathy of prematurity (ROP) is a multifactorial disease with evidence of many associated risk factors. Erythropoietin has been reported to be associated with this disorder in a murine model, as well as in humans in some single-center reports. We reviewed the data from two large tertiary NICUs in Italy to test the hypothesis that the use of erythropoietin may be associated with the development of the most severe stages of ROP in extremely low birth weight (ELBW) neonates.Retrospective study by review of patient charts and eye examination index cards on infants with birth weight1000g admitted to two large tertiary NICUs in Northern Italy (Sant'Anna Hospital NICU in Torino, and Ca' Foncello Hospital Neonatology in Treviso) in the years 2005 to 2007. Standard protocol of administration of EPO in the two NICUs consisted of 250 UI/kg three times a week for 6-week courses (4-week in 1001-1500g infants). Univariate analysis was performed to assess whether the use of EPO was associated with severe (threshold) ROP. A control, multivariate statistical analysis was performed by entering into a logistic regression model a number of neonatal and perinatal variables that - in univariate analysis - had been associated with threshold ROP.During the study period, 211 ELBW infants were born at the two facilities and survived till discharge. Complete data were obtained for 197 of them. Threshold retinopathy of prematurity occurred in 26.9% (29 of 108) of ELBW infants who received erythropoietin therapy, as compared with 13.5% (12 of 89) of those who did not receive erythropoietin (OR 2.35; 95% CI 1.121-4.949; p=0.02 in univariate analysis, and p=0.04 at multivariate logistic regression after controlling for the following variables: birth weight, gestational age, days on supplemental oxygen, systemic fungal infection, vaginal delivery). Use of erythropoietin was not significantly associated with other major sequelae of prematurity (intraventricular hemorrhage, bronchopulmonary dysplasia, necrotizing enterocolitis). © 2014 Elsevier Ireland Ltd. All rights reserved.Use of erythropoietin is an additional, independent predictor of threshold ROP in ELBW neonates. Larger prospective, population-based studies should further clarify the extent of this association.

Neonatal sepsis caused by fungi (mainly Candida spp.) causes a huge burden of morbidity and mortality, poor late outcomes, as well as increased hospital costs. Invasive Candida Infections (ICI) include bloodstream, urine, cerebrospinal, peritoneal infections, infections starting from burns and wounds, or from any other usually sterile site. Premature neonates are particularly prone to this kind of disease, due to their decreased innate and adaptive immunities, translating into a specific, decreased resistance to candidiasis. This specific, increased risk for ICI is greatest when gestational age and birth weight are lowest. As the burden of ICI has been increasing over the last years, research efforts have been focused towards identifying key risk factors, effective preventative strategies, and efficacious and well-tolerated antifungal drugs for the neonatal population. This article summarizes the most remarkable issues in these areas, and features an overview of the current diagnostic, preventative and treatment strategies.

