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We present the case of a 79-year-old patient with multiple cardiovascular morbidities, classified as ASA III (American Society of Anesthesiology). An upper digestive endoscopy was performed due to chronic anemia and a subepithelial lesion was identified in the subcardial region of 30 x 25 mm, without other relevant findings.

Surgical management has been the main approach for enteral fistulae. This approach is usually complex due to comorbidities, a wasted nutritional state and anatomical difficulties related to prior multiple interventions. Therefore, endoscopic methods such as clips, self-expanding metal stent (SEMS) and recently, the over scope clip (OTSC®) are increasing in popularity and use. Herein, we present the case of a patient with a HIV infection who was admitted due to respiratory symptoms. Radiological and microbiological studies documented a tracheoesophageal fistula due to tuberculosis (TB) and cytomegalovirus (CMV) infection. Therefore, an esophageal fully-covered stent was placed, which migrated into the stomach. The thoracic surgeons considered an esophagectomy with gastric ascent and muscle patch in the trachea. However, due to his poor nutritional status and comorbidity, an OTSC was placed to treat the fistulae. The patient also received medical treatment with anti-tuberculotics and anti-retrovirals.

Background: Hepatitis B virus (HBV) vaccination has decreased the prevalence of chronic HBV infections and their sequelae. However, whether vaccination at birth provides lifelong protection is unclear., Objective: To assess long-term immunity following neonatal HBV immunization in a large population-based cohort., Methods: Using the database of a 2 million member sick fund in Israel, we identified all subjects born after introduction of universal HBV vaccination in Israel (January 1992 through December 2014), that were tested for hepatitis B surface antibody (anti-HBs Ab's). Years since vaccination were categorized into 5-year groups and linear trends in the seroprevalence of HBV immunity were calculated. Anamnestic response and presence of Hepatitis B surface antigen (HBs Ag) were assessed., Results: Included were 20,634 tested individuals. Mean (±SD) age at testing was 14.8 (±5.4) years. Mean anti-HBs Ab levels declined with time to 16.39 mIU/ml in the 15-20 year group (P < 0.001). The proportion of negative results increased gradually (P < 0.001) to 66.7% after 15 years. Anamnestic response assessment showed that 604 of 644 seronegative subjects (93.8%, 95% CI: 91.6-95.5%) became seropositive after a booster dose. HBs Ag was identified in 91 of the 20,634 (4.4 per 1000 study participants)., Conclusions: Following vaccination, anti-HB's Ab's progressively decline, with only a third of the population retaining protective levels after 15 years. In adolescence, anamnestic response shows that nearly all revaccinated adolescents exhibit immunity. A low rate of Hepatitis B infection was demonstrated despite vaccination of nearly all newborns., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Aims: Metformin is used to treat type 2 diabetes, polycystic ovary syndrome associated infertility, and gestational diabetes. This study aims to evaluate the safety of metformin in early pregnancy., Method: We evaluated the risk of major birth defects and pregnancy losses in a cohort of pregnant women exposed to metformin during the first trimester for different indications relative to a matched unexposed reference group., Results: The risk of major birth defects was 5.1% (20/392) in pregnancies exposed to metformin during the first trimester and 2.1% (9/431) in the reference group [adjusted odds ratio (OR) 1.70; 95% CI 0.70-4.38]. Among metformin users, this risk was 7.8% (17/219) in patients with pre-gestational diabetes and 1.7% (3/173) in those without this diagnosis. Compared to the unexposed reference, the OR for metformin user with diabetes was 3.95 (95% CI 1.77-9.41) and for metformin with other indications it was 0.83 (95% CI 0.18-2.81). The risk of pregnancy losses (spontaneous abortions and stillbirths) was 20.8% in women on metformin during the first trimester and 10.8% in the reference group [adjusted hazard ratio (HR) 1.57; 95% CI 0.90-2.74]. The risks for women on metformin with and without pre-gestational diabetes were 24.0% and 16.8% respectively, with adjusted HR of 2.51 (95% CI 1.44-4.36) and 1.38 (95% CI 0.74-2.59) when compared to the reference., Conclusion: Pregnant women with pre-gestational diabetes on metformin are at a higher risk for adverse pregnancy outcomes than the general population. This appears to be due to the underlying diabetes since women on metformin for other indications do not present meaningfully increased risks., (© 2017 The British Pharmacological Society.)

Aims: The present study evaluates the effect of antenatal lamotrigine exposure, on short- and long-term paediatric outcome., Methods: The study included the children of 83 epileptic women treated with lamotrigine during pregnancy, at a tertiary medical centre between 2004-2014. All newborns were monitored for vital signs, congenital malformations and Finnegan score. In addition, the parents completed a questionnaire regarding their child's development and health up to the age of 12 years., Results: No major malformations were found in the newborns. None of the newborns had significant withdrawal symptoms by Finnegan score. The children were followed-up to the age of 12 years (56.6% were 6-12 years at the time of evaluation). There were no significant findings in the incidence of neurodevelopmental disorders., Conclusions: According to our experience, lamotrigine is generally safe for pregnancy use, associated with minimal short-term complications with no long-term effects on the outcome., (© 2017 The British Pharmacological Society.)

Cannabis, commonly called marijuana, is often used during pregnancy, likely due to the perception that it is a "safe" drug. Changes in legislation in many countries have lead to the increased availability of this drug and to its increasing use during pregnancy, often with other concomitant exposures such as alcohol, tobacco, and other drugs. Herein, we review the medical literature regarding effects of marijuana on the fetus and newborn. Possible effects of in utero exposure to marijuana focus on fetal growth, increase in the rates of stillbirth and preterm delivery, congenital malformations, and neurodevelopmental effects on the child. Published studies for all these outcomes are inconsistent. Fetal weight growth may be somewhat decreased, but the magnitude of this decrease is no greater than 100 g. There is insufficient evidence to conclude on any effect on the stillbirth rate. Although there are some reports of a slight increase in the rate of prematurity, most reports do not support this effect. Marijuana does not appear to be a major teratogen; however, a small increased risk for some congenital birth defects may be associated with early pregnancy use. Neurodevelopmental effects have been associated with marijuana use, but it is difficult to control for the effect of confounders. Despite the lack of conclusive evidence, it is important to remember that marijuana has not been shown to be a harmless drug during pregnancy and may affect the long-term neurodevelopment of the newborn infant., (Copyright© of YS Medical Media ltd.)

