Serious Bacterial Infections in Preterm Infants: Should Their Age Be "Corrected"?

Adjusting the chronological age of preterm infants according to their gestational age is a widely accepted practice in the field of neurodevelopment. It has been suggested for the assessment of preterm infants with suspected infection, but has been poorly validated. Correcting for chronological age is especially critical in infants with a chronological age above 3 months, but a corrected age below 3 months due to the differences in assessment protocols. This study assessed the difference in incidence of serious bacterial infection (SBI) according to chronological and corrected age in preterm infants. A retrospective analysis of pediatric emergency department (PED) presentations was conducted for all 448 preterm infants born in between January 2010 and August 2019. Of the 448 preterm infants, 204 (46%) presented at one of 3 PEDs in Jerusalem, Israel, during their first year of life. Overall, 141 (31.4%) presented with fever and were included in the study. The infants were divided into 3 age groups: 1-corrected age >3 months; 2-chronological age >3 months, but corrected age <3 months; 3-chronological and corrected age <3 months. SBI was diagnosed in 2.6%, 16.7%, and 33.3% of the infants in groups 1, 2 and 3, respectively; (p < 0.01, p = 0.17, p < 0.001). The incidence of SBI in the control group of 300 term infants <3 months presenting to the PED due to fever was 15.3%. Preterm infants with a corrected age <3 months are at increased risk for SBI, similarly to term infants <3 months of age. Age correction should thus be considered for preterm infants presenting with fever.

The Validity of Positive Coagulase-Negative Staphylococcus Cultures for the Diagnosis of Sepsis in the Neonatal Unit.

OBJECTIVE: Coagulase-negative Staphylococcus (CoNS) is the most frequent pathogen causing late-onset sepsis (LOS) in neonatal intensive care units (NICUs). Technical difficulties hinder blood culture (BC) collection and obtaining only one culture before initiating antibiotic therapy is a common practice. We sought to assess specific clinical information and CoNS cultures for the diagnosis of true bacteremia in the NICU. STUDY DESIGN: This historical cohort study was conducted in NICUs at the Hadassah-Hebrew University Medical Center of Jerusalem in Israel. Clinical and laboratory data in every CoNS bacteremia were collected and compared between bacteremia groups as follows: true positive, two positive BCs; contaminant, one positive BC out of two; undefined, one BC obtained and found positive. RESULTS: For 3.5 years, CoNS was isolated in 139 episodes. True positive was identified in 44 of 139 (31.7%), contaminant in 42 of 139 (30.2%), and the event was undefined in 53 of 139 (38.1%). Vancomycin treatment was more frequent in the true positive and undefined groups than the contaminant group (100, 90.6, and 73.8% respectively, p = 0.001); treatment was also prolonged in these two groups (p < 0.001). No clinical variables were associated with true bacteremia on multivariable analysis. CONCLUSION: Diagnosis should definitely be based on at least two positive BCs, despite objective difficulties in obtaining BCs in neonates. KEY POINTS: · CoNS is a frequent pathogen causing LOS in neonates.. · Due to technical difficulties, often only one culture is collected prior to antibiotic therapy.. · No clinical/laboratory variables were associated with the diagnosis of true CoNS bacteremia.. · Diagnosis should definitely be based on at least two positive BCs..

Diabetes during Pregnancy: A Maternal Disease Complicating the Course of Pregnancy with Long-Term Deleterious Effects on the Offspring. A Clinical Review.

In spite of the huge progress in the treatment of diabetes mellitus, we are still in the situation that both pregestational (PGDM) and gestational diabetes (GDM) impose an additional risk to the embryo, fetus, and course of pregnancy. PGDM may increase the rate of congenital malformations, especially cardiac, nervous system, musculoskeletal system, and limbs. PGDM may interfere with fetal growth, often causing macrosomia, but in the presence of severe maternal complications, especially nephropathy, it may inhibit fetal growth. PGDM may also induce a variety of perinatal complications such as stillbirth and perinatal death, cardiomyopathy, respiratory morbidity, and perinatal asphyxia. GDM that generally develops in the second half of pregnancy induces similar but generally less severe complications. Their severity is higher with earlier onset of GDM and inversely correlated with the degree of glycemic control. Early initiation of GDM might even cause some increase in the rate of congenital malformations. Both PGDM and GDM may cause various motor and behavioral neurodevelopmental problems, including an increased incidence of attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Most complications are reduced in incidence and severity with the improvement in diabetic control. Mechanisms of diabetic-induced damage in pregnancy are related to maternal and fetal hyperglycemia, enhanced oxidative stress, epigenetic changes, and other, less defined, pathogenic mechanisms.