NEC is a common and severe complication in premature neonates, particularly those with very-low-birth-weight (VLBW,1500 g at birth). Probiotics including lactobacillus rhamnosus GG (LGG) proved effective in preventing NEC in preterm infants in several RCTs.Lactoferrin, a mammalian milk glycoprotein involved in innate immune host defences, can reduce the incidence of NEC in animal models, and its action is enhanced by LGG. We tried to assess whether bovine lactoferrin (BLF), alone or with the probiotic LGG, has a similar effect in human infants, something that has not yet been studied.An international, multicenter, randomized, double-blind, placebo-controlled trial conducted from October 1st, 2007 through July 31st, 2010.Thirteen Italian and New Zealand tertiary neonatal intensive care units.743 VLBW neonates were assessed until discharge for development of NEC.Infants were randomly assigned to receive orally either BLF (100 mg/day) alone (group LF; n = 247) or with LGG (at 6×10(9) CFU/day; group BLF + LGG; n = 238), or placebo (Control group; n = 258) from birth until day 30 of life (45 for neonates1000 g at birth).≥ stage 2 NEC; death-and/or-≥ stage 2 NEC prior to discharge.Demographics, clinical and management characteristics of the 3 groups were similar, including type of feeding and maternal milk intakes. NEC incidence was significantly lower in groups BLF and BLF + LGG [5/247 (2.0%)] and 0/238 (0%), respectively] than in controls [14/258 (5.4%)] (RR = 0.37; 95% CI: 0.136-1.005; p = 0.055 for BLF vs. control; RR = 0.00; p0.001 for BLF + LGG vs. control). The incidence of death-and/or-NEC was significantly lower in both treatment groups (4.0% and 3.8% in BLF and BLF + LGG vs. 10.1% in control; RR = 0.39; 95% CI: 0.19-0.80; p = 0.008. RR = 0.37; 95% CI: 0.18-0.77; p = 0.006, respectively). No adverse effects or intolerances to treatment occurred.Compared with placebo, BLF supplementation alone or in combination with LGG reduced the incidence of ≥ stage 2 NEC and of death-and/or ≥ stage 2 NEC in VLBW neonates. BLF might be a promising strategy to prevent NEC in NICU settings. Further data on larger sample sizes are warranted before BLF can be widespreadly used in clinical settings.ISRCTN53107700-http://www.controlled-_trials.com/ISRCTN53107700.

Accumulation of transactive response DNA binding protein (TDP-43) fragments in motor neurons is a post mortem hallmark of different neurodegenerative diseases. TDP-43 fragments are the products of the apoptotic caspases-3 and -7. Either excessive or insufficient cellular Ca2+ availability is associated with activation of apoptotic caspases. However, as far as we know, it is not described whether activation of caspases, due to restricted intracellular Ca2+, affects TDP-43 cleavage. Here we show that in various cell lineages with restricted Ca2+ availability, TDP-43 is initially cleaved by caspases-3 and -7 and then, also by caspases-6 and -8 once activated by caspase-3. Furthermore, we disclose the existence of a TDP-43 caspase-mediated fragment of 15 kDa, in addition to the well-known fragments of 35 and 25 kDa. Interestingly, with respect to the other two fragments this novel fragment is the major product of caspase activity on murine TDP-43 whereas in human cell lines the opposite occurs. This outcome should be considered when murine models are used to investigate TDP-43 proteinopathies.

The diagnosis of congenital CMV is usually guided by a number of specific symptoms and findings. Unusual presentations may occur and diagnosis is challenging due to uncommon or rare features. Here we report the case of two preterm, extremely low birthweight, 28-week gestational age old twin neonates with CMV infection associated with severe lung involvement and persistent pulmonary hypertension of the newborn (PPHN). They were born to a HIV-positive mother, hence they underwent treatment with zidovudine since birth. Both infants featured severe refractory hypoxemia, requiring high-frequency ventilation, inhaled nitric oxide and inotropic support, with full recovery after 2 months. Treatment with ganciclovir was not feasible due the concomitant treatment with zidovudine and the risk of severe, fatal toxicity. Therefore administration of intravenous hyperimmune anti-CMV immunoglobulin therapy was initiated. Severe lung involvement at birth and subsequent pulmonary hypertension are rarely described in preterm infants as early manifestations of CMV congenital disease. In the two twin siblings here described, the extreme prematurity and the treatment with zidovudine likely worsened immunosuppression and ultimately required a complex management of the CMV-associated lung involvement.