Objective: To evaluate maternal and breastfed infant's outcome following post-partum maternal use of methylergonovine., Methods: A prospective, controlled observational study design was used. Mothers who contacted Beilinson Teratology Information Service (BELTIS) were followed by phone interview. Data on lactation, neonatal symptoms and outcomes at the age of 1-3 years were obtained. Mothers' breastfeeding while treated with methylergonovine and their infants were compared to a matched control group of breastfeeding mothers using a drug known to be safe during lactation (amoxicillin)., Results: Follow-up was obtained for 38 of 42 women (90.5%). Of whom, six stopped breastfeeding because of concerns regarding drug treatment and three refused to participate. The remaining 29 women and infant pairs were compared to a control group of 58 women and their infants. Comparison showed no effect of methylergonovine on lactation and similarly showed no difference in rate of neonatal complications (p = 1). At time of follow-up there were no differences in growth or in adverse neurodevelopment outcomes (p = 0.26)., Conclusions: No increase in adverse long-term outcomes was found in infants exposed to methylergonovine through breastfeeding. Our data in conjunction with previous estimates of very low drug exposure support continuation of breastfeeding in women requiring treatment with methylergonovine.

Objective: To determine the independent association of post-term pregnancy with neonatal outcome in low-risk newborns., Design: Retrospective cohort., Setting: Tertiary university-affiliated medical centre., Patients: All newborns of low-risk singleton pregnancies born at 39+0 to 44+0 weeks' gestation over a 5-year period., Exclusion Criteria: multiple gestation, maternal hypertensive disorder, diabetes or cholestasis, placental abruption or intrapartum fever (>38°C), small for gestational age (<10th centile) and major congenital or chromosomal anomalies., Interventions: None., Outcome Measures: Admission to the neonatal intensive care unit (NICU), hospital length of stay, 5-min Apgar score, birth trauma, respiratory, neurological, metabolic and infectious morbidities and neonatal mortality. The adverse outcome rate was compared among three groups based on gestational age at birth: post-term (≥42+0 weeks), late term (41+0 to 41+6 weeks) and full term (39+0 to 40+6 weeks)., Results: Of the 23 524 eligible neonates, 747 (3.2%) were born post-term, 4632 (19.7%) late term and 18 145 (77.1%) full term. Women in the post-term group versus the late-term group had a significantly higher rate of caesarean section (8.9% vs 5.6%, p<0.001) and operative vaginal delivery (9.6% vs 7.4%, p=0.024). Post-term pregnancy versus full-term pregnancy was associated with an increased risk of NICU admission (OR 2.0, 95% CI 1.4 to 2.8), respiratory morbidity (OR 2.2, 95% CI 1.3 to 3.8) and infectious morbidity (OR 1.88, 95% CI 1.32 to 2.69). Post-term pregnancy versus late-term pregnancy was similarly associated with an increased risk of NICU admission (OR 2.0, 95% CI 1.4 to 2.9), respiratory morbidity (OR 2.7, 95% CI 1.5 to 5.0) and infectious morbidity (OR 1.8, 95% CI 1.2 to 2.7) and with hypoglycaemia (OR 2.6, 95% CI 1.2 to 5.4). Post-term delivery was not associated with neonatal mortality., Conclusions: Post-term pregnancy is an independent risk factor for neonatal morbidity even in low-risk singleton pregnancies., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Children born small for gestational age without early catch-up of somatic growth and head circumference subsequently remain short and suffer from various degrees of neurocognitive and psychological impairment. Based upon the role of growth hormone (GH) and insulin-like growth factor-I on early brain growth and maturation, we propose that GH treatment of these infants be instituted prior to their 2nd birthday., (Copyright© of YS Medical Media ltd.)

Objective: Post-hemorrhagic hydrocephalus (PHH) is associated with morbidity and mortality among very low birth weight (VLBW) infants. This study aimed to determine risk factors for PHH among VLBW infants with peri-intraventricular hemorrhage (PIVH)., Study Design: This is a population-based cohort of VLBW infants of 24 to 28 weeks gestation, born in Israel from 1995 to 2012. Infants in whom a brain ultrasound was not performed before 28 days or with major congenital malformations were excluded. Univariate and multivariable analyses identified risk factors associated with PHH., Results: The final study cohort comprised 2811 infants with grade 2 or higher PIVH, of whom 610 (21.7%) developed PHH. PHH was independently associated with PIVH severity, with bilateral grade 3 PIVH and PIVH grade 3 and contralateral grade 4 having the highest risks (odds ratio (OR) 12.2, 95% confidence interval (CI) 8.56 to 17.4 and OR 13.7, 95% CI 9.4 to 20.1, respectively). Unilateral grade 3 or 4 PIVH's had moderately increased risks of PHH (OR 3.50, 95% CI 2.26 to 5.42 and OR 3.79, 95% CI 2.35 to 6.12, respectively). PHH was independently associated with increasing gestational age (GA) and with neonatal morbidities including patent ductus arteriosus (OR 1.47, 95% CI 1.15 to 1.88 if medically treated and OR 3.01, 95% CI 2.11 to 4.29 if surgically treated), sepsis (OR 1.79, 95% CI 1.44 to 2.22) and necrotizing enterocolitis (OR 1.60, 95% CI 1.18 to 2.17)., Conclusions: Among VLBW infants with PIVH, PHH was independently associated with PIVH severity group, increasing GA and acute neonatal morbidities. Unilateral grade 3 or 4 PIVH was associated with a moderate risk of developing PHH compared with bilateral severe hemorrhages.

