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Nutrition in early life has an impact on white matter (WM) development in preterm-born babies. Quantitative analysis of pixel brightness intensity (PBI) on cranial ultrasound (CUS) scans has shown a great potential in the evaluation of periventricular WM echogenicity in preterm newborns. We aimed to investigate the employment of this technique to objectively verify the effects of parenteral nutrition (PN) on periventricular WM damage in preterm infants. Prospective observational study including newborns with gestational age at birth ≤32 weeks and/or birth weight ≤1500 g who underwent CUS examination at term-equivalent age. The echogenicity of parieto-occipital periventricular WM relative to that of homolateral choroid plexus (RE CP ) was calculated on parasagittal scans by means of quantitative analysis of PBI. Its relationship with nutrient intake through enteral and parenteral routes in the first postnatal week was evaluated. The study included 42 neonates for analysis. We demonstrated that energy and protein intake administered through the parenteral route positively correlated with both right and left RE CP values (parenteral energy intake vs. right RE CP : r = 0.413, p = 0.007; parenteral energy intake vs. left RE CP : r = 0.422, p = 0.005; parenteral amino acid intake vs. right RE CP : r = 0.438, p = 0.004; parenteral amino acid intake vs. left RE CP : r = 0.446, p = 0.003). Multivariate linear regression analysis confirmed these findings. Quantitative assessment of PBI could be considered a simple, risk-free, and repeatable method to investigate the effects of PN on WM development in preterm neonates.

Microbiota plays a crucial role in intestinal maturation in preterm newborns. The clinical manifestation of the immaturity of the gastro-intestinal tract is called feeding intolerance (FI). This condition may resolve spontaneously or dramatically evolve into necrotizing enterocolitis. One of the most challenging tasks for the neonatologist is to identify those neonates that will develop the disease early in order to adequately provide nutrition to these patients, from the very first hours of life. A close interplay between the maturity of the gastro-intestinal tract and gut microbiota has been described; however, in preterm neonates, this relationship is still undefined. We analyzed the bacterial composition of stool samples, collected early in life, from 30 preterm newborns classified as intolerant or tolerant according to the degree of readiness of the gastro-intestinal tract to receive enteral nutrition. The Pielou evenness index was significantly increased in intolerant compared with tolerant newborns. Data corrected for confounding variables confirmed that the occurrence of gut maturation was independently influenced by Pielou evenness at birth. A lower bacterial diversity very early in life is associated with improved feeding tolerance in preterm newborns. The abundance analysis showed that neonates not ready to receive enteral nutrition for feeding intolerance show, after birth, an increased abundance of Proteobacteria , Lachnospiracae , Enterobacter and Acinetobacter . We can argue that those are the taxa that prevent the establishment of pioneer bacteria. A lower alpha-diversity, in the first days of life, may facilitate the seeding of beneficial pioneer bacteria that, in turn, drive healthy microbial colonization during neonatal life.

Besides suppressing immune responses, regulatory T cells (Tregs) maintain tissue homeostasis and control systemic metabolism. Whether iron is involved in Treg-mediated tolerance is completely unknown. Here, we showed that the transferrin receptor CD71 was upregulated on activated Tregs infiltrating human liver cancer. Mice with a Treg-restricted CD71 deficiency spontaneously developed a scurfy-like disease, caused by impaired perinatal Treg expansion. CD71-null Tregs displayed decreased proliferation and tissue-Treg signature loss. In perinatal life, CD71 deficiency in Tregs triggered hepatic iron overload response, characterized by increased hepcidin transcription and iron accumulation in macrophages. Lower bacterial diversity, and reduction of beneficial species, were detected in the fecal microbiota of CD71 conditional knockout neonates. Our findings indicate that CD71-mediated iron absorption is required for Treg perinatal expansion and is related to systemic iron homeostasis and bacterial gut colonization. Therefore, we hypothesize that Tregs establish nutritional tolerance through competition for iron during bacterial colonization after birth.

Background: Phthalates are a family of industrial chemicals noncovalently bonded to plastic materials to enhance flexibility and durability. These compounds are extensively used in a variety of consumer products and even in many medical devices. Newborns present a higher susceptibility to phthalates., Objective: To assess the short- and long-term health consequences of exposure to phthalates during the neonatal period., Methods: Systematic review in accordance with the PRISMA statements. Eligible articles in English language were searched in MEDLINE, Scopus, ISI Web of Science, and Ovid databases using the following terms: "phthalate", "newborn", and "neonate". Unpublished data were searched in ClinicalTrials.gov website. All in vivo studies of any design published before May 16th, 2023 and fulfilling the following criteria were included: 1) investigations in which preterm and/or term newborns underwent one or more measurement of concentrations of phthalates on biological samples taken during the neonatal period; 2) studies in which quantitative measurement of phthalates was related to any kind of health outcome. Subgroup analysis was conducted by type of outcome. The quality assessment was performed according to the criteria from the "NIH Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies"., Results: 11,895 records were identified; finally, 5 articles were included for review. A mixture of phthalates was associated with improved performance on the NNNS summary scales of Attention, Handling, and Non-optimal reflexes before NICU discharge. At 2 months' corrected age, some phthalates were positively associated with problem-solving and gross motor abilities; increased levels of mono (2-ethylhexyl) phthalate, mono (2-ethyl-5-carboxypentyl) phthalate, and sum of di (2-ethylhexyl) phthalate (DEHP) metabolites (∑ 3 DEHP and ∑ 4 DEHP) were associated with worse fine motor performance. Furthermore, DEHP was associated with transient alteration of gut microbiota and increased IgM production after vaccine. A linear positive association between a mixture of phthalates and slope of the first growth spurt was even reported in preterm newborns. No relationship emerged between phthalates and bronchopulmonary dysplasia. Three studies out of 5 had fair quality., Conclusion: Given some methodological issues and the paucity of related studies, further investigations of flawless quality aimed at clarifying the relationship between early exposure to phthalates and health outcomes are needed., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Despite multifactorial pathogenesis, dysregulation of inflammatory immune response may play a crucial role in necrotizing enterocolitis (NEC). Regulatory T cells (Tregs) are involved in immune tolerance early in life. We aimed to investigate the predicting role of Tregs in developing NEC in neonates at high risk., Methods: We studied six newborns with a diagnosis of NEC (cases) in comparison with 52 controls (without NEC). We further classified controls as neonates with feeding intolerance (FI) and neonates without it (FeedTol). The rate of female and male neonates (sex defined as a biological attribute) was similar. We analyzed the blood frequency of Tregs (not overall numbers) at three time points: 0-3 (T0), 7-10 (T1), and 27-30 (T2) days after birth by flow cytometry. Neonates' sex was defined based on the inspection of external genitalia at birth., Results: We observed, at T0, a significantly lower frequency of Tregs in NEC cases (p < 0.001) compared with both FI (p < 0.01) and FeedTol controls (p < 0.01). Multivariate analysis reported that the occurrence of NEC was independently influenced by Treg frequency at birth (ß 2.98; p = 0.039)., Conclusion: Tregs frequency and features in the peripheral blood of preterm neonates, early in life, may contribute to identifying neonates at high risk of developing NEC., Impact: Regulatory T cells may play a pivotal role in regulating the immune response in early life. Reduction of Tregs in early life could predispose preterm newborns to necrotizing enterocolitis. Early markers of necrotizing enterocolitis are still lacking. We demonstrated a predicting role of assessment of regulatory T cells in the diagnosis of this gastrointestinal emergency. Early identification of newborns at high risk of necrotizing enterocolitis through measurement of regulatory T cells may guide clinicians in the management of preterm newborns in order to reduce the development of this severe condition., (© 2023. The Author(s).)