Circulating lymphocytes of obese individuals with and without type 2 diabetes have derangements of pyruvate dehydrogenase (PDH) that are described as reflecting a disorder underlying systemic insulin resistance, namely basal activity below normal and, in vitro, unresponsiveness to insulin at 33 pmol/l and activation at 330 pmol/l instead of activation and inhibition as in controls.To explore whether the above enzyme derangements are overcome in obese individuals on dexfenfluramine treatment, known to improve poor peripheral insulin sensitivity.Fifteen obese diabetic patients and 15 age-matched euglycaemic obese subjects with normal glucose tolerance were enrolled for a trial composed of two 21-day periods; in the first (D-21-D0), participants received a placebo, and in the second (D0-D21), dexfenfluramine (30 mg/day). At D-21, D0 and D21 participants were evaluated for weight, BMI, fasting glycaemia (FG), fasting insulinaemia (FI), fasting insulin resistance index (FIRI), area under the glycaemic (G-AUC) and insulinaemic (I-AUC) curves from an OGT test, and for PDH activity assayed in their circulating lymphocytes before (basal activity) and after incubation with 33 or 330 pmol/l insulin. At D2, basal PDH activity and clinical parameters were assayed.In both groups of participants at D0 all parameters tested were constant with respect to D-21; at D2, only basal PDH activity rose significantly; at D21, basal and insulin stimulated PDH activities were normalized and weight decreased significantly, as did FG, FI, FIRI and G-AUC in the diabetic, and FI, FIRI, G-AUC and I-AUC in the non-diabetic participants.In obese, non-diabetic and diabetic individuals on dexfenfluramine treatment, amelioration of clinical parameters and indexes of poor insulin sensitivity of blood glucose homeostasis are preceded by correction, in their circulating lymphocytes, of PDH derangements described as reflecting a disorder underlying insulin resistance.

Two proteins were isolated, in a stable form, from bovine brain by ion exchange chromatography, gel filtration and ultracentrifugation on glycerol gradient. They were identified as 20S and 26S proteasomes on the basis of molecular mass, migration velocity on non-denaturing gels, immunoreactivity, multipeptidase activity and the 26S proteasome also for dependence on ATP for the degradation of short peptides and ubiquitinylated proteins. However, the 26S proteasome has some properties not yet described for its counterpart of other tissues and from brain of this and other species. In particular, the ATP concentration required by the 26S proteasome to reach maximal peptidase activity was approximately 40-fold lower than the one required for maximal proteolytic activity on polyubiquitinylated substrates. Moreover, plots of substrate concentration vs. velocity gave a saturation curve for the 26S proteasome only, which, for the trypsin-like and post-glutamyl peptide hydrolase activities fitted the Michaelis–Menten equation, whereas for the chymotrypsin-like activity indicated multibinding site kinetics with positive cooperativity (n=2.32±0.38). As concerns the 20S proteasome, its electrophoretic pattern on native gel revealed a single protein band, a feature, to our knowledge, not yet described for the brain particle of any species.

Fecal calprotectin level has been reported to correlate with inflammation in inflammatory bowel disease in adults, and recently its relationship with infantile colic has also been described. Fecal calprotectin is elevated in infants with hematochezia and possible allergic colitis. The objectives were to evaluate fecal calprotectin at the time of enrollment and its variation after 3 weeks of therapy with a probiotic ( Lactobacillus reuteri DSM 17938) in infants with severe infantile colic admitted to our hospital for either hematochezia, …

Aims In circulating lymphocytes of NIDDM patients pyruvate dehydrogenase (PDH), the major determinant in glucose consumption through oxidative pathways, is poorly active. The aim of this study is to examine whether sulphonylurea drug treatment revives PDH activity in circulating lymphocytes from NIDDM patients. Methods Twenty normal-weight individuals with NIDDM were enrolled in this study. They had maintained their glycaemic levels close to normal by means of a restricted diet that had no longer been successful in the proceeding 2 months. The treatment protocol consisted in 160 mg gliclazide daily for 5 weeks. Twenty healthy subjects, matched for age, body mass index and gender, were enrolled as a control group. Patients, before and after treatment, as well as controls were tested for PDH activity in their circulating lymphocytes. Nine other untreated patients and nine healthy subjects, with the above mentioned characteristics, were recruited for the assay of PDH activity in their circulating lymphocytes before and after exposure, in vitro, to gliclazide, to insulin, and to gliclazide and insulin in combination. Results In gliclazide-treated NIDDM patients, PDH activity in circulating lymphocytes recovered. In vitro, in circulating lymphocytes of untreated patients and controls insulin at 5 μU ml−1 was ineffective and highly effective, respectively, in raising enzyme activity; gliclazide at 10 ng ml−1 was ineffective on PDH in both groups, but in combination with insulin at 5 μU ml−1 in both groups PDH was as active as in cells of controls exposed to insulin only. In cells of controls, gliclazide alone at 25–50 ng ml−1 caused enzyme activation, whereas above 50 ng ml−1 it caused inhibition; in cells of patients below 50 ng ml−1 it had no effects, but at 50 ng ml−1 and above raised enzyme activity to the basal level of controls. Conclusions This study suggests that free gliclazide concentrations determine recovery of PDH activity in circulating lymphocytes of treated patients through drug-mediated enhanced insulin control over PDH or through the drug alone.