Background: Palivizumab reduces the severity of respiratory syncytial virus infection in premature infants, but whether there is a protective effect beyond the preschool age is unknown. This study sought to assess the short- and long-term effects of palivizumab immunization on respiratory morbidity and pulmonary function at school age in children born extremely prematurely., Methods: Infants born before 29 weeks' gestation in 2000 to 2003 were assessed at school age by parental questionnaire, hospital chart review, and lung function tests. Children born immediately before the introduction of routine palivizumab prophylaxis were compared with age-matched children who received palivizumab prophylaxis during the first respiratory syncytial virus season., Results: Sixty-three children with a mean age 8.9 years were included: 30 had received palivizumab and 33 had not (control subjects). The groups were similar in terms of gestational age, birth weight, need for mechanical ventilation, and oxygen supplementation. Fifty-three percent of the palivizumab group, compared with 39% of the control group, had bronchopulmonary dysplasia (P = .14). Wheezing occurred in the first 2 years of life in 27% of the palivizumab group and in 70% of control subjects (P = .008); respective hospitalization rates were 33% and 70% (P = .001). At school age, rates of hyperresponsiveness (provocative concentration leading to a 20% fall in FEV1 < 1 mg/mL) were 33% and 48%, respectively (P = .38). Spirometry, lung volumes, diffusion, and exhaled nitric oxide were within normal limits, with no significant differences between groups., Conclusion: Palivizumab prophylaxis was associated with reduced wheezing episodes and hospitalizations during the first 2 years of life in children born extremely prematurely. However, it did not affect pulmonary outcome at school age., (Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Objective: Determine the grade of agreement between the colangiopancreatography by magnetic resonance (CPRM) and the endoscopic retrograde colangio pancreatography (ERCP) in hospitalized patients by biliary lithiasis in a period of time in a reference hospital., Material and Methods: Type of study, retrospective evaluation of diagnostic tool, the size of the sample was calculated from the pilot simple and was 320 patients. We recolected 354 patients that urderwent both studies (CPRM and ERCP), to evaluate the correlation between both procedures we used Kappa variation., Results: 354 pacients were included, 226 women (63.8%), men 128 (36.2%), with mean age of 48 years. There was dilatation of the choledocus by CRMN in 60%, sensibility of 96, 7%, especificity of 40%, Kappa index 0,406 (IC 95%: 0, 32-0, 50) that indicates a moderate agreement. For the presence of choledocus calculi with CPRM was 54%, with sensibility of 72.6%, specificity of 68.3%, Kappa index 0.409 (IC 95%: 0.31-0.51), moderate agreement. For caculi in the gallbladder the kappa index was 0.246 weak. We identify 27% de false negatives for CRMN in detecting choledocusd lithiasis., Conclusions: The CPRM and ERCP had a moderate correlation according to the Kappa index detecting dilatation and choledocus calculi in our patients. The number of false negatives for choledocolithiasis by CPRM leads us to seek in other prospective aleatory studies like endoscopic biliiopancreatic ultrasonopgraphy to compare the CPRM in patients with intermediate probability for choledocolithiasis.

This multicenter, observational prospective cohort study addresses the risk associated with exposure to mirtazapine during pregnancy. Pregnancy outcomes after exposure to mirtazapine were compared with 2 matched control groups: (1) exposure to any selective serotonin reuptake inhibitor (SSRI, control subjects with a psychiatric condition) and (2) no exposure to medication known to be teratogenic or any antidepressant (general control subjects). Data were collected by members of the European Network of Teratology Information Services between 1995 and 2011. Observations from 357 exposed pregnancies were compared with 357 pregnancies from each control group. The rate of major birth defects between the mirtazapine and the SSRI group did not differ significantly (4.5% vs 4.2%; odds ratio [OR], 1.1; 95% confidence interval [95% CI], 0.5-2.3; P = 0.9). A trend toward a higher rate of birth defects in the mirtazapine group compared with general control subjects (4.5% vs 1.9%; OR, 2.4; 95% CI, 0.9-6.3; P = 0.08) reached statistical significance after exclusion of chromosomal or genetic anomalies (4.1% vs 1.3%; OR, 3.3; 95% CI, 1.04-10.3; P = 0.03), but this difference became again nonsignificant if cases of exposure not comprising the first trimester were excluded from the analysis (3.4% vs 1.9%; OR, 1.8; 95% CI, 0.6-5.0; P = 0.26). The crude miscarriage rate did not differ significantly between the mirtazapine, the SSRI, and the general control groups (12.1% vs 12.0% vs 9.3%; P = 0.44). However, a higher rate of elective pregnancy termination was observed in the mirtazapine group compared with SSRI and general control subjects (7.8% vs 3.4% vs 5.6%; P = 0.03). This study did not observe a statistically significant difference in the rate of major birth defects after first-trimester exposure between mirtazapine, SSRI-exposed, and nonexposed pregnancies. A marginally higher rate of birth defects was, however, observed in the mirtazapine and SSRI groups compared with the low rate of birth defects in our general control subjects. Overall pregnancy outcome after mirtazapine exposure was similar to that of the SSRI-exposed control group.

Introduction: Surgical antibiotic prophylaxis (AP) guidelines balance the need to prevent infection with the risks of adverse drug effects. Our aim was to assess compliance with AP guidelines., Methods: A retrospective study was performed in a pediatric medical center. Included were patients aged 0 to 18 years that underwent clean-contaminated surgery during a 1-year period (2008-2009) and required AP. Compliance with four AP bundle guidelines was evaluated. Risk factors for noncompliance were identified using univariate and multivariate analyses., Results: AP was given to 239 of 247 (96.8%) of patients. Complete compliance with AP guidelines was achieved in 16 of 247 (6.5%) patients. Compliance with guidelines for appropriate antibiotic, drug dose, correct timing, and treatment duration were found in 97.1, 52.2, 31.9, and 35.9% of patients, respectively. Multivariable analysis showed that inappropriate timing was associated with age ≥ 4 years (p = 0.002), urgent surgery (p = 0.0018), surgical department AP administration (p = 0.0001), and night-time surgery (p = 0.015). Incorrect AP dose was associated with presence of comorbidities (p = 0.006). No risk factor was related to incorrect AP duration., Conclusions: We have found a low rate of full compliance with AP guidelines. AP should only be given in the operating room. Increased awareness to AP guidelines is needed., (Georg Thieme Verlag KG Stuttgart · New York.)

Objective: This study evaluated the outcome of infants exposed to colchicine during lactation., Subjects and Methods: A prospective observational cohort study design was used. Mothers who contacted Beilinson Teratology Information Service (BELTIS) regarding use of colchicine while breastfeeding were followed up by phone interview. Data on lactation, neonatal symptoms, and outcome 1-3 years after initial consultation were obtained. Mothers breastfeeding while taking colchicine (n=37) and their infants (n=38) were compared with a matched control group of mothers using a drug known to be safe during lactation (n=75) and their infants (n=76)., Results: Follow-up was obtained for 59 of 76 (78%) women who contacted BELTIS regarding use of colchicine. Of the 59 women, 37 breastfed while taking colchicine, five did not take colchicine, 16 did not breastfeed, and one declined to participate. The mean duration of breastfeeding was similar in both groups. Adverse neonatal symptoms were seen in three of 38 colchicine-exposed infants versus four of 76 of control group infants (p=0.68). Delayed development or neurological abnormalities were seen in two infants in both study groups (p=0.60). None of the colchicine-exposed infants showed abnormal growth., Conclusions: No increase in adverse long-term outcomes was found in colchicine-exposed breastfed infants. Our data support continuation of breastfeeding in women treated with colchicine.