S-Adenosine Methionine (SAMe) and Valproic Acid (VPA) as Epigenetic Modulators: Special Emphasis on their Interactions Affecting Nervous Tissue during Pregnancy.

S-adenosylmethionine (SAMe) is involved in many transmethylation reactions in most living organisms and is also required in the synthesis of several substances such as monoamine neurotransmitters and the N-methyl-D-aspartate (NMDA) receptor. Due to its important role as an epigenetic modulator, we discuss in some length the process of DNA methylation and demethylation and the critical periods of epigenetic modifications in the embryo, fetus, and thereafter. We also discuss the effects of SAMe deficiency and the attempts to use SAMe for therapeutic purposes such as the treatment of major depressive disorder, Alzheimer disease, and other neuropsychiatric disorders. SAMe is an approved food additive and as such is also used during pregnancy. Yet, there seems to scanty data on the possible effects of SAMe on the developing embryo and fetus. Valproic acid (VPA) is a well-tolerated and effective antiepileptic drug that is also used as a mood stabilizer. Due to its high teratogenicity, it is contraindicated in pregnancy. A major mechanism of its action is histone deacetylase inhibition, and therefore, it acts as an epigenetic modulator, mainly on the brain. This prompted clinical trials using VPA for additional indications i.e., treating degenerative brain disease such as Alzheimer disease, dementia, HIV, and even cancer. Therefore, we discuss the possible effects of VPA and SAMe on the conceptus and early postnatally, during periods of susceptibility to epigenetic modifications. VPA is also used as an inducer of autistic-like behavior in rodents and was found by us to modify gene expression when administered during the first postnatal week but not when administered to the pregnant dams on day 12 of gestation. In contrast, SAMe modified gene expression when administered on day 12 of pregnancy but not postnatally. If administered together, VPA prevented the changes in gene expression induced by prenatal SAMe administration, and SAMe prevented the gene expression changes and autistic-like behavior induced by early postnatal VPA. It is concluded that both VPA and SAMe are powerful epigenetic modifiers with antagonistic actions on the brain that will probably be used in the future more extensively for the treatment of a variety of epigenetic diseases of the nervous system.

Prenatal S-Adenosine Methionine (SAMe) Induces Changes in Gene Expression in the Brain of Newborn Mice That Are Prevented by Co-Administration of Valproic Acid (VPA).

In previous studies, we produced changes in gene expression in the brain of mice by early postnatal administration of valproic acid (VPA), with distinct differences between genders. The addition of S-adenosine methionine (SAMe) normalized the expression of most genes in both genders, while SAMe alone induced no changes. We treated pregnant dams with a single injection of VPA on day 12.5 of gestation, or with SAMe during gestational days 12-14, or by a combination of VPA and SAMe. In the frontal half of the brain, we studied the expression of 770 genes of the pathways involved in neurophysiology and neuropathology using the NanoString nCounter method. SAMe, but not VPA, induced statistically significant changes in the expression of many genes, with differences between genders. The expression of 112 genes was changed in both sexes, and another 170 genes were changed only in females and 31 only in males. About 30% of the genes were changed by more than 50%. One of the most important pathways changed by SAMe in both sexes was the VEGF (vascular endothelial growth factor) pathway. Pretreatment with VPA prevented almost all the changes in gene expression induced by SAMe. We conclude that large doses of SAMe, if administered prenatally, may induce significant epigenetic changes in the offspring. Hence, SAMe and possibly other methyl donors may be epigenetic teratogens.

Gender Related Changes in Gene Expression Induced by Valproic Acid in A Mouse Model of Autism and the Correction by S-adenosyl Methionine. Does It Explain the Gender Differences in Autistic Like Behavior?