Non-cystic white matter (WM) injury has become prevalent among preterm newborns and is associated with long-term neurodevelopmental impairment. Magnetic resonance is the gold-standard for diagnosis; however, cranial ultrasound (CUS) is more easily available but limited by subjective interpretation of images. To overcome this problem, we enrolled in a prospective observational study, patients with gestational age at birth < 32 weeks with normal CUS scans or grade 1 WM injury. Patients underwent CUS examinations at 0-7 days of life (T 0 ), 14-35 days of life (T 1 ), 37 0/7 -41 6/7  weeks' postmenstrual age (T 2 ), and 42 0/7 -52 0/7  weeks' postmenstrual age (T 3 ). The echogenicity of parieto-occipital periventricular WM relative to that of homolateral choroid plexus (RE CP ) was calculated on parasagittal scans by means of pixel brightness intensity and its relationship with Bayley-III assessment at 12 months' corrected age was evaluated. We demonstrated that: (1) Left RE CP values at T 1 negatively correlated with cognitive composite scores; (2) Right RE CP values at T 2 and T 3 negatively correlated with language composite scores; (3) Left RE CP values at T 1 and T 2 negatively correlated with motor composite scores. Thus, this technique may be used as screening method to early identify patients at risk of neurodevelopmental issues and promptly initiate preventive and therapeutic interventions., (© 2023. Springer Nature Limited.)

(1) Background: An increased protein intake via parenteral nutrition (PN) in early life is associated with an improvement of the nitrogen balance in preterm newborns. However, the role of energy intake on amino acid (AA) utilization provided by PN remains to be defined. We investigated the effects of energy intake on blood AA levels and profiles. (2) Methods: Quasi-experimental study including preterm very low birth weight newborns who received an energy enhanced PN (Cohort A) or an energy standard PN (Cohort B), with a similar protein amount in the first week of life. Blood AA levels were measured between three and seven days of life (T0) and at fifteen days of life (T1) and compared between the two study cohorts. (3) Results: AA levels of 40 newborns from each group were analyzed. No difference was found for total essential and non-essential blood AA concentration at T0 between the two study cohorts. At T1, we found a significantly higher blood concentration of leucine, isoleucine and proline, and a significantly lower concentration of tyrosine in Cohort B. However, multivariate analysis did not confirm this result. (4) Conclusions: An enhanced PN protocol in terms of energy but not of protein did not influence AA levels and profiles. Considering the high risk of side effects, we suggest exercising caution when administering high energy intake via PN in the first week of life.

Fetal alcohol spectrum disorder (FASD) is a set of conditions resulting from prenatal alcohol exposure (PAE). FASD is estimated to affect between 2% and 5% of people in the United States and Western Europe. The exact teratogenic mechanism of alcohol on fetal development is still unclear. Ethanol (EtOH) contributes to the malfunctioning of the neurological system in children exposed in utero by decreasing glutathione peroxidase action, with an increase in the production of reactive oxygen species (ROS), which causes oxidative stress. We report a case of a mother with declared alcohol abuse and cigarette smoking during pregnancy. By analyzing the ethyl glucuronide (EtG, a metabolite of alcohol) and the nicotine/cotinine in the mother's hair and meconium, we confirmed the alcohol and smoking abuse magnitude. We also found that the mother during pregnancy was a cocaine abuser. As a result, her newborn was diagnosed with fetal alcohol syndrome (FAS). At the time of the delivery, the mother, but not the newborn, had an elevation in oxidative stress. However, the infant, a few days later, displayed marked potentiation in oxidative stress. The clinical complexity of the events involving the infant was presented and discussed, underlining also the importance that for cases of FASD, it is crucial to have more intensive hospital monitoring and controls during the initial days.

Background: Preterm birth and subsequent NICU admission can be a traumatic experience for parents who may subsequently develop post-traumatic stress (PTS) disorder (PTSD). Given that developmental issues are common among children of parents with PTSD, interventions for prevention and treatment are essential., Objective: To assess the most effective non-pharmacological interventions to prevent and/or treat PTS symptoms in parents of preterm newborns., Methods: Systematic review performed in accordance with the PRISMA statements. Eligible articles in English language were searched in MEDLINE, Scopus, and ISI Web of Science databases using the following medical subject headings and terms: "stress disorder, post-traumatic," "parents," "mothers," "fathers," "infant, newborn," "intensive care units, neonatal," and "premature birth." The terms "preterm birth" and "preterm delivery" were also used. Unpublished data were searched in ClinicalTrials.gov website. All intervention studies published until September 9th, 2022 and including parents of newborns with gestational age at birth (GA b ) <37 weeks which underwent ≥1 non-pharmaceutical interventions for prevention and/or treatment of PTS symptoms related to preterm birth were included. Subgroup analyses were conducted by type of intervention. The quality assessment was performed according to the criteria from the RoB-2 and the "NIH Quality Assessment Tool for Before-After studies.", Results: Sixteen thousand six hundred twenty-eight records were identified; finally, 15 articles (1,009 mothers, 44 fathers of infants with GA b  ≤ 36 6/7 weeks) were included for review. A good standard of NICU care (effective as sole intervention: 2/3 studies) and education about PTSD (effective in association with other interventions: 7/8 studies) could be offered to all parents of preterm newborns. The 6-session Treatment Manual is a complex intervention which revealed itself to be effective in one study with low risk of bias. However, the effectiveness of interventions still remains to be definitively established. Interventions could start within 4 weeks after birth and last 2-4 weeks., Conclusion: There is a wide range of interventions targeting PTS symptoms after preterm birth. However, further studies of good quality are needed to better define the effectiveness of each intervention., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Laccetta, Di Chiara, De Nardo and Terrin.)