Objective: This study evaluated the outcome of infants exposed to tranexamic acid during lactation., Subjects and Methods: A prospective, controlled observational study design was used. Mothers who contacted the Beilinson Teratology Information Service (BELTIS) regarding use of tranexamic acid while breastfeeding were followed up by phone interview. Data on lactation, neonatal symptoms, and outcomes at the age of 1-3 years were obtained. Mothers' breastfeeding while taking tranexamic acid and their infants were compared with those of a matched control group of breastfeeding mothers using a drug known to be safe during lactation (amoxicillin) and their infants., Results: Follow-up was obtained for 28 of 32 women who sought advice regarding use of tranexamic acid during breastfeeding. Of the 28 women, six did not take the drug, and one refused to participate. The 21 remaining women (study group) were compared with 42 control women. A decreased amount of breastmilk was reported by one woman in the study group versus two women in the control group (p=1.0). Possible adverse drug effects were reported for one of 21 study group infants (restlessness) and for one of 42 control group infants (gastroesophageal reflux) (p=1.0). Growth below the 3rd percentile was found in one of 21 study group infants versus four of 42 control group infants (p=0.66). Development was normal for all study group infants., Conclusions: No increase in adverse long-term outcomes was found in infants exposed through breastfeeding to tranexamic acid. Our data in conjunction with previous estimates of very low drug exposure support continuation of breastfeeding in women requiring treatment with tranexamic acid.

Objective: To assess the association of anthropometric measurements with neonatal complications in macrosomic newborns of non-diabetic mothers., Design: Retrospective cohort study., Patients: All liveborn, singleton, full term newborns with birth weight ≥4000 g born to non-diabetic mothers at a tertiary medical centre in 1995-2005 (n=2766, study group) were matched to the next born, healthy, full term infant with a birth weight of 3000-4000 g (control group). Exclusion criteria were multiple birth, congenital infection, major malformations and pregnancy complications., Intervention: Data collection by file review., Outcome Measures: Complication rates were compared between study and control groups and between symmetric and asymmetric macrosomic newborns, defined by weight/length ratio (WLR), Body Mass Index and Ponderal Index., Results: The 2766 non-diabetic macrosomic infants identified were matched to 2766 control infants. The macrosomic group had higher rates of hypoglycaemia (1.2% vs 0.5%, p=0.008), transient tachypnoea of the newborn (1.5% vs 0.5%, p<0.001), hyperthermia (0.6% vs 0.1%, p=0.012), and birth trauma (2% vs 0.7%, p<0.001), with no cases of symptomatic polycythaemia, and only one case of hypoglycaemia. Hypoglycaemia was positively associated with birth weight. It was significantly higher in the asymmetric than the symmetric macrosomic newborns, defined by WLR (1.7% vs 0.3%, p<0.001)., Conclusions: Macrosomic infants of non-diabetic mothers are at increased risk of neonatal complications. However, routine measurements of haematocrit and calcium may not be necessary. Symmetric macrosomic infants (by WLR) have a similar rate of hypoglycaemia as normal-weight infants. Thus, repeat glucose measurements in symmetric macrosomic infants are not justified., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Neonatal hemochromatosis (NH) is an acute liver disease associated with both hepatic and extrahepatic iron deposition and is a leading cause of neonatal liver transplantation. The concept that NH is an alloimmune disease has led to the emergence of a new treatment approach utilizing exchange transfusion and intravenous immunoglobulin therapy. We present a two-day old neonate with progressive liver dysfunction who was diagnosed with NH. Magnetic resonance imaging confirmed tissue iron overload. Treatment with intravenous immunoglobulins and exchange transfusion led to rapid improvement in liver function. Follow-up physical examination at the age of 8 months showed normal development and near normal liver function. A repeat abdominal magnetic resonance scan at 8 months showed no signs of iron deposition in the liver, pancreas, or adrenal glands. The present report provides further support for the use of exchange transfusion and immunoglobulin therapy in NH and is the first to document resolution of typical iron deposition by magnetic resonance imaging.

Oxcarbazepine is an antiepileptic agent that has been used during pregnancy, although its safety during pregnancy has not been sufficiently established. This article presents an infant born with renal and cardiac malformations who developed a withdrawal syndrome and hyponatremia following in utero exposure to oxcarbazepine. The infant was born at 35 weeks' gestation by urgent cesarean section to a mother in status epilepticus who had been treated with oxcarbazepine throughout her pregnancy. Evaluation for congenital anomalies identified mild aortic stenosis, a bicuspid aortic valve, patent foramen ovale, patent ductus arteriosus, and severe left hydronephrosis due to left ureteropelvic junction stenosis. On the third day of life the infant developed clinical signs of a withdrawal syndrome, which peaked on day 7 and resolved by day 12. Transient hyponatremia resolved by day 8 of life. Follow-up showed normal development at 15 months. The association of a withdrawal syndrome with oxcarbazepine exposure has not been previously reported. The hyponatremia is consistent with adult reports. The possible association of oxcarbazepine with renal and cardiac malformations requires further confirmation., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: We previously demonstrated the ability of matrilin-3 to modulate the gene expression profile of primary human chondrocytes (PHCs) toward a state favoring cartilage catabolism. The structure within matrilin-3 responsible for the induction of these catabolic genes is unknown. Here, we investigated the potential of matrilin-3 (MATN3) and truncated matrilin-3 proteins, in both monomeric and oligomeric form, to stimulate interleukin (IL)-6 release in PHCs., Methods: We expressed full-length matrilin-3 oligomers, matrilin-3 von Willebrand factor A (VWA) domain oligomers, matrilin-3 four epidermal growth factor (EGF) domain oligomers, matrilin-3 monomers without oligomerization domains, matrilin-3 VWA domain monomers, and matrilin-3 4EGF monomers. We then incubated PHCs in the absence or presence of full-length matrilin-3 or one of the truncated matrilin-3 proteins and finally determined the release of IL-6 in cell-culture supernatants., Results: The addition of full-length matrilin-3 oligomers, matrilin-3 VWA domain oligomers, and, less pronounced, matrilin-3 monomers without oligomerization domains, and matrilin-3 4EGF-oligomers to the cell-culture medium led to a significant induction of IL-6 in PHCs., Discussion: Based on recombinant expression of different matrilin-3 domains in both monomeric and oligomeric form, this work demonstrated that the VWA1 domain of matrilin-3 is primarily responsible for the induction of IL-6 release and that the oligomerization of the VWA1 domain markedly promotes its activity., (Copyright © 2013 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objective: The incidence of psychotic disorders during the postpartum period is higher than at any other time during a women's life and coincides with the time when breastfeeding is most recommended. As a result, safety data on use of antipsychotic drugs during lactation is essential. Our aim was to analyze the medical literature for information on antipsychotic drug use during breastfeeding and to determine the safety of their use for the exposed infant., Data Sources: Medline (U.S. National Library of Medicine), LactMed (U.S. National Library of Medicine) and Reprotox (Reproductive Toxicology Center) databases were searched to identify all relevant medical literature on antipsychotic medications and lactation. The database search, updated to March, 2012, used the generic name of each antipsychotic drug in combination with the terms breastfeeding or lactation or breast-milk., Study Selection: 4 prospective studies, 12 case series, 28 case reports and 1 pharmaceutical registry were included., Data Extraction: Infant outcomes focusing on long-term outcome were summarized from all reports of breastfeeding mothers taking antipsychotic medications. Recommendations for drug use during breastfeeding were based on safety data and on pharmaco kinetic drug properties. Recommendatins were categorized as acceptable, possible under medical supervision, or, not recommended., Results: Among 21 antipsychotic drugs used in clinical practice, for 7 there are no data at all regarding breastfeeding and for 6 others the data are based only on few infant exposures. Only few prospective studies assessing'use of haloperidol, chlorpromazine and olanzapine during breastfeeding were identified. Olanzapine and quetiapine were categorized as acceptable for breastfeeding. Chlorpromazine, haloperidol, risperidone and zuclopenthixol were categorized as possible for breastfeeding under medical supervision. Breastfeeding cannot be currently recommended for the following medications: aripiprazole, asenapine, chlorprothixene, clozapine, droperidol, fluphenazine, flupenthixol, iloperidone, lurasidone, paliperidone, perphenazine, pimozide, trifluoperazine, thiothixene and ziprasidone., Conclusions: With a limited number of infants exposed to antipsychotic drugs during breastfeeding, for most drugs a firm and evidence-based conclusion cannot be reached. Counseling of breastfeeding mothers should be carefully assessed. Pharmacokinetic drug characteristics, disease severity, behavioral or psychosocial alternatives, preventative interventions and possible impact of discontinuing breastfeeding on the maternal-infant relationship should all be considered.