Neonatal sepsis causes a huge burden of morbidity and mortality and includes bloodstream, urine, cerebrospinal, peritoneal, and lung infections as well as infections starting from burns and wounds, or from any other usually sterile sites. It is associated with cytokine - and biomediator-induced disorders of respiratory, hemodynamic, and metabolic processes. Neonates in the neonatal intensive care unit feature many specific risk factors for bacterial and fungal sepsis. Loss of gut commensals such as Bifidobacteria and Lactobacilli spp., as occurs with prolonged antibiotic treatments, delayed enteral feeding, or nursing in incubators, translates into proliferation of pathogenic microflora and abnormal gut colonization. Prompt diagnosis and effective treatment do not protect septic neonates form the risk of late neurodevelopmental impairment in the survivors. Thus prevention of bacterial and fungal infection is crucial in these settings of unique patients. In this view, improving neonatal management is a key step, and this includes promotion of breast-feeding and hygiene measures, adoption of a cautious central venous catheter policy, enhancement of the enteric microbiota composition with the supplementation of probiotics, and medical stewardship concerning H2 blockers with restriction of their use. Additional measures may include the use of lactoferrin, fluconazole, and nystatin and specific measures to prevent ventilator associated pneumonia.

Human milk feeding protects against oxidative stress-induced damage in preterm neonates, including severe multifactorial diseases such as retinopathy of prematurity (ROP), necrotizing enterocolitis (NEC), and bronchopulmonary dysplasia (BPD). The carotenoids, which are not found in formula milk, might play a key role in these actions.A multicenter, double-blind, randomized controlled trial was conducted in three tertiary Italian neonatal intensive care units. All preterm infants32(+6) weeks' gestational age were eligible and were randomized to a single, oral, daily 0.5-mL dose of carotenoid supplementation (0.14 mg lutein + 0.0006 mg zeaxanthin) or placebo (5% glucose solution) from birth till 36 weeks' corrected gestational age. Primary outcomes were threshold ROP, NECsecond stage, and BPD. Surveillance for detection of these diseases and for intolerance/adverse effects was performed.No treatment-related adverse effect was documented in the 229 analyzed infants, whose clinical/demographical characteristics were similar in the two groups. Threshold ROP incidence did not significantly differ in treated (6.2%) versus not treated infants (10.3%; p = 0.18). The same occurred for NEC (1.7% versus 5.1%; p = 0.15) and BPD (4.5% versus 10.3%; p = 0.07). Noteworthy, the progression rate from early ROP stages to threshold ROP was decreased by 50% (0.30 versus 0.44; p = 0.23).Lutein/zeaxanthin supplementation in preterm infants is well tolerated. No significant effect was seen on threshold ROP, NEC, or BPD. The decreasing trends of these outcomes in the treatment group need to be assessed and confirmed on larger sample-sizes.