Hyperglycemia (HG) is an independent risk factor of mortality and morbidity in very low birth weight newborns (VLBW). Achievement of high nutritional intakes in the first days of life (DoL) by parenteral nutrition (PN) increases the risk of HG. We aim to assess if a delayed achievement of the PN macronutrient target dose could reduce the occurrence of HG in VLBW. We enrolled 353 VLBW neonates in a randomized controlled clinical trial comparing two PN protocols that differed in the timing of energy and amino acid target dose achievement: (1) early target dose achievement (energy within 4-5 DoL; amino acids within 3-4 DoL) vs. (2) late target dose achievement (energy within 10-12 DoL; amino acids within 5-7 DoL). The primary outcome was the occurrence of HG during the first week of life. An additional endpoint was long-term body growth. We observed a significant difference in the rate of HG between the two groups (30.7% vs. 12.2%, p = 0.003). Significant differences were observed in terms of body growth at 12 months of life between the two groups (weight Z-Score: -0.86 vs. 0.22, p = 0.025; length: -1.29 vs. 0.55, p < 0.001). Delayed achievement of energy and amino acid intake may be useful to reduce the risk of HG along with an increase of growth parameters in VLBW neonates.

Background: Recommended vaccinations are the cheapest and most effective measure to reduce the risk of transmission and related complications, especially in high-risk healthcare settings. This study aimed to evaluate the knowledge, attitudes and behaviours of HCWs in relation to national recommendations. Methods: A transversal study was conducted through administration of a questionnaire by personal interview. The following care units were involved: Paediatric, Neonatal, Cardiac Surgery and General Intensive Care Units and Infectious Diseases Unit. Results: The study sample comprised 308 HCWs. Half the sample were aware of the vaccination recommendations, with occupation and age found to be predictive factors (OR = 9.38, 95%CI: 2.07−42.41; OR = 0.36, 95%CI: 0.22−0.60). A higher percentage defined the diseases as a risk for their patients’ health, although this perception was lower in the over-40 age group. In several cases, there were statistically significant differences between the care units (p < 0.001). Around three-quarters of the sample agreed that vaccination should be mandatory; willingness to undergo a future booster vaccination was statistically correlated with the variables of age and care unit (p < 0.001, p = 0.03). Conclusion: The protection of health in the workplace can be achieved through some strategic actions, such as the implementation of educational strategies, and protocols for the monitoring of immunocompetence and the improvement of vaccination.

Background: Preterm birth and admission to the neonatal intensive care unit (NICU) could induce post-traumatic stress disorder (PTSD). PTSD is an important factor to focus on, as it is associated with parental mental health difficulties and with changes in caregiving quality such as increased intrusiveness, reduced sensitivity, and increased attachment insecurity for the child., Aims: We aimed to study the main risk factors, in the early life of newborns, and preventive measures for PTSD in parents of neonates hospitalized in the NICU., Methods: We included parents of preterm newborns, consecutively admitted to the NICU of the University La Sapienza of Rome. The presence of PTSD following preterm birth and NICU admission was assessed using the Clinician-administered PTSD scale (CAPS) at enrollment and at 28-30 days following NICU admission or the moment of discharge. We also evaluated the Family Environment Scale which measures the social environment of all types of families; the Parental Stressor Scale which measures parental anxiety and stress; the Spielberger State-Trait Anxiety Inventory consisting of two parts measuring the State (response to present situation) and Trait (pre-disposition to be anxious) anxieties separately, and the Beck Depression Inventory Second Edition assessing depressive symptoms., Results: We found, in a multivariate analysis, that the gestational age of newborns admitted to NICU significantly (β = 2.678; p = 0.040) influences the occurrence of PTSD. We found that the cases showed significantly (β = 2.443; p = 0.020) more pathological Parental Stressor Scale sights and sounds scores compared to controls. The early Kangaroo-Care (KC) significantly (β = -2.619; p = 0.015) reduces the occurrence of PTSD., Conclusion: Post-traumatic stress disorder in parents of preterm newborns is a pathological condition that should be properly managed, in the very first days after birth. The NICU environment represents a main risk factor for PTSD, whereas KC has been demonstrated to have a protective role in the occurrence of PTSD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Di Chiara, Laccetta, Gangi, De Santis, Spiriti, Attenni, Bertolaso, Boscarino, De Nardo, Ciambra, Parisi and Terrin.)

Introduction: Parenteral nutrition (PN) may have detrimental effects on neurodevelopment in preterm newborns. Moreover, enteral nutrition (EN) seems to be protective. To understand the mechanisms of how neurological development can be influenced by the route of administration of nutritional intake, we investigated the relationship between the serum levels of the nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) and nutritional intake received in early life by preterm newborns., Materials and Methods: Specimens of blood were obtained at 28 days of life (DOL) for NGF/BDNF determination in neonates <32 weeks of gestation and/or with birth weight <1,500 g, consecutively observed in the neonatal intensive care unit. We analyzed the relation between amino acid content and energy intake and NGF/BDNF measurements at 28 DOL. PN protein intake was referred to as the total amounts of amino acid intake received daily., Results: We enrolled 20 newborns (gestational age 30.45 ± 1.76 weeks, birth weight 1,340 ± 352.63 g). Serum NGF value at 28 DOL was positively correlated with enteral protein and energy intake ( r = 0.767; r = 0.746, p < 0.001), whereas, negatively correlated with parenteral amino acid and energy intake ( r = -0.652, p < 0.001; r = -0.466, p < 0.05). Similar significant correlations were described between BDNF level at 28 DOL and enteral energy intake ( r = 0.493, p < 0.05). Multivariate regression analysis showed that NGF level at 28 DOL depends on enteral protein and energy intake administrated in the 1st week of life., Conclusion: Neurotrophin values varied according to the route of nutrition administration in preterm newborns. NGF/BDNF serum levels are influenced positively and negatively by EN and PN, respectively., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 De Nardo, Petrella, Di Chiara, Di Mario, Deli, Travaglia, Baldini, Russo, Parisi, Fiore and Terrin.)