Purpose: To identify risk factors for intestinal perforation in very-low-birth-weight (VLBW) infants with necrotizing enterocolitis (NEC)., Methods: Retrospective case-control study over a 10-year period, using univariate and multivariate logistic regression analyses to compare all VLBW infants treated for perforated NEC, with two age and weight-matched groups: infants with non-perforated NEC and infants without NEC., Results: Twenty infants with perforated NEC were matched to 20 infants with non-perforated NEC and 38 infants without NEC. Infants with perforated NEC were younger (p<0.01) and had higher rates of abdominal distention, metabolic acidosis, hyperglycemia and elevated liver enzymes (p<0.05). On logistic regression analysis, abdominal distention was associated with an increased risk of intestinal perforation (OR 39.8, 95% CI 2.71-585) and late onset of NEC (one-day increments) was associated with a decreased risk (OR 0.93, 95% CI 0.87-1.0)., Conclusion: Identification of abdominal distention at an early age in VLBW infants should lead to increased vigilance for signs of perforated NEC and may enable early intervention., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: To identify possible effects of levonorgestrel used as an emergency contraceptive during breastfeeding on mothers and their infants., Study Design: A prospective observational cohort study of all women who contacted the Teratology Information Service between January, 2005 and January, 2010. Breastfeeding women who used levonorgestrel as an emergency contraceptive (study group) were compared to breastfeeding women who used either ethynodiol diacetate or desogestrel (control group). Women were followed for 6-24 months. Main outcome measures were adverse maternal and infant effects and continuation of breastfeeding., Results: We followed 71 of 128 study group women and 72 of 100 control group women. Maternal adverse effects were mainly vaginal bleeding, which was less frequent in the study vs. control group (16 of 71 vs. 27 of 72, p = 0.068). Decreased lactation was uncommon and similar in both groups. Breastfeeding was reinitiated within less than 8 h in 75% of the levonorgestrel group women. Adverse infant effects were rare (0 of 72 infants vs. 2 of 72 infants, p = 0.5 in the study vs. control group)., Conclusions: Our findings support the safety of using levonorgestrel as an emergency contraceptive during lactation without the need for withholding breastfeeding.

Objective: We sought to assess the independent effect of perinatal factors on the risk for bronchopulmonary dysplasia (BPD) in very-low-birthweight infants., Study Design: This was a population-based observational study. Data were prospectively collected by the Israel Neonatal Network. Multivariable analyses identified independent risk factors for BPD., Results: Of 12,139 infants surviving to a postmenstrual age of 36 weeks, 1663 (13.7%) developed BPD. BPD was independently associated with young maternal age (odds ratio [OR], 1.53), maternal hypertensive disorders (OR, 1.28), antepartum hemorrhage (OR, 1.26), male gender (OR, 1.41), non-Jewish ethnicity (OR, 1.23), birth defects (OR, 1.94), small for gestational age (GA) (OR, 2.65), and delivery room resuscitation (OR, 1.86). Stratified analysis by GA groups showed that postdelivery resuscitation had a more pronounced effect with increasing maturity., Conclusion: Perinatal factors and pregnancy complications were independently associated with development of BPD in very-low-birthweight infants. Most risk factors identified were consistent within GA groups., (Copyright © 2013 Mosby, Inc. All rights reserved.)

Objective: To evaluate the diagnostic and therapeutic approach to full term neonates born to mothers with intrapartum fever., Methods: In a retrospective study, neonates born to mothers with intrapartum fever, (≥ 37.8°C), were compared to control group matched by gestational age and birthweight., Results: Overall, 159 singleton full term neonates born to women with intrapartum fever (study group) were compared to 159 control infants. No differences in neonatal outcomes were found between the two groups except for a higher rate of meconium-stained amniotic fluid in the maternal-fever group. There were no cases of neonatal infection, severe neonatal morbidity, or neonatal mortality in either of the groups. Full sepsis workup and intravenous antibiotic treatment were provided to 17.6% of the neonates in the study group. Logistic regression analysis revealed that delivery by Cesarean section was the only factor independently associated with the decision to perform a full sepsis work up and antibiotic treatment in cases of maternal intrapartum fever (OR 32.0, 95% CI 9.4-112.1)., Conclusions: In low-risk women with asymptomatic intrapartum fever, neonatal infection is uncommon, so that aggressive evaluation and management of these infants may not be necessary and should be balanced against the low risk of neonatal sepsis.

Background: Diclectin (pyridoxine 10 mg and doxylamine 10 mg) has traditionally been used to treat nausea and vomiting of pregnancy (NVP); however, this drug is unavailable in many countries., Objectives: To evaluate the efficacy and safety of a simple bi-daily treatment regimen with the combination of pyridoxine (50 mg twice daily) and doxylamine (25-50 mg) as an alternative treatment for NVP., Methods: A prospective case-controlled observational study of mother-infant pairs was conducted between February 2008 and December 2010. All women who contacted the Beilinson Teratology Information Service (BELTIS) regarding treatment of NVP were eligible for inclusion. Using data on NVP severity, treatment efficacy and outcomes, we compared the two groups of women: those treated with the combination of pyridoxine and doxylamine (treatment group, n=29) and those treated with metoclopramide (control group, n=29)., Results: Moderate to severe symptoms were present in 97% of the treatment group women vs. 69% of control group women (P < 0.01). Despite increased symptom severity in the treatment group, the combination regimen was efficacious: 20/29 (69%) vs. 18/25 (72%) in the treatment vs. control women respectively (P = 0.65). There were no congenital anomalies in the treatment group. Follow-up was normal for all infants., Conclusions: Bi-daily combination therapy with pyridoxine and doxylamine for NVP is safe, has comparable efficacy to metoclopramide, and is a treatment alternative in countries where Diclectin is not available. Despite symptoms warranting counseling by a teratology information service, more than a third of women do not take the suggested treatment.