In previous studies we produced autism like behavioral changes in mice by Valproic acid (VPA) with significant differences between genders. S-adenosine methionine (SAM) prevented the autism like behavior in both genders. The expression of 770 genes of pathways involved in neurophysiology and neuropathology was studied in the prefrontal cortex of 60 days old male and female mice using the NanoString nCounter. In females, VPA induced statistically significant changes in the expression of 146 genes; 71 genes were upregulated and 75 downregulated. In males, VPA changed the expression of only 19 genes, 16 were upregulated and 3 downregulated. Eight genes were similarly changed in both genders. When considering only the genes that were changed by at least 50%, VPA changed the expression of 15 genes in females and 3 in males. Only Nts was similarly downregulated in both genders. SAM normalized the expression of most changed genes in both genders. We presume that genes that are involved in autism like behavior in our model were similarly changed in both genders and corrected by SAM. The behavioral and other differences between genders may be related to genes that were differently affected by VPA in males and females and/or differently affected by SAM.

Prevention or Amelioration of Autism-Like Symptoms in Animal Models: Will it Bring Us Closer to Treating Human ASD?

Since the first animal model of valproic acid (VPA) induced autistic-like behavior, many genetic and non-genetic experimental animal models for Autism Spectrum Disorder (ASD) have been described. The more common non-genetic animal models induce ASD in rats and mice by infection/inflammation or the prenatal or early postnatal administration of VPA. Through the establishment of these models, attempts have been made to ameliorate or even prevent ASD-like symptoms. Some of the genetic models have been successfully treated by genetic manipulations or the manipulation of neurotransmission. Different antioxidants have been used (i.e., astaxanthin, green tea, piperine) to reduce brain oxidative stress in VPA-induced ASD models. Agents affecting brain neurotransmitters (donepezil, agmatine, agomelatine, memantine, oxytocin) also successfully reduced ASD-like symptoms. However, complete prevention of the development of symptoms was achieved only rarely. In our recent study, we treated mouse offspring exposed on postnatal day four to VPA with S-adenosine methionine (SAM) for three days, and prevented ASD-like behavior, brain oxidative stress, and the changes in gene expression induced by VPA. In this review, we describe, in addition to our data, the existing literature on the prevention/amelioration of ASD-like symptoms. We also discuss the possible mechanisms underlying some of these phenomena. Finally, we describe some of the clinical trials in children with ASD that were carried out as a result of data from animal studies, especially those with polyunsaturated fatty acids (PUFAs).

S-adenosyl methionine prevents ASD like behaviors triggered by early postnatal valproic acid exposure in very young mice.

INTRODUCTION: A common animal model of ASD is the one induced by valproic acid (VPA), inducing epigenetic changes and oxidative stress. We studied the possible preventive effect of the methyl donor for epigenetic enzymatic reactions, S-adenosine methionine (SAM), on ASD like behavioral changes and on redox potential in the brain and liver in this model. METHODS: ICR albino mice were injected on postnatal day 4 with one dose of 300 mg/kg of VPA, with normal saline (controls) or with VPA and SAM that was given orally for 3 days at the dose of 30 mg/kg body weight. From day 50, we carried out neurobehavioral tests and assessment of the antioxidant status of the prefrontal cerebral cortex, liver assessing SOD and CAT activity, lipid peroxidation and the expression of antioxidant genes. RESULTS: Mice injected with VPA exhibited neurobehavioral deficits typical of ASD that were more prominent in males. Changes in the activity of SOD and CAT increased lipid peroxidation and changes in the expression of antioxidant genes were observed in the prefrontal cortex of VPA treated mice, more prominent in females, while ASD like behavior was more prominent in males. There were no changes in the redox potential of the liver. The co-administration of VPA and SAM alleviated most ASD like neurobehavioral symptoms and normalized the redox potential in the prefrontal cortex. CONCLUSIONS: Early postnatal VPA administration induces ASD like behavior that is more severe in males, while the redox status changes are more severe in females; SAM corrects both. VPA-induced ASD seems to result from epigenetic changes, while the redox status changes may be secondary.