There is a wide range of variability in the reported frequencies of fungal colonization in NICUs due to several factors. Inconsistencies in surveillance culture policies make it difficult to compare the incidence rates of different settings and institutions: as a result, NICUs performing weekly (or semiweekly) cultures for each patient will claim higher incidence rates of colonization than those that do not have such a policy. Moreover, it is known that in preterm neonates colonization originates from both acquired (horizontal transmission) and endogenous source, and also from colonized mothers (vertical transmission). These two different modalities show some overlap over time, making it difficult to ascertain both the origin and frequency of colonization in neonatal settings.

Objectives We compare the outcome of medical treatment for ranula versus surgery in children. Study Design Multicentric cohort study. Methods The case series includes 37 children with ranulas (diameter 2.7 ± 1.5 cm). Eighteen patients, including 3 who had relapsed after either simple marsupialization or ranula removal alone, received oral nickel gluconate, mercurius heel, and glandula submandibularis suis D10/D30/D200. Fifteen cases underwent marsupialization with packing, and 2 underwent sublingual gland and ranula en-bloc excision. Two patients who recovered spontaneously shortly after diagnosis were excluded. Results No recurrences occurred among medical patients. Of the 17 surgical patients, 3 treated with marsupialization with packing relapsed. With the 3 surgical failures from other centers a total of 6 of 20 relapses were considered. Swelling or tension was common in surgical cases but unusual in medical patients. Conclusions In this case series oral medical treatment for ranula was very effective and more effective than marsupialization with packing.

Neonatal congenital infections are an important cause of mortality, morbidity and long-term neurodevelopmental and sensorineural sequelae. Many pathogens can cause in utero infection, and among them, cytomegalovirus (CMV) plays a prominent role. In developed countries, CMV poses major health problems as it is the most common pathogen leading to congenital infection, and the leading cause of nonhereditary deafness in children. Evaluation of central nervous system (CNS) involvement in congenital CMV infected newborns is mandatory to better assess the severity of the disease, to guide adequate treatment, to define prognosis, and to tailor follow-up observations and parents’ counselling. Cerebral ultrasonography (cUS), Computed Tomography (CT), and Magnetic Resonance Imaging (MRI) are the currently available techniques to evaluate infants with suspected or proven congenital CMV infection. In congenital CMV infection, their role in early detection and confirmation of cerebral involvement within the first month of life is crucial to initiate specific treatment with antivirals. Neonatologists, paediatricians and radiologists should be aware of the role, the limitations and the inherent risks related to the use of these specific neuroimaging diagnostic tools in these infants. In this article we will discuss from a neonatological perspective the advantages, disadvantages, risks and limitations of each imaging technique. ©

Sepsis-related morbidity and mortality is an increasing concern in all neonatal ICUs (NICUs). Sepsis occurs in 20-40% of all preterm patients, and although much is known on the origin, the incidence is reported to be constantly increasing. Many risk factors account for the increased risk of sepsis in preterms, including use of broad-spectrum antibiotics selecting resistant microflora and pathogenic gut colonization, parenteral nutrition, acid inhibitors and steroids, as well as the systematic and long-lasting use of invasive management and in-dwelling lines. As treatment does not prevent severe long-term neurodevelopmental impairment and sequelae in septic premature neonates, the best strategy is to avoid infections rather than to treat them.Published results from several recent randomized controlled trials currently show a level I evidence that fluconazole for prevention of fungal sepsis, probiotics for prevention of necrotizing enterocolitis, and bovine lactoferrin for prevention of bacterial sepsis should be considered as preventive strategies in NICUs.In this article, the current evidence in favour of lactoferrin use in preterm neonates will be reviewed and the areas of further research and future improvements will be discussed in order to illustrate the implications of the recent findings for clinical practice or research.