Antifungal prophylaxis is increasingly used in very low birth weight (VLBW) infants who are at risk for severe fungal infections. Our objective was to assess the effectiveness of targeted fluconazole prophylaxis for high-risk VLBW infants. A retrospective cohort study with historical controls was performed. During the period 2007-2008, all high-risk VLBW infants (birth weight, ≤1,000 g; gestational age, ≤28 weeks; seven antimicrobial therapy or additional risk factors present) received fluconazole prophylaxis until risk factors were not present. Treated infants were compared to a gestational age- and birth weight-matched untreated cohort. Statistical analyses used univariate and multivariate analyses. The main outcome variable was a breakthrough fungal bloodstream infection (BSI). The prophylaxis cohort of 130 VLBW infants was compared to 319 control infants. The rate of fungal infections was significantly lower in the fluconazole prophylaxis group (1 of 130 vs. 19 of 319, p = 0.016); however, they did not differ in mortality (16.2 vs. 15 %, p = 0.77) or complications of prematurity. Fluconazole prophylaxis was associated with a significant decrease in candidal BSI (odds ratio, 0.05; 95 % confidence interval, 0.005-0.523). Selective vs. nonselective prophylaxis reduced the number of infants treated from 247 to 130. Conclusion Targeted fluconazole prophylaxis in VLBW infants is effective in preventing fungal infections without increasing the risk of BSI among low-risk infants.

Objective: The aim of this study was to determine the long-term pulmonary outcome of extreme prematurity at a single tertiary-care center from 1997 to 2001 in the postsurfactant era., Methods: We assessed symptoms, exhaled nitric oxide, spirometry, methacholine challenge (provocative concentration of methacholine required to decrease FEV₁ by 20% [PC(20)]), lung volumes, diffusion, and cardiopulmonary exercise tolerance., Results: Of 279 infants born, 192 survived to discharge, and 79 of these developed bronchopulmonary dysplasia (BPD) (65 mild, 12 moderate, two severe). We studied a subgroup of 53 neurologically intact preterm subjects aged 10 ± 1.5 years (28 with BPD [born, 26.2 ± 1.4 weeks; birth weight, 821 ± 164 g] and 25 without BPD [born, 27.2 ± 1 weeks; birth weight, 1,050 ± 181 g]) and compared them with 23 term control subjects. Of the BPD cases, 21 were mild, seven were moderate, and none was severe; 77.4% of subjects received antenatal steroids, and 83% received postnatal surfactant. Sixty percent of the preterm subjects wheezed at age < 2 years compared with 13% of the control subjects (P < .001), but only 13% wheezed in the past year compared with 0% of control subjects (not significant). For preterm and control subjects, respectively (mean ± SD), FEV₁ % predicted was 85% ± 10% and 94% ± 10% (P < .001), with limited reversibility; residual volume/total lung capacity was 29.3% ± 5.5% and 25% ± 8% (P < .05); diffusing capacity/alveolar volume was 89.6% ± 9.2% and 97% ± 10% (P < .005); and PC(20) was 6.5 ± 5.8 mg/mL and 11.7 ± 5.5 mg/mL (P < .001). PC(20) was < 4 mg/mL in 49% of preterm subjects despite normal exhaled nitric oxide. Most measurements were similar in premature subjects with and without BPD. Peak oxygen consumption and breathing reserve were normal, but % predicted maximal load (measured in Watts) was 69% ± 15% for subjects with BPD compared with 88% ± 23% for subjects without and 86% ± 20% for control subjects (P < .01)., Conclusions: Pulmonary outcome was encouraging at mid-childhood for neurologically intact survivors in the postsurfactant era. Despite mechanical ventilation and oxygen therapy, most had no or mild BPD. Changes found probably reflect the hypoplastic lungs of prematurity.

Use of 17-alpha-hydroxyprogesterone caproate for the prevention of spontaneous preterm birth in women at risk is reviewed. Early studies regarding this topic reached contradicting conclusions, however recent studies showed that weekly injections of 17-alpha-hydroxyprogesterone caproate beginning at 16-20 weeks' gestation resulted in a substantial reduction in the rate of spontaneous recurrent preterm birth. Long-term follow-up of children exposed in-utero to the drug has shown normal growth and development and normal scores for gender specific roles. In conclusion, 17-alpha-hydroxyprogesterone caproate is currently the only drug with sufficient evidence to support its use for prevention of spontaneous recurrent preterm birth., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: To assess the long-term neurodevelopment of children exposed in utero to selective serotonin reuptake inhibitors (SSRIs) that developed a neonatal abstinence syndrome (NAS)., Study Design: Neurodevelopmental evaluation was performed at the age of 2 to 6 years. Children who developed NAS were compared with those who did not using univariate and logistic regression analyses., Result: Thirty children with NAS and 52 without NAS participated in the study. Both groups were similar in mean cognitive ability (106.9±14.0 vs 100.5±14.6, P=0.12) and developmental scores (98.9±11.4 vs 95.7±9.9, P=0.21). However, there was a trend towards small head circumference in the NAS group (20 vs 6%, P=0.068). NAS was associated with an increased risk of social-behavior abnormalities (odds ratio (OR) 3.03, 95% confidence interval (CI) 1.07 to 8.60, P=0.04) and advanced maternal age (OR 1.12, 95% CI 1.00 to 1.25, P=0.04)., Conclusion: Infants who developed NAS had normal cognitive ability, but were at an increased risk for social-behavioral abnormalities. Follow-up evaluation of symptomatic neonates should be considered.