High sucrose low copper diet in pregnant diabetic rats induces transient oxidative stress, hypoxia, and apoptosis in the offspring's liver.

BACKGROUND: Hyperglycemia-related oxidative stress and hypoxia are important mechanisms responsible for diabetes-induced embryopathy and other complications. High sucrose low copper diet (HSD), but not regular diet (RD), induces type 2 diabetes in the inbred Cohen diabetic sensitive (CDs) rats but not in the Sabra control rats. We recently demonstrated long-term changes of DNA methylation and gene expression in various groups of genes, including genes involved in oxidant-antioxidant activity in the liver of 2-4-week-old CDs offspring of diabetic dams. We now studied the postnatal effects of diabetes and/or HSD on several liver metabolic parameters in these offspring. METHODS: we studied lipid peroxidation, activity of the antioxidants enzymes superoxide dismutase (SOD) and Catalase (CAT). By immunohistochemistry: protein oxidation by nitrotyrosine staining, hypoxia inducing factor1α (HIF1α), apoptosis [caspase 3, bcl-2-like protein (BAX)], proliferation [proliferating cell nuclear antigen (PCNA)] and NF-κB. RESULTS: In the Sabra rats fed HSD only few, early and transitional changes were observed in lipid peroxidation, SOD and CAT activity. In the CDs fed HSD more significant changes in lipid and protein oxidation, HIF1α, apoptosis and proliferation were observed, persisting for longer. CONCLUSIONS: The changes in the Sabra rats HSD were attributed to the pro-oxidant effects of the diet and those in the diabetic CDs to the HSD and maternal diabetes. In light of the DNA methylation changes in the liver of the CDs HSD, we presume that changes in gene expression are responsible for our findings, and that similar changes may lead to the metabolic syndrome at adulthood.

Antidepressants, Antipsychotics, and Mood Stabilizers in Pregnancy: What Do We Know and How Should We Treat Pregnant Women with Depression.

Depression is generally treated with antidepressants, but may often need antipsychotics and mood stabilizers. We discuss the updated data regarding the safety in pregnancy of antidepressants and antipsychotics, except selective serotonin reuptake inhibitors, and their possible impact on the long-term development of the offspring. Several earlier studies demonstrated a slight increase in the rate of major anomalies following maternal tricyclic antidepressant treatment, but most current literature shows their relative safety in pregnancy. Data on the development of the offspring are also reassuring. The antipsychotic drugs are also safe for the developing fetus and do not seem to induce developmental delay. Both groups of drugs may cause perinatal withdrawal symptoms and difficulties in neonatal adaptation. The mood stabilizers, lithium, and several anti-epileptic drugs, may adversely affect the developing embryo and fetus. While valproic acid, carbamazepine, and topiramate are teratogenic and may also affect postnatal development, the newer antiepileptic and mood stabilizers, lamotrigine and levetiracetam, seem to be safe in pregnancy and apparently have no long-term neurodevelopmental damage. Lithium may increase the rate of cardiac anomalies, especially of Ebstein's anomaly, and may warrant a mid-trimester fetal echocardiography. Although data on the development of the offspring are reassuring, we should remember that most studies were carried out during early childhood, at a time when inattention, learning difficulties, behavioral and psychiatric problems are not yet identifiable. When considering medical treatment for depression in women at child-bearing age, we have to weigh the severity of the symptoms and their impact on the developing fetus and child. Birth Defects Research 109:933-956, 2017.© 2017 Wiley Periodicals, Inc.

Parvovirus B19 infection during pregnancy and risks to the fetus.