Fungal-related morbidity and mortality is a major concern for most neonatal intensive care units (NICUs) worldwide. Incidence rates are increasing and might be higher than reported due to the challenges associated with diagnosing fungal infections. As preterm neonates display clinical characteristics that make them prone to Candida spp infections, and there is a high frequency of severe neurodevelopmental sequelae in those who survive neonatal fungal infections, specific prevention – rather than empiric or pre-emptive treatment – should be the optimal strategy. Besides stewardship of drug use and efforts to minimize invasive cares, pharmacological prevention with use of fluconazole has proved highly effective in decreasing the rates of fungal sepsis in very low birth weight (VLBW) neonates. Alternative options needing further and more conclusive assessments include use of nystatin, bovine lactoferrin or probiotics.

An episode of sepsis occurs in 20 to 40% of all preterm patients, and such figures have been reported constantly increasing in Neonatal Intensive Care Units. Neonatal sepsis include bloodstream, urine, cerebrospinal, peritoneal infections, infections starting from burns and wounds, or from any other usually sterile sites. Many specific risk factors account for the increased risk of sepsis, including employment of broad-spectrum antibiotics selecting resistant microflora, parenteral nutrition, acid inhibitors and steroids, as well as the systematic and long-lasting use of invasive management. In preterm neonates, loss of gut commensals such as bifidobacteria and lactobacilli, due to the difficulties in oral feeding, or a slower acquisition of them, translates into an increased susceptibility to pathogenic gut colonization. Prompt diagnosis, effective treatment, and specific prophylaxis with antibacterial and antifungal drugs are the milestones of management of these life-threatening events. This article discusses the recent advances in prevention and shows how fluconazole for prevention of fungal sepsis, probiotics for prevention of necrotizing enterocolitis, and bovine lactoferrin for prevention of bacterial sepsis may be considered as effective preventive strategies.

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.To establish whether bovine lactoferrin (BLF), alone or in combination with LGG, reduces the incidence of late-onset sepsis in VLBW neonates.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.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 neonates1000 g at birth).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.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.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.isrctn.org Identifier: ISRCTN53107700.

In circulating lymphomonocytes (CLM) of patients with Type 2 diabetes (DM2) pyruvate dehydrogenase (PDH), the major determinant of glucose oxidative breakdown, is affected by a cohort of alterations reflecting impaired insulin-stimulated glucose utilization. The cohort is also expressed, although incompletely, in 40% of healthy young subjects with a DM2-family history (FH). Pregnancy restrains glucose utilization in maternal peripheral tissues to satisfy fetal requirements. Here we explore whether pregnant women develop the PDH alterations and, if so, whether there are differences between women with and without FH (FH+, FH−). Ten FH+ and 10 FH — were evaluated during pregnancy (12–14, 24–26, and 37–39 weeks) and 1 yr after (follow-up) for fasting plasma glucose and insulin as well as body mass index (BMI), and for the PDH alterations. Twenty FH — and 20 FH+ non-pregnant women served as controls. All FH+ and FH — controls exhibited normal clinical parameters and 8 FH+ had an incomplete cohort of PDH alterations. In FH — and FH+ pregnant women at 12–14 weeks clinical parameters were normal; from 24–26 weeks, with unvaried glucose, insulin and BMI rose more in FH — and only in the latter recovered the 12–14 weeks values at follow-up. In all FH−, the cohort of PDH alterations was incomplete at 24–26 weeks, complete at 37–39 weeks, and absent at follow-up but complete from 12–14 weeks including follow-up in all FH+. In FH−, the cohort is an acquired trait restricted to pregnancy signaling transiently reduced insulin-stimulated glucose utilization; in FH+, instead, it unveils the existence of an inherited DM2-related background these women all have, that is awakened by pregnancy and as such lastingly impairs insulin-stimulated glucose utilization.