This study sought to expand current knowledge on the clinical and epidemiological characteristics of persistent coagulase-negative Staphylococcus (CoNS) bacteremia in very-low-birth-weight (VLBW) infants. Background and disease-related data were collected prospectively on 143 VLBW infants diagnosed with CoNS bacteremia at a pediatric tertiary medical center in 1995-2003. Findings were compared between those with persistent (positive blood cultures for >72 h under appropriate treatment ) and nonpersistent disease. Fifty-eight infants (40.6%) were found to have persistent bacteremia. There were no between-group differences in maternal characteristics, mode of delivery, newborn characteristics, dwell time of central venous and umbilical catheters, complications of prematurity, or mean hospital stay. The persistent bacteremia group had significantly higher rates of hypothermia at presentation (37.9% vs. 17.6%, p < 0.04), creatinine >1.2 mg% on treatment day 7 (13.7% vs. 2.4%, p < 0.02; transient phenomenon), and endocarditis (p < 0.03); one infant had an aortic thrombus. Predominantly breast-fed infants had a higher rate of negative cultures within 72 h of appropriate treatment than predominantly formula-fed infants (60% vs. 19%, p < 0.02). In conclusion, persistence of CoNS bacteremia is common in VLBW infants. Endocarditis should be excluded in all infants with persistent disease. Breast-feeding is associated with a shorter disease duration.

Objective: This study evaluated the outcome of infants exposed to olanzapine during lactation., Methods: A prospective, controlled observational study design was used. Mothers who contacted Beilinson Teratology Information Service regarding use of olanzapine while breastfeeding were followed by phone interview. Data on lactation, neonatal symptoms, and outcome at the age of 1-2 years were obtained. Mother-infant groups were compared. Mothers breastfeeding while taking olanzapine (n = 22) were compared to two control groups of mothers who continued to take olanzapine but did not breastfeed (n = 15) and to breastfeeding mothers using a drug known to be safe during lactation (n = 51)., Results: Follow-up was obtained for 37 of 70 women. Comparison of olanzapine-exposed breastfed versus control breastfed infants showed a similar duration of breastfeeding; however, early discontinuation of breastfeeding was more common in the olanzapine-exposed breastfed group (five of 22 vs. none of 51, p = 0.02). The rate of adverse outcomes in olanzapine-exposed breastfed infants did not differ from those of the control groups. Among the 30 newborns exposed in utero to olanzapine, no congenital birth defects were found. Neonatal symptoms were seen in six of 30 of olanzapine-exposed infants versus two of 51 of nonexposed infants (p < 0.05). A withdrawal syndrome was seen in three of 30 (10%) infants., Conclusions: No increase in adverse long-term outcomes in olanzapine-exposed breastfed infants were found. Our data in conjunction with previous estimates of very low drug exposure support continuation of breastfeeding in women treated with olanzapine. However, until additional long-term studies are available, infants exposed to olanzapine through breastmilk should be followed up.

We investigated the role of transforming growth factor-beta activated kinase 1 (TAK1) in collagen II signaling in primary human chondrocytes (PHCs). We asked whether TAK1 acts as a modulator of collagen II signaling with respect to collagen-II-dependent induction of cyclooxigenase-2 (COX-2) in PHCs and release of PGE2 from PHCs. Therefore, PHCs were incubated with collagen II, and cells were then analyzed by RT-PCR for the expression of COX-2. ELISA was used to quantify PGE2 release. To examine the influence of TAK1 on these events, TAK1 gene silencing was performed by RNAi in PHCs prior to collagen II treatment. Results indicated that COX-2 gene expression and PGE2 release are specific outcomes of collagen II signaling and that both depend on TAK1 mediation. These findings are promising in that therapeutic inhibition of TAK1 might be used to reduce pain and relieve inflammatory symptoms that are common in osteoarthritis.

We compared ibuprofen and indomethacin for the treatment of patent ductus arteriosus (PDA) in preterm infants. A retrospective comparative study was conducted at a pediatric tertiary center in preterm infants diagnosed with PDA. Infants born from January 2000 to June 2003 were treated with indomethacin, whereas infants born from July 2003 to November 2005 were treated with ibuprofen. The two treatment groups were compared. Demographic data and clinical, laboratory, and outcome data were collected from the medical files. Seventy-three infants were included in the ibuprofen group and 46 in the indomethacin group. No significant difference in efficacy was found between indomethacin and ibuprofen. Compared with ibuprofen, indomethacin treatment was associated with significantly higher mean creatinine levels and a higher percent of infants with creatinine >1.2 mg/dL, hyponatremia <120 mmol/L, and platelet level <100,000 platelets/mL(3). There were no significant differences in bilirubin levels, incidence and grade of intraventricular hemorrhage, necrotizing enterocolitis, retinopathy of prematurity, rate of surgical duct ligation, sepsis, length of hospital stay, or mortality. Indomethacin and ibuprofen are equally effective for PDA closure in premature infants. Treatment with ibuprofen is safer, decreasing the risk of renal failure, thrombocytopenia, and hyponatremia., (Copyright Thieme Medical Publishers.)

Background: Early-onset sepsis (EOS) is associated with significant morbidity and mortality among infants with a very low birth weight (VLBW); however, there is a sparse amount of complete data on large cohorts., Objective: To evaluate the mortality and major morbidities among VLBW infants with EOS., Methods: This was a population-based observational study. Data were prospectively collected by the Israel Neonatal Network on all VLBW infants born in Israel from 1995 through 2005. Univariate and multivariable analyses were performed to assess the independent association of EOS on morbidity and mortality of VLBW infants., Results: The study cohort included 15 839 infants, of whom 383 (2.4%) developed EOS. EOS was associated with significantly increased odds for mortality (odds ratio [OR]: 2.57 [95% confidence interval (CI): 1.97-3.35]), severe intraventricular hemorrhage (OR: 2.24 [95% CI: 1.67-3.00]), severe retinopathy of prematurity (OR: 2.04 [95% CI: 1.32-3.16]), and bronchopulmonary dysplasia (OR: 1.74 [95% CI: 1.24-2.43]). EOS was associated with an increased risk of death and/or severe neurologic morbidity (OR: 2.92 [95% CI: 2.27-3.80])., Conclusions: Although only 2.4% of VLBW infants had an episode of EOS, these infants were at an approximately threefold excess risk of death or major neurologic morbidities.

Background: Neonatal limb reduction defects may be caused by exposure to an external agent. The azole derivatives are used in the treatment of systemic and dermal mycoses. Their relative teratogenic risk is still controversial., Cases: We describe two newborns with severe limb defects who were exposed to high doses of oral (an unacceptable route) and/or intravaginal bifonazole during the entire first trimester of pregnancy., Conclusion: Although only two cases are insufficient to establish a relationship, our data suggest that maternal intake of bifonazole in early pregnancy poses a risk of morphogenic malformations. The literature suggests several possible mechanisms., (Copyright 2009 Wiley-Liss, Inc.)

In rare cases, severe fetal vitamin K deficiency bleeding may occur in utero as a result of insufficient vitamin K placental transfer. We present a case of a 32-week-preterm infant born with severe intracranial hemorrhage to a pregnant woman who suffered from hyperemesis gravidarum. Neonatal hematologic status was compatible with vitamin K deficiency whereas the maternal coagulation function was normal. This case emphasizes the potential risk of fetal bleeding owing to vitamin K deficiency in pregnancies complicated with hyperemesis gravidarum. These women should be closely monitored and vitamin K prophylaxis might be considered.