Background: The differential diagnosis of abdominal pain in pregnant women is broad. Liver diseases as the origin of abdominal pain in pregnancy are rare, and severe forms occur in less than 0.1% of pregnancies. Some disorders, such as hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome and preeclampsia, are unique to pregnancy, while others, such as antiphospholipid antibody syndrome, may manifest in pregnancy but have consequences beyond the current pregnancy. All of them require prompt identification and treatment., Case Presentation: A 27-year-old Caucasian woman who was 15 +1 weeks pregnant reported to the emergency department twice due to stabbing right-upper-quadrant abdominal pain. Initial laboratory testing revealed mild leukocytosis and slightly elevated liver enzymes. On second presentation, the patient was febrile and had an increased C-reactive protein concentration. Over the course of the next days, nonhemolytic anemia and thrombocytopenia emerged with elevated liver enzymes. Coagulation studies also revealed a prolongation of activated partial thromboplastin time. Magnetic resonance imaging showed nonspecific alterations in the right liver lobe, possibly corresponding to infection or infarction. A hepatic viral infection was ruled out. At that time, the most likely diagnosis was cholangitis with liver abscess formation, and antibiotic therapy was started. Further worsening of the anemia and thrombocytopenia, development of proteinuria, together with a miscarriage on the fourth day of hospitalization resulted in the tentative diagnosis of (triple-positive) antiphospholipid antibody syndrome, which was confirmed 12 weeks after the initial investigation. Treatment consisted of prompt anticoagulation with heparin and later on with a vitamin K antagonist as well as high-dose glucocorticoid therapy. There was no need for intravenous immunoglobulin therapy or plasma exchange, although we suspected a catastrophic form of antiphospholipid antibody syndrome due to infarctions of the liver, placenta, and possibly kidneys (proteinuria). The outcome was favorable., Conclusion: We report a 27-year-old pregnant woman whose abdominal pain was caused by liver infarctions as the first manifestation of catastrophic antiphospholipid antibody syndrome. The antiphospholipid antibody syndrome was possibly secondary to hitherto clinically silent systemic lupus erythematosus since the antinuclear antibodies were increased later on. Hydroxychloroquine therapy was initiated to prevent antiphospholipid antibody syndrome recurrence in a future pregnancy., (© 2022. The Author(s).)

Evidences demonstrated that timing of weaning influences long-term growth in full term infants. However, studies on preterm infants are still lacking, and the international guidelines are focused only on healthy full-term newborn, without consensus for preterms. We aimed at evaluating, in a cohort study, the consequences of different timing of weaning on auxological outcomes up to 12 months of corrected age in a population of neonates born with gestational age < 32 weeks or birth weight < 1500 g. We divided the enrolled neonates in two cohorts according to the timing of weaning: (i) Early Weaning: introduction of complementary food before 6 months of corrected age; (ii) Late Weaning: complementary food introduced after 6 months of corrected age. Growth parameters (weight, length, body mass index, and ponderal index) were measured at 12 months of life. The two groups were statistically comparable for baseline clinical characteristics, and differences on growth parameters were not reported between the two study groups. These results were confirmed in linear and binary logistic regression multivariate models. Timing of weaning is not related to growth of preterm newborns in the first 12 months of corrected age. Studies are needed to reach consensus for the appropriate nutritional approach for preterm babies after discharge.

(1) Background: The tolerance of preterm newborns for the high nutritional intakes given by parenteral nutrition (PN) is still debated because of the risk of metabolic complications. Despite enteral nutrition (EN) being the preferred route of nutrition, an exclusive enteral feeding is not always possible, as in preterm newborns, the gut is immature and less tolerant of EN. We aimed to study the impact of a minimal enteral feeding (MEF) on the possible early metabolic complications of PN in a cohort of preterms with gestational age at birth GA ≤ 29 + 6/7 weeks of postmenstrual age. (2) Methods: We divided the study sample in two cohorts: 1) Late-Feeding (cohort 1), newborns who received MEF starting from the 8th day of age, and (2) Early-Feeding (cohort 2), newborns who received MEF, consisting of the administration of at least 4-5 mL/kg/day by the enteral route, in the first 7 days of age. The primary outcome of the study was the rate of at least one metabolic complication, including hyperglycemia, hypertriglyceridemia, or metabolic acidosis. (3) Results: We enrolled 80 newborns (Late-Feeding cohort 51 vs. Early-Feeding cohort 29). The rate of all metabolic complications was statistically higher in the Late-Feeding cohort compared to the Early-Feeding cohort. Binary logistic regression analysis showed that late administration of MEF negatively influenced the rate of all metabolic complications. (4) Conclusions: Early minimal administration of EN is associated with less frequent PN-related metabolic side effects and a higher rate of survival in critically ill newborns.

(1) Background: Preterm birth exposes the infant to the known risk factors for atopic diseases. We aimed to study the neonatal risk factors and to describe the clinical manifestations of atopy, including the march of symptoms, in a cohort of preschool children born preterm. (2) Methods: We enrolled neonates with gestational age < 32 weeks or birth weight < 1500 g. We classified patients in cases and controls according to the presence of at least one atopic manifestation. (3) Results: We observed 72 cases and 93 controls. Multivariate models showed that the administration of more than one cycle of antibiotics (B 0.902, p = 0.026) and gestational diabetes (B 1.207, p = 0.035) influence the risk of atopy in babies born preterm. In addition, risk of atopic dermatitis was influenced by gestational age < 29 weeks (B -1.710, p = 0.025) and gestational diabetes (B 1.275, p = 0.027). The risk of wheeze was associated with familiarity for asthma (B 1.392, p = 0.022) and the administration of more than one cycle of antibiotics (B 0.969, p = 0.025). We observed a significant reduction in the rate of atopic manifestation after 2 years of life (33.9% vs. 23.8%, p < 0.05). (4) Conclusions: Modifiable (gestational diabetes, antibiotics use) and unmodifiable (familiarity for asthma) conditions influence the risk of atopy in babies born preterm. Extreme prematurity reduces the risk of atopic dermatitis. Preterm babies showed a peculiar atopic march.

Current guidelines for preterm newborns recommend high energy nutrition soon after birth in order to limit growth retardation. However, long-term effects of this nutritional approach are still debated, and it has been demonstrated that cerebral growth depends on protein intake in early life. A negative impact of early high energy intake by parenteral nutrition (PN) has been reported for patients in critically ill conditions, observed in intensive care unit. We aimed at evaluating the impact of energy intake on cerebral growth in preterm neonates early in life. We included preterm newborns with gestational age < 32 weeks or birth weight (BW) < 1500 g. Measurement of cerebral structures was performed by cranial Ultrasonography (cUS) between 3 and 7 days of life (DOL, T0) and at 28 DOL (T1). We evaluated the relation between energy intake and cerebral growth in the first 28 DOL. We observed in 109 preterm newborns a significant (p < 0.05) negative correlation between energy intake received by PN and right caudate head growth (r = - 0.243*) and a positive correlation between total energy intake and transverse cerebellum diameter (r = 0.254*). Multivariate analysis showed that energy intake administered by enteral nutrition (EN), independently increased growth of left caudate head (β = 0.227*) and height cerebellar vermis (β = 0.415*), while PN independently affected growth of both right and left caudate head (β = - 0.164* and β = - 0.228*, respectively) and cerebellum transverse diameter (β = - 0.849*). The route of energy administration may exert different effects on cerebral growth in early life. High energy intake administered through EN seems to be positively correlated to cerebral growth; conversely, PN energy intake results in a poorer cerebral growth evaluated with cUS., (© 2021. The Author(s).)