Parvovirus B19 infects 1 to 5% of pregnant women, generally with normal pregnancy outcomes. During epidemics, the rate of infection is higher. Major congenital anomalies among offspring of infected mothers are rare, as the virus does not appear to be a significant teratogen. However, parvovirus B19 infection may cause significant fetal damage, and in rare cases, brain anomalies and neurodevelopmental insults, especially if infection occurs in the first 20 weeks of pregnancy. Parvovirus B19 is also an important cause of fetal loss, especially in the second half of pregnancy when spontaneous fetal loss from other causes is relatively rare. Parvovirus B19 infection may affect many fetal organs and can cause severe anemia, following fetal erythroid progenitor cells infection and apoptosis, especially in fetuses, that have shortened half-life of erythrocytes. Severe anemia may cause high output cardiac failure and nonimmune hydrops fetalis. In addition, parvovirus B19 may directly infect myocardial cells and produce myocarditis that further aggravates the cardiac failure. Intrauterine fetal transfusion is commonly used for the treatment of severe fetal anemia with survival rates of 75 to 90% and significant reduction of fetal morbidity. Only 66 cases were evaluated neurodevelopmentally, of which 10 (16%) had slight or severe neurodevelopmental problems. Because parvovirus B19 infection can cause severe fetal morbidity and mortality, it should be part of the routine work-up of pregnant women who have been exposed to the virus or of pregnancies with suspected fetal hydrops. Assessment for maternal infection during pregnancy is especially important during epidemics, when sero-conversion rates are high. Birth Defects Research 109:311-323, 2017. © 2017 Wiley Periodicals, Inc.

Genetic Syndromes, Maternal Diseases and Antenatal Factors Associated with Autism Spectrum Disorders (ASD).

Autism spectrum disorder (ASD) affecting about 1% of all children is associated, in addition to complex genetic factors, with a variety of prenatal, perinatal, and postnatal etiologies. In addition, ASD is often an important clinical presentation of some well-known genetic syndromes in human. We discuss these syndromes as well as the role of the more important prenatal factors affecting the fetus throughout pregnancy which may also be associated with ASD. Among the genetic disorders we find Fragile X, Rett syndrome, tuberous sclerosis, Timothy syndrome, Phelan-McDermid syndrome, Hamartoma tumor syndrome, Prader-Willi and Angelman syndromes, and a few others. Among the maternal diseases in pregnancy associated with ASD are diabetes mellitus (PGDM and/or GDM), some maternal autoimmune diseases like antiphospholipid syndrome (APLS) with anti-ß2GP1 IgG antibodies and thyroid disease with anti-thyroid peroxidase (TPO) antibodies, preeclampsia and some other autoimmune diseases with IgG antibodies that might affect fetal brain development. Other related factors are maternal infections (rubella and CMV with fetal brain injuries, and possibly Influenza with fever), prolonged fever and maternal inflammation, especially with changes in a variety of inflammatory cytokines and antibodies that cross the placenta and affect the fetal brain. Among the drugs are valproic acid, thalidomide, misoprostol, and possibly SSRIs. ß2-adrenergic receptor agonists and paracetamol have also lately been associated with increased rate of ASD but the data is too preliminary and inconclusive. Associations were also described with ethanol, cocaine, and possibly heavy metals, heavy smoking, and folic acid deficiency. Recent studies show that heavy exposure to pesticides and air pollution, especially particulate matter < 2.5 and 10 µm in diameter (PM2.5 and PM10) during pregnancy is also associated with ASD. Finally, we have to remember that many of the associations mentioned in this review are only partially proven, and not all are "clean" of different confounding factors. The associations described in this review emphasize again how little we know about the etiology and pathogenesis of ASD. It is obvious that we need more epidemiologic data to establish many of these associations, but if proven, they might be promising avenues for prevention.

Genetic and non-genetic animal models for autism spectrum disorders (ASD).

Autism spectrum disorder (ASD) is associated, in addition to complex genetic factors, with a variety of prenatal, perinatal and postnatal etiologies. We discuss the known animal models, mostly in mice and rats, of ASD that helps us to understand the etiology, pathogenesis and treatment of human ASD. We describe only models where behavioral testing has shown autistic like behaviors. Some genetic models mimic known human syndromes like fragile X where ASD is part of the clinical picture, and others are without defined human syndromes. Among the environmentally induced ASD models in rodents, the most common model is the one induced by valproic acid (VPA) either prenatally or early postnatally. VPA induces autism-like behaviors following single exposure during different phases of brain development, implying that the mechanism of action is via a general biological mechanism like epigenetic changes. Maternal infection and inflammation are also associated with ASD in man and animal models.

[PREDICTION OF LATE ONSET SEPSIS IN VERY LOW BIRTH WEIGHT INFANTS BY A SOFTWARE APPLICATION--ARE WE THERE YET?].