Here, we tested the matrilin-3-dependent induction of osteoarthritis-associated genes in primary human chondrocytes. Matrilin stimulation leads to the induction of MMP1, MMP3, MMP13, COX-2, iNOS, IL-1beta, TNFalpha, IL-6 and IL-8. Furthermore, we show the participation of ADAMTS4 and ADAMTS5 in the in vitro degradation of matrilin-3. We provide evidence for a matrilin-3-dependent feed-forward mechanism of matrix degradation, whereby proteolytically-released matrilin-3 induces pro-inflammatory cytokines as well as ADAMTS4 and -5 indirectly via IL-1beta. ADAMTS4 and ADAMTS5, in turn, cleave matrilin-3 and may release more matrilin-3 from the matrix, which could lead to further release of pro-inflammatory cytokines and proteases in cartilage.

Background: Selective serotonin reuptake inhibitors (SSRIs) have been suspected of cardiac teratogenicity, but reports have been inconsistent. Our aim was to investigate the rate of nonsyndromic congenital heart defects in newborns exposed in utero to SSRIs compared with unexposed controls., Methods: This prospective study of women who gave birth at our tertiary center from 2000 to 2007 yielded 235 women who reported first-trimester SSRI use during pregnancy. All newborns born during the study period and found to have a persistent cardiac murmur on day 2 or 3 of life were referred for examination by a pediatric cardiologist and by echocardiography. The findings were compared between the newborns who were exposed to SSRIs and those who were not., Results: Nonsyndromic congenital heart defects were identified by echocardiography in 8 of 235 (3.40%) newborns exposed in utero to SSRIs and in 1083 of 67,636 (1.60%) non-exposed newborns. The difference in prevalence between the two groups was significant (relative risk, 2.17; 95% confidence interval, 1.07-4.39). The prevalence rates for paroxetine and fluoxetine exposure were 4.3% and 3.0%, respectively. All cardiac defects in the study group were mild: ventricular septal defect (6), bicuspid aortic valve (1) and right superior vena cava to coronary sinus (1)., Conclusions: Newborns exposed in utero to SSRIs, have a twofold higher risk of mild nonsyndromic heart defects than unexposed infants. The data suggest that women who require SSRI treatment during pregnancy can be reassured that the fetal risk is low and possible cardiac malformations will probably be mild. Late-targeted ultrasound and fetal echocardiography at 22 to 23 weeks' gestation are recommended in this patient group.

Differentiation of bacterial from aseptic meningitis may be difficult. Our aim was to determine the pattern of distribution of lactate dehydrogenase (LDH) isoenzymes in the cerebrospinal fluid (CSF) of patients with bacterial and aseptic meningitis. One hundred and fifty-seven patients with suspected meningitis were enrolled in the study. They were divided into 3 groups according to the culture- or bacterial antigen assay-proven diagnosis and CSF findings: bacterial meningitis (n = 31), aseptic meningitis (n = 65), and non-meningitis (n = 61). Total LDH level and percentages of LDH isoenzymes in the CSF were measured in each patient. Each group showed a distinct LDH isoenzyme distribution pattern, with a statistically significant difference among the groups in the percentages of the various isoenzymes. Compared with the non-meningitis group, total LDH activity in the CSF was high in the aseptic meningitis group (49.82+/-35.59 U/L, P < 0.001) and exaggerated in the bacterial meningitis group (944.53+/-112.3 U/L, P < 0.001). Low LDH-2 levels were unique to bacterial meningitis (P < 0.01), whereas high LDH-3 levels were characteristic of aseptic meningitis (P < 0.05). Both groups had low levels of LDH-1 and high levels of LDH-4 and LDH-5. In conclusion, the LDH isoenzyme pattern may be of clinical diagnostic value in meningitis, particularly when culture results are pending.

Objective: To estimate the effect of gestational age on short-term neonatal morbidity in cases of spontaneous, low-risk singleton late preterm deliveries and to identify predictors of adverse neonatal outcome., Methods: This was a retrospective study of all spontaneous, low-risk late preterm deliveries (34 0/7 to 36 6/7 weeks of gestation) during the years 1997 to 2006 (n=2,478). Multiple gestations and pregnancies complicated by preterm premature rupture of membranes (PROM) or maternal or fetal complications were excluded. Short-term neonatal outcome was compared with a control group of full-term deliveries in a 3:1 ratio (n=7,434). Logistic regression analysis was used to identify risk factors for neonatal morbidity among late preterm infants., Results: Compared with full-term infants, spontaneous late preterm delivery was independently associated with an increased risk of neonatal morbidity, including respiratory distress syndrome (4.2% compared with 0.1%, P<.001), sepsis (0.4% compared with 0.04%, P<.001), intraventricular hemorrhage (0.2% compared with 0.02%, P<.001), hypoglycemia (6.8% compared with 0.4%, P<.001), and jaundice requiring phototherapy (18% compared with 2.5%, P<.001). Cesarean delivery (odds ratio [OR] 2.1, 95% confidence interval [CI] 1.6-2.6), male sex (OR 1.4, 95% CI 1.1-1.8), and multiparity (OR 2.2, 95% CI 1.7-2.8) were independent risk factors for neonatal respiratory morbidity in cases of late preterm deliveries. The relationship between gestational age and neonatal morbidity was of continuous nature with a nadir at about 39 weeks rather than a term-preterm threshold phenomenon and was unrelated to birth weight., Conclusion: Late prematurity is associated with significant neonatal morbidity in cases of spontaneous low-risk singleton deliveries. This information is important for appropriate counseling and should stimulate efforts to decrease the rate of late preterm deliveries., Level of Evidence: II.

Objective: The purpose of this study was to determine the incidence, causative pathogens, and risk factors for early onset sepsis (EOS) among very-low-birthweight (VLBW) infants., Study Design: This was a population based observational study. Data were prospectively collected by the Israel Neonatal Network between 1995 and 2005. Multivariable analyses identified independent risk factors for EOS., Results: EOS developed in 383 of 15,839 infants (2.42%). Fifty-five percent of pathogens isolated were gram-negative bacteria. Lack of prenatal care (odds ratio [OR], 1.94; 95% confidence interval [CI], 1.32-2.86), delivery room resuscitation (OR, 2.49; 95% CI, 1.91-3.24), membrane rupture > 24 hours without amnionitis (OR, 2.10; 95% CI, 1.53-2.88), amnionitis with membrane rupture < 24 hours (OR, 4.28; 95% CI, 2.97-6.16), and amnionitis with membrane rupture >or