Objectives: Preterm births are at higher risk for neurodevelopment (NDV) disabilities. To limit long-term consequences, guidelines recommend aggressive parenteral nutrition (PN) soon after birth. The aim of this study was to examine the effects of energy-enhanced PN in the first week of life on long-term NDV in preterm neonates., Methods: We compared two cohorts of newborns (group A: energy-enhanced PN and group B: energy-standard PN) with different energy intake in the first 7 d of life (DoL) given by PN with the same protein amount, to study the influences of an energy-enhanced PN on NDV at 24 mo of life evaluated with the Bayley Scale of Infant Development-III edition., Results: We analyzed 51 newborns (A: n = 24 versus B: n = 27). The two cohorts were similar in baseline characteristics (gestational age group A 29 wk, 95% confidence interval [CI], 28-30 wk versus group B 29 wk, 95% CI, 28-30 wk; birth weight A: 1214 g, 95% CI, 1062-1365 g versus B 1215 g, 95% CI, 1068-1363 g; boys A 62.5% versus B 55.6%). Infants in cohort B showed significantly (P < 0.05) better gross motor, total scaled, and total composite motor scores (A: 8 (1) versus B 9 (2); A 17 (4) versus B 19 (5); A 91 (12) versus B 97 (15); respectively). Cohort A showed a higher percentage of infants with delayed socioemotional competence (A 30.4% versus B 7.7%, P < 0.05). No differences were found in growth parameters at 24 mo of life. Linear regression analysis showed that socioemotional competence and motor score were negatively associated with energy intake of the first 7 DoL given by PN., Conclusions: A more aggressive PN strategy results in lower motor score and socioemotional competence performance at 24 mo of life. More caution might be advocated for an energy-enhanced PN protocol, particularly in neonates with lower birth weight, for long-term NDV in preterm neonates., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: An early diagnosis of necrotizing enterocolitis (NEC), a major gastrointestinal emergency in preterm newborns, is crucial to improve diagnostic approach and prognosis. We evaluated whether fecal high-mobility group box protein 1 (HMGB1) may early identify preterms at risk of developing NEC. Materials and Methods: A case-control study including neonates admitted at the Neonatal Intensive Care Unit (NICU) of the Sapienza University Hospital "Umberto I" in Rome, from July 2015 to December 2016. Stool samples obtained from cases (preterm newborns with NEC) and controls (newborns without NEC) were collected at the enrolment (T0) and within 7-14 days after the first sample collection (T1). HMGB1, extracted and measured with western blot, was reported as densitometry units (DUS). Results: HMGB1 levels in 30 cases ( n = 28-Bell stage 1, n = 2 Bell stage 2) were higher [T0: 21,462 DUS (95% CI, 16,370-26,553 DUS)-T1: 17,533 DUS (95% CI, 13,052-22,014 DUS)] than in 30 preterm controls [T0: 9,446 DUS (95% CI, 6,147-12,746 DUS)-T1: 9,261 DUS (95% CI, 5,126-13,396 DUS), p < 0.001). Preterm newborns showed significant higher levels of HMGB1 (15,690 DUS (95% CI, 11,929-19,451 DUS)] in comparison with 30 full-term neonates with birth weight >2,500 g [6,599 DUS (95% CI, 3,141-10,058 DUS), p = 0.003]. Multivariate analysis showed that the risk of NEC was significantly ( p = 0.012) related to the HMGB1 fecal levels at T0. Conclusions: We suggest fecal HMGB1 as a reliable marker of early NEC in preterm neonates. This study supports further investigation on the role of fecal HMGB1 assessment in managing preterm newborns at risk of NEC. Further studies are advocated to evaluate diagnostic accuracy of this marker in more severe forms of the disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Vitali, Terrin, Palone, Laudadio, Cucchiara, Boscarino, Di Chiara and Stronati.)

(1) Background: Hypertriglyceridemia (HiTG) is a metabolic complication of intravenous lipid emulsions (ILEs) infusion. We aimed to evaluate the influence of HiTG on the respiratory outcome of preterm babies; (2) Methods: We enrolled, in a case-control study, newborns with gestational age <32 weeks or birth weight <1500 g, over a 3-year period. They were divided into cases and controls; cases were defined by the detection of HiTG defined as serum triglycerides (TG) value >150 mg/dL; (3) Results: We enrolled 40 cases and 105 controls. Cases had an increased incidence of bronchopulmonary dysplasia (30.0% vs. 14.3%, p < 0.05) and longer duration of invasive mechanical ventilation (7 days, 95% CI 4-10 days vs. 4 days, 95% CI 1-7 days, p < 0.01) compared to controls. Multivariate analysis confirmed that HiTG independently influenced the duration of invasive mechanical ventilation, also in the subgroups with gestational age ≤28 + 6/7 weeks or birth weight ≤1000 g; (4) Conclusion: Newborns with HiTG related to ILEs had a longer duration of invasive mechanical ventilation. Temporary suspension or reduction in ILEs in the case of HiTG is associated with an improvement of respiratory outcome.

Umbilical cord care can be a stressful practice for parents. Complications of cord care can increase neonatal morbidity and mortality. The extracts of Arnica montana (AM) have been reported to possess antibacterial, anti-inflammatory, antifungal, and immunomodulatory activities. We aim to demonstrate the efficacy of AM on cord detachment and parents' stress level induced by cord medication in healthy full-term newborns. We enrolled full-term infants with a birth weight ≥ 2500 g in healthy conditions. Cord stumps of infants in the PRE-group were cleaned and dried, while cord stumps of infants in the POST-group were cleaned, dried, and medicated with a natural topic dermo-protective powder containing AM. After discharge, we interviewed parents on the stump status during follow-up visits in a pediatric office at 7 and 14 days of life, or by phone calls after follow-up visits. Long-rank test showed that time of cord separation of newborns in the PRE-group was significantly higher compared to that in the POST-group (p < 0.001). Parents of newborns in the PRE-group were significantly more stressed during cord medication compared to parents in the POST-group (2.0 (1.2 to 2.1) vs 1.0 (0.8 to 1.3), p = 0.011). Multivariate analysis showed a significantly linear relation with group assignment for cord separation (p < 0.001) and parents' stress during the medication (p = 0.033).Conclusion: The use of a natural topic dermo-protective powder containing AM reduces the time of cord separation, improves parents' stress level, and reduces the risk of complications. What is Known: • Cord stump care can be a stressful practice for parents. • Antiseptic treatment recommended for cord care could be associated with side effects such as burning and sensitization. What is New: • The medication of cord stump with a natural topic dermo-protective powder containing Arnica montana reduces time of cord detachment and of complication such as redness', bleeding, or secretions. • The use of Arnica montana for cord medication may have a positive impact on the family, reducing parents' stress, and the use of other medications.

Introduction: Association between persistency of a patent ductus arteriosus (PDA) and morbidity in preterm newborns is still controversial. We aimed to investigate the relation between PDA and morbidity in a large retrospective study., Methods: A case-control study including neonates consecutively admitted to the Neonatal Intensive Care Unit (NICU), with gestational age (GA) < 32 weeks or body birth weight (BW) < 1500 g, over a 5-year period. Newborns were divided into Cases and Controls, according with the presence or absence of a hemodynamically significant PDA (hs-PDA)., Results: We enrolled 85 Cases and 193 Controls. Subjects with hs-PDA had significantly (p < 0.001) lower GA (26.7 w, 95%CI 27.1-28.0 vs. 30.1 w, 95%CI 29.7-30.4), BW (1024 g, 95% CI 952-1097 vs. 1310 g 95%CI 1263-1358) and an increased morbidity (60.0% vs. 18.7%). In a sub-group of extremely preterm newborns (GA ≤ 28 weeks and BW ≤ 1000 g), the rate of bronchopulmonary dysplasia (BPD) was significantly increased in Cases (31.7%) compared with Controls (5.9%, p = 0.033). Multivariate analysis showed that morbidity significantly depended on hs-PDA, GA and BW, and that, in extremely preterms, the hs-PDA represented an independent risk factor for BPD., Conclusions: Occurrence of the main morbidities of prematurity depended by hs-PDA, in association with GA, BW, and use of prenatal steroids. In extremely premature babies, hs-PDA is a risk factor for BPD, one of the most important morbidity of prematurity, independently by other confounding variables.

Introduction: Echocardiography (ECHO) with color flow Doppler is considered as the gold standard to identify a hemodynamic patent ductus arteriosus (hs-PDA). However, the optimal diagnostic and therapeutic management for newborns with hs-PDA is still controversial. We aimed to investigate two clinical strategies: (1) targeted treatment based on ECHO criteria and (2) treatment based on ECHO criteria in addition to clinical signs and symptoms. Materials and Methods: This is a cohort study including all neonates consecutively admitted in the Neonatal Intensive Care Unit of University La Sapienza in Rome, with gestational age <32 weeks or body birth weight <1,500 g and with a diagnosis of hs-PDA as confirmed by ECHO evaluation performed within 72 h of life. We classified the babies in two cohorts: (A) pharmacological treatment immediately after ECHO screening and (B) pharmacological therapy for PDA was administered when the relevance of a hs-PDA was associated with clinical signs of hemodynamic instability. Results: We considered as primary outcome newborns who survived without any morbidities (A: 48.1% vs. B: 22.2%, p = 0.022). In particular, we found that the rate of intraventricular hemorrhage stage ≥2 was increased in cohort B (A: 3.7% vs. B 24.4%, p = 0.020). A multivariate analysis showed that assignment to cohort A independently influences the primary outcome. Conclusions: Adopting an hs-PDA management option based on ECHO-directed therapy regardless of symptoms may reduce the morbidity and improve the survival of very low birth weight infants., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Terrin, Di Chiara, Boscarino, Versacci, Di Donato, Giancotti, Pacelli, Faccioli, Onestà, Corso, Ticchiarelli and De Curtis.)

Introduction: To limit extrauterine growth restriction, recent guidelines on nutrition of preterm neonates recommended high protein intake since the first day of life (DOL). The impact of this nutritional strategy on the brain is still controversial. We aimed to evaluate the effects of protein intake on early cerebral growth in very low birth weight newborns. Materials and Methods: We performed serial cranial ultrasound (cUS) scans at 3-7 DOL and at 28 DOL in very low birth weight newborns consecutively observed in the neonatal intensive care unit. We analyzed the relation between protein intake and cerebral measurements at 28 DOL performed by cUS. Results: We enrolled 100 newborns (gestational age 29 ± 2 weeks, birth weight 1,274 ± 363 g). A significant ( p < 0.05) positive correlation between enteral protein intake and biparietal diameter ( r = 0.490 ** ), occipital-frontal diameter ( r = 0.608 ** ), corpus callosum (length r = 0.293 * , genu r = 0.301 * ), caudate head (right r = 0.528 ** , left r = 0.364 ** ), and cerebellum (transverse diameter r = 0.440 ** , vermis height r = 0.356 ** , vermis width r = 0.377 ** ) was observed at 28 DOL. Conversely, we found a significant negative correlation of protein intake given by parenteral nutrition (PN) with biparietal diameter ( r = -0.524 ** ), occipital-frontal diameter ( r = -0.568 ** ), body of corpus callosum ( r = -0.276 * ), caudate head (right r = -0.613 ** , left r = -0.444 ** ), and cerebellum (transverse diameter r = -0.403 ** , vermis height r = -0.274 * , vermis width r = -0.462 ** ) at 28 DOL. Multivariate regression analysis showed that measurements of occipital-frontal diameter, caudate head, and cerebellar vermis at 28 DOL depend positively on protein enteral intake ( r = 0.402 * , r = 0.305 * , and r = 0.271 * ) and negatively by protein parenteral intake ( r = -0.278 * , r = -0.488 * , and r = -0.342 * ). Conclusion: Brain development in neonatal life depends on early protein intake. High protein intake affects cerebral structures' measurements of preterm newborn when administered by PN. Positive impact on brain development encourages the administration of recommended protein intake mainly by enteral nutrition., (Copyright © 2020 Terrin, De Nardo, Boscarino, Di Chiara, Cellitti, Ciccarelli, Gasparini, Parisi, Urna, Ronchi, Russo, Sabatini and De Curtis.)

Aim: To assess the best energy intake in Parenteral Nutrition (PN) for preterm newborns, considering both possible benefits for growth and risk of complications., Methods: Quasi-experimental study comparing two cohorts of newborns, receiving Energy-Enhanced vs. Standard PN (Cohort A, from 1st January 2015 to 31 January 2016 and Cohort B from 1st February 2016 to 31 March 2017; respectively) after implementation of a change in the PN protocol. The primary outcome measure was growth at 24 months of life. The PN associated complications were also measured., Results: We enrolled 132 newborns in two Cohorts, similar for prenatal and postnatal clinical characteristics. Although, body weight and length at 24 months of life were significantly higher (p<0.05) in the Cohort A (11.1, 95% CI 10.6 to 11.6 Kg; 85.0 95% CI 83.8 to 86.2 cm) compared with Cohort B (10.4, 95% CI 9.9 to 10.9 Kg; 81.3 95% CI 79.7 to 82.8 cm), body weight and length Z-Score in the first 24 months of life were similar between the two Cohorts. The rate of PN associated complications was very high in both study Cohorts (up to 98% of enrolments). Multivariate analysis showed that length at 24 months was significantly associated with receiving standard PN (cohort A) in the first week of life and on the energy intake in the first week of life. We also found a marginally insignificant association between Cohort A assignment and body weight at 24 months of life (p = 0.060)., Conclusions: Energy-enhanced PN in early life has not significant effects on long-term growth in preterm newborns. The high prevalence of PN associated complications, poses concerns about the utility of high energy intake recommended by current guidelines for PN., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Since 2011, the French government estimates that about 500 French children have been born in or taken by their parents to areas where terrorist operations prevail. Since May 2017, 75 children who returned to France have benefited from a dedicated health care system., Method: This article is the result of clinical interviews conducted with 53 patients evaluated and taken care of at Avicenne Hospital in Bobigny. To our knowledge, no studies have been published on this subject., Results: A total of 32 evaluations have been completed, all of which indicated the need for care for these children. Of these children, 64% are under 5 years old, and 59% were born in France. Their clinical profiles are heterogeneous and fluctuate with time., Discussion: The multiple adverse events experienced by these children and the uniqueness of children born to families suspected by authorities of having participated in activities related to terrorism make this situation unprecedented. How can we make a diagnosis of PTSD without the help of a precise anamnesis? How can we help these children form a structuring narrative that avoids the pitfalls inherent to generalized fascination?, (Copyright © 2020 Klein, Mapelli, Veyret-Morau, Levy-Bencheton, Giraud, di Chiara, Fumagalli, Lida-Pulik, Moscoso, Payen de la Garanderie, Palazzi, Baleyte, Speranza, Rezzoug and Baubet.)

(1) Background: Zinc is a key element for protein synthesis in preterm newborns. Early aggressive nutrition, promoting protein synthesis, may increase zinc consumption; (2) Methods: We performed a prospective observational study, to assess the relationship between early macronutrients intake and serum zinc levels, in preterm newborns with Gestational Age (GA) of 24-35 weeks, consecutively observed in Neonatal Intensive Care Unit (NICU). (3) Results: We enrolled 130 newborns (GA 31.5 ± 2.8). A significant negative correlation between serum zinc level at 28 days of life and energy (r -0.587, p < 0.001) and protein intake (r -0.556, p < 0.001) in the first week of life was observed. Linear regression analysis showed that zinc levels depended on energy (β -0.650; p < 0.001) and protein (β -0.669; p < 0.001) intake given through parenteral nutrition (PN) in the first week of life; (4) Conclusions: zinc status of preterm neonates was influenced by early protein and energy intake. An additional zinc supplementation should be considered when high protein and energy intake are received by preterm newborns in the first week of life.

Chances and Pitfalls of ANA and ANCA Diagnostics Abstract. In the context of clinical manifestations, if analysed with high quality laboratory methods and correctly interpreted, ANA and ANCA are an essential tool in the differential diagnosis of rheumatic diseases. Neither ANA nor ANCA, however, are pathognomonic markers of rheumatic diseases and they do not have a reliable negative predictive value. Commercially available screening tests such as ENA screen or CTD screen are offered widely. Unfortunately, the results from such tests may in some cases create more insecurity rather than confirming the diagnosis, as the presented case shows.

Background: A multidisciplinary committee composed of a panel of experts, including a member of the American Academy of Pediatrics and American Institute of Architects, has suggested that the delivery room (DR) and the neonatal intensive care units (NICU) room should be directly interconnected. We aimed to investigate the impact of the architectural design of the DR and the NICU on neonatal outcome., Methods: Two cohorts of preterm neonates born at < 32 weeks of gestational age, consecutively observed during 2 years, were compared prospectively before (Cohort 1: "conventional DR") and after architectural renovation of the DR realized in accordance with specific standards (Cohort 2: "new concept of DR"). In Cohort 1, neonates were initially cared for a conventional resuscitation area, situated in the DR, and then transferred to the NICU, located on a separate floor of the same hospital. In Cohort 2 neonates were assisted at birth directly in the NICU room, which was directly connected to the DR via a pass-through door. The primary outcome of the study was morbidity, defined by the proportion of neonates with at least one complication of prematurity (i.e., late-onset sepsis, patent ductus arteriosus, intraventricular hemorrhage, periventricular leukomalacia, bronchopulmonary dysplasia, retinopathy of prematurity and necrotizing enterocolitis). Secondary outcomes were mortality and duration of hospitalization. Statistical analysis was performed using standard methods by SPSS software., Results: We enrolled 106 neonates (56 in Cohort 1 and 50 in Cohort 2). The main clinical and demographic characteristics of the 2 cohorts were similar. Moderate hypothermia (body temperature ≤ 35.9 °C) was more frequent in Cohort 1 (57%) compared with Cohort 2 (24%, p = 0.001). Morbidity was increased in Cohort 1 (73%) compared with Cohort 2 (44%, p = 0.002). No statistically significant differences in mortality and median duration of hospitalization were observed between the 2 cohorts of the study., Conclusions: If realized according to the proposed architectural standards, renovation of DR and NICU may represent an opportunity to reduce morbidity in preterm neonates.

Zinc is a key element for growth and development. In this narrative review, we focus on the role of dietary zinc in early life (including embryo, fetus and preterm neonate), analyzing consequences of zinc deficiency and adequacy of current recommendations on dietary zinc. We performed a systematic search of articles on the role of zinc in early life. We selected and analyzed 81 studies. Results of this analysis showed that preservation of zinc balance is of critical importance for the avoidance of possible consequences of low zinc levels on pre- and post-natal life. Insufficient quantities of zinc during embryogenesis may influence the final phenotype of all organs. Maternal zinc restriction during pregnancy influences fetal growth, while adequate zinc supplementation during pregnancy may result in a reduction of the risk of preterm birth. Preterm neonates are at particular risk to develop zinc deficiency due to a combination of different factors: (i) low body stores due to reduced time for placental transfer of zinc; (ii) increased endogenous losses; and (iii) marginal intake. Early diagnosis of zinc deficiency, through the measurement of serum zinc concentrations, may be essential to avoid severe prenatal and postnatal consequences in these patients. Typical clinical manifestations of zinc deficiency are growth impairment and dermatitis. Increasing data suggest that moderate zinc deficiency may have significant subclinical effects, increasing the risk of several complications typical of preterm neonates (i.e., necrotizing enterocolitis, chronic lung disease, and retinopathy), and that current recommended intakes should be revised to meet zinc requirements of extremely preterm neonates. Future studies evaluating the adequacy of current recommendations are advocated.