INTRODUCTION: Early prediction of late onset sepsis is imperative in order to improve survival and reduce long-term complications. Since clinical deterioration is detrimental, empiric antibiotic treatment is initiated once sepsis is suspected. Symptoms that may indicate invasive infection are non-specific. Previous risk scores offered to improve clinical decision-making but provided low predictive values. AIMS: To evaluate the quantitative early alert of software application compared to clinical judgment by the treating physician, and the "gold standard" of positive blood and/or positive cerebrospinal fluid. METHODS: Weight, heart and respiratory rates, episodes of bradycardia and desaturation, and temperature were collected for each neonate and loaded daily into the system for a period of 30 days by a registered nurse. The medical team and the registered nurse were blind to the system alerts. Analysis of the correlation between the software alerts, the clinical suspicion of sepsis and bacteremia was conducted. RESULTS: Forty-five very low birth weight consecutively born infants who did not have early onset sepsis and survived, were evaluated, of whom 17 infants had culture proven bloodstream infection. The software positive predictive value was 6%, 23%, 31%, at 12, 24, 48, hours respectively for alerts approximately to positive cultures. The positive predictive value of clinical suspicion of LOS was 28% but increased from 25% with low levels of clinical suspicion to 34% with high levels of clinical suspicion. DISCUSSION: The software application did not improve sepsis prediction. However, further trials may develop a more accurate algorithm that will alert the physician to be more attentive to infants in special cases.

Diabetes in the Cohen Rat Intensifies the Fetal Pancreatic Damage Induced by the Diabetogenic High Sucrose Low Copper Diet.

Intrauterine hyperglycemic environment could harm the fetus making it more susceptible to develop postnatal glucose intolerance. A possible mechanism is compromise of the fetal pancreatic development. We previously found that a high sucrose low copper diabetogenic diet induces type 2 diabetes in the Cohen diabetic sensitive rats, but not in the Sabra control rats. However, oxidative stress was observed in the placenta and term fetal liver of diabetic and nondiabetic controls. We now investigated whether the fetal pancreas is affected by this diet and whether the effects result from oxidative stress, maternal hyperglycemia, or both. Term fetal pancreases were evaluated for morphology, beta cells, oxidative stress, apoptosis, and DNA methylation. There were no microscopic changes in hematoxylin and eosin stained sections and beta cells immunostaining in the pancreas of fetuses of both strains. Fetuses of the sensitive strain fed diabetogenic diet had significantly higher activity of superoxide dismutase and catalase, elevated levels of low molecular weight antioxidants, and more intense immunostaining for nuclear factor kappa-B and hypoxia inducing factor-1α. Both strains fed diabetogenic diet had increased immunostaining for Bcl-2-like protein and caspase 3 and decreased immunostaining for 5-methylcytosine in their islets and acini. Our data suggest that maternal diabetogenic diet alters apoptotic rate and epigenetic steady states in the term fetal pancreas, unrelated to maternal diabetes. Maternal hyperglycemia further increases pancreatic oxidative stress, aggravating the pancreatic damage. The diet-induced insults to the fetal pancreas may be an important contributor to the high susceptibility to develop diabetes following metabolic intrauterine insults.

Very High Intrapartum Fever in Term Pregnancies and Adverse Obstetric and Neonatal Outcomes.

BACKGROUND: Intrapartum fever is a well-known risk factor for adverse perinatal outcomes. Maternal intrapartum fever ≥39.0°C at term is a rare event during labor, and there is scarce evidence regarding its implications. OBJECTIVES: To investigate the association between very high intrapartum maternal fever and perinatal outcomes in term pregnancies. METHODS: A retrospective cohort analysis including 43,560 term, singleton live births in two medical centers between the years 2003 and 2011 was performed. We compared parturients who experienced a maximal intrapartum fever of <38.0°C with two subgroups of parturients who experienced respective maximal fevers of 38.0-38.9°C and ≥39°C. Adjusted risks for adverse perinatal outcomes were calculated by using multiple logistic regression models to control for confounders. RESULTS: Compared with normal intrapartum temperature, intrapartum fever ≥39.0°C was associated with an extremely elevated risk for neonatal sepsis 16.08 (95% CI: 2.15, 120.3) as well as with low Apgar scores and neonatal intensive care unit admissions (p < 0.001). Additionally, very high intrapartum fever was related to significantly higher risk for operative delivery (p < 0.001). CONCLUSIONS: Extremely elevated intrapartum fever is an important indicator of severe neonatal morbidity and operative delivery.