Background: It is controversial whether thrombocytopenia is suggestive of one (or more) causative agents of neonatal sepsis: a low platelet count has been related in turn to Gram-positive, Gram-negative or fungal sepsis. Methods: A retrospective, cohort study on 514 very low-birthweight (VLBW) neonates admitted over a 9 year period to a large tertiary neonatal intensive care unit (NICU) in Italy was carried out. Through database search, data on platelet counts, sepsis, clinical course, and microbiological culture were collected and analyzed. Statistical analysis was performed to look for significant association between thrombocytopenia and sepsis caused by different (Gram-positive, Gram-negative or fungal) organisms. Results: Sepsis diagnosed on microbiological criteria occurred in 197 of 514 VLBW neonates (38.3%), and thrombocytopenia (at least one finding of platelet count

Background: We have previously demonstrated efficacy against fungal colonization and infection of fluconazole prophylaxis that was routinely administered since 2001 in our ICU for preterm infants

Candida-related morbidity and mortality have increased in neonatal intensive care units (NICUs) in the last 20 years. Invasive fungal infections (IFIs) in preterm infants are associated with high severity, high attributable mortality, substantial morbidity and poor outcomes owing to the frequent association with late neurodevelopmental impairment and retinopathy of prematurity in the survivors. Preterm very-low birth weight infants in NICUs have a specific, increased risk for IFIs, mainly because up to 60% of them may become colonized during their first month of life. Prevention of Candida colonization and infection is the key in these settings of unique patients, and solid data have recently been added to the very first promising results obtained in the early 2000’s with administation of fluconazole. In a multicenter randomized trial, this azole caused a striking reduction in the incidences of Candida spp. colonization (from 33 to 9%) and infection (from 13.2 to 3.2%), with no occurrence of significant side-effects and no signs of selective resistance during the 15-month study period. New guidelines incorporating the recent multicenter results are urgently needed.

1. 1. The incubation of human fresh circulating lymphocytes with insulin leads to modifications in the behaviour of the pyruvate dehydrogenase complex (PDH) when the contact medium is supplemented with 50 μM Ca 2+ and Mg 2+ 2. 2. To investigate the mechanism involved in the PDH responsiveness to insulin in circulating lymphocytes and the role of Ca 2+ and Mg 2+ in this process, the PDH activity was assayed in lymphocytes combined with insulin and/or a number of substances whose mechanism of action is partially known. 3. 3. Of these some have been seen to mimick insulin effects on PDH, whereas other were tested for the first time in this study.

Aim The incidence of invasive fungal infection in preterm newborns is rising steadily. Early recognition and treatment are imperative, but diagnosis is difficult as data from microbiological investigations are often poor, and clinical and laboratory signs do not help in differentiating bacterial from fungal infections. We evaluated whether glucose intolerance could represent a possible surrogate marker predictor of invasive fungal infection in preterm neonates. Methods We performed a case-control study on neonates with birthweight less than 1250 g admitted to our tertiary-level unit during the years 1998-2004 (n = 383), comparing those with invasive fungal infection (n = 45, group A) to matched controls with late-onset sepsis caused by bacterial agents (n = 46, group B). We investigated in both groups the occurrence of hyperglycaemia (serum glycaemia > 215 mg/dl, i.e. 12 mmol/l) in the first month of life, and its temporal relationship with the episodes of sepsis. Results Hyperglycaemia occurred significantly more often in group A (21/45, 46.6%) than in group B neonates (11/46, 23.9%) (OR 1.95, 95% CI 1.235-4.432, p = 0.008). Moreover, in 19 of 21 (90.4%) neonates with hyperglycaemia in group A, the carbohydrate intolerance episode typically occurred 72 h prior to the onset of invasive fungal infection; in contrast, no temporal relationship was found in neonates with bacterial sepsis (p = 0.002). Correction of hyperglycaemia was successfully achieved in all neonates of both groups, with no significant differences in the number of days of insulin treatment needed to normalize glycaemia (p = 0.15). Conclusions Hyperglycaemia is significantly more frequent in neonates who subsequently develop fungal rather than bacterial late-onset sepsis, with a typical 3-d interval. We suggest that a preterm neonate whose birthweight is less than 1250 g in its first month of life should be carefully evaluated for systemic fungal infection whenever signs of carbohydrate intolerance occur.