The Rab GTPase-activating protein TBC1D4 (AS160) controls trafficking of the glucose transporter GLUT4 in adipocytes and skeletal muscle cells. TBC1D4 is also highly abundant in the renal distal tubule, although its role in this tubule is so far unknown. In vitro studies suggest that it is involved in the regulation of renal transporters and channels such as the epithelial sodium channel (ENaC), aquaporin-2 (AQP2), and the Na+-K+-ATPase. To assess the physiological role of TBC1D4 in the kidney, wild-type (TBC1D4+/+) and TBC1D4-deficient (TBC1D4-/-) mice were studied. Unexpectedly, neither under standard nor under challenging conditions (low Na+/high K+, water restriction) did TBC1D4-/- mice show any difference in urinary Na+ and K+ excretion, urine osmolarity, plasma ion and aldosterone levels, and blood pressure compared with TBC1D4+/+ mice. Also, immunoblotting did not reveal any change in the abundance of major renal sodium- and water-transporting proteins [Na-K-2Cl cotransporter (NKCC2) NKCC2, NaCl cotransporter (NCC), ENaC, AQP2, and the Na+-K+-ATPase]. However, the abundance of GLUT4, which colocalizes with TBC1D4 along the distal nephron of TBC1D4+/+ mice, was lower in whole kidney lysates of TBC1D4-/- mice than in TBC1D4+/+ mice. Likewise, primary thick ascending limb (TAL) cells isolated from TBC1D4-/- mice showed an increased basal glucose uptake and an abrogated insulin response compared with TAL cells from TBC1D4+/+ mice. Thus, TBC1D4 is dispensable for the regulation of renal Na+ and water transport, but may play a role for GLUT4-mediated basolateral glucose uptake in distal tubules. The latter may contribute to the known anaerobic glycolytic capacity of distal tubules during renal ischemia., (Copyright © 2015 the American Physiological Society.)

Circulating aldosterone levels are increased in human pregnancy. Inadequately low aldosterone levels as present in preeclampsia, a life-threatening disease for both mother and child, are discussed to be involved in its pathogenesis or severity. Moreover, inactivating polymorphisms in the aldosterone synthase gene have been detected in preeclamptic women. Here, we used aldosterone synthase-deficient (AS(-/-)) mice to test whether the absence of aldosterone is sufficient to impair pregnancy or even to cause preeclampsia. AS(-/-) and AS(+/+) females were mated with AS(+/+) and AS(-/-) males, respectively, always generating AS(+/-) offspring. With maternal aldosterone deficiency in AS(-/-) mice, systolic blood pressure was low before and further reduced during pregnancy with no increase in proteinuria. Yet, AS(-/-) had smaller litters due to loss of fetuses as indicated by a high number of necrotic placentas with massive lymphocyte infiltrations at gestational day 18. Surviving fetuses and their placentas from AS(-/-) females were smaller. High-salt diet before and during pregnancy increased systolic blood pressure only before pregnancy in both genotypes and abolished the difference in blood pressure during late pregnancy. Litter size from AS(-/-) was slightly improved and the differences in placental and fetal weights between AS(+/+) and AS(-/-) mothers disappeared. Overall, an increased placental efficiency was observed in both groups paralleled by a normalization of elevated HIF1α levels in the AS(-/-) placentas. Our results demonstrate that aldosterone deficiency has profound adverse effects on placental function. High dietary salt intake improved placental function. In this animal model, aldosterone deficiency did not cause preeclampsia.

TBC1D4 (or AS160) was identified as a Rab-GTPase activating protein (Rab-GAP) that controls insulin-dependent trafficking of the glucose transporter GLUT4 in skeletal muscle cells and in adipocytes. Recent in vitro cell culture studies suggest that TBC1D4 may also regulate the intracellular trafficking of kidney proteins such as the vasopressin-dependent water channel AQP2, the aldosterone-regulated epithelial sodium channel ENaC, and the Na(+)-K(+)-ATPase. To study the possible role of TBC1D4 in the kidney in vivo, we raised a rabbit polyclonal antibody against TBC1D4 to be used for immunoblotting and immunohistochemical studies. In immunoblots on mouse kidney homogenates, the antibody recognizes specific bands at the expected size of 160 kDa and at lower molecular weights, which are absent in kidneys of TBC1D4 deficient mice. Using a variety of nephron-segment-specific marker proteins, immunohistochemistry reveals TBC1D4 in the cytoplasm of the parietal epithelial cells of Bowman's capsule, the thin and thick limbs of Henle's loop, the distal convoluted tubule, the connecting tubule, and the collecting duct. In the latter, both principal as well as intercalated cells are TBC1D4-positive. Thus, with the exception of the proximal tubule, TBC1D4 is highly expressed along the nephron and the collecting duct, where it may interfere with the intracellular trafficking of many renal transport proteins including AQP2, ENaC and Na(+)-K(+)-ATPase. Hence, TBC1D4 may play an important role for the control of renal ion and water handling and hence for the control of extracellular fluid homeostasis.

Doripenem, a new carbapenem, has shown to be more active against Pseudomonas aeruginosa than other carbapenems. The activity of doripenem, imipenem and meropenem was evaluated against 93 P. aeruginosa isolates, by agar dilution and disk diffusion methods. MIC50 and MIC90, were as follows (microg/ml): doripenem, 2 and 4; meropenem, 2 and 8; and imipenem, 4 and 8, respectively. Doripenem MICs were 1 to 3 dilutions lower (i.e. more active) than those for imipenem in 82% of the isolates. In comparison with meropenem, doripenem was 1 to 3 dilutions more active in 50% of the isolates. Forty-nine percent of isolates showed the same MIC for both antibiotics. Resistance percentages for both methods were (dilution/diffusion): imipenem = 7.5%/49.5% and meropenem = 3.2%/9.7%. As the CLSI has not established cut off values for doripenem yet, resistance rates for this antibiotic were estimated by considering (a) the same cut off values for imipenem/meropenem set up by the CLSI, and (b) those suggested by Brown et al. In case (a), resistance rates would be 1.1%/2.2% whereas in case (b) 1.1%/17.2% for agar dilution and disk diffusion, respectively. In scenarios where resistance to carbapenem is based on mechanisms other than carbapenemases, doripenem has a promising future for treating P. aeruginosa infections.

Fifteen unique isolates of carbapenem-resistant Pseudomonas aeruginosa were selected for time-kill studies to assess the bactericidal activity of cefepime (CFP) and ceftazidime (CZD) (at 4 and 16 microg/mL), alone and associated with amikacin (AMK) (4 microg/mL). CFP proved more active than CZD (p < 0.05, Student's t test). Bactericidal activity after 24-h incubation was only achieved by the combination of CFP (16 microg/mL) plus AMK. The higher in vitro activity of cefepime over that of ceftazidime against imipenem-resistant P. aeruginosa strains highlights the differences of these drugs beyond Enterobacterspp. and Staphylococcus aureus.