Gestational Diabetes Alters Offspring DNA Methylation Profiles in Human and Rat: Identification of Key Pathways Involved in Endocrine System Disorders, Insulin Signaling, Diabetes Signaling, and ILK Signaling.

Gestational diabetes is associated with risk for metabolic disease later in life. Using a cross-species approach in rat and humans, we examined the hypothesis that gestational diabetes during pregnancy triggers changes in the methylome of the offspring that might be mediating these risks. We show in a gestation diabetes rat model, the Cohen diabetic rat, that gestational diabetes triggers wide alterations in DNA methylation in the placenta in both candidate diabetes genes and genome-wide promoters, thus providing evidence for a causal relationship between diabetes during pregnancy and DNA methylation alterations. There is a significant overlap between differentially methylated genes in the placenta and the liver of the rat offspring. Several genes differentially methylated in rat placenta exposed to maternal diabetes are also differentially methylated in the human placenta of offspring exposed to gestational diabetes in utero. DNA methylation changes inversely correlate with changes in expression. The changes in DNA methylation affect known functional gene pathways involved in endocrine function, metabolism, and insulin responses. These data provide support to the hypothesis that early-life exposures and their effects on metabolic disease are mediated by DNA methylation changes. This has important diagnostic and therapeutic implications.

Congenital fulminant Kaposiform hemangioendothelioma of the leg.

Kaposiform hemangioendothelioma is a rare locally aggressive vascular tumor associated with Kasabach Merritt syndrome. We present a case of congenital Kaposiform hemangioendothelioma of the leg in a female infant who was born to a mother treated with various medications including etanercept, a TNF antagonist, due to rheumatoid arthritis. The neonate suffered from a fulminant form of Kasabach Merritt syndrome with disseminated intravascular coagulation (DIC) resulting in multi-organ failure which led to her demise.

Placental oxidative stress and decreased global DNA methylation are corrected by copper in the Cohen diabetic rat.

Fetal Growth Restriction (FGR) is a leading cause for long term morbidity. The Cohen diabetic sensitive rats (CDs), originating from Wistar, develop overt diabetes when fed high sucrose low copper diet (HSD) while the original outbred Sabra strain do not. HSD induced FGR and fetal oxidative stress, more prominent in the CDs, that was alleviated more effectively by copper than by the anti-oxidant vitamins C and E. Our aim was to evaluate the impact of copper or the anti-oxidant Tempol on placental size, protein content, oxidative stress, apoptosis and total DNA methylation. Animals were mated following one month of HSD or regular chow diet and supplemented throughout pregnancy with either 0, 1 or 2 ppm of copper sulfate or Tempol in their drinking water. Placental weight on the 21st day of pregnancy decreased in dams fed HSD and improved upon copper supplementation. Placental/fetal weight ratio increased among the CDs. Protein content decreased in Sabra but increased in CDs fed HSD. Oxidative stress biochemical markers improved upon copper supplementation; immunohistochemistry for oxidative stress markers was similar between strains and diets. Caspase 3 was positive in more placentae of dams fed HSD than those fed RD. Placental global DNA methylation was decreased only among the CDs dams fed HSD. We conclude that FGR in this model is associated with smaller placentae, reduced DNA placental methylation, and increased oxidative stress that normalized with copper supplementation. DNA hypomethylation makes our model a unique method for investigating genes associated with growth, oxidative stress, hypoxia and copper.

Amyand's hernia with perforated appendicitis in a premature infant.

We present a case of Amyand's hernia with perforated appendicitis in a premature infant. The favorable outcome compared to perforated abdominal appendicitis is discussed. Despite its rarity, this diagnosis should be considered in the differential diagnosis of a scrotal mass in premature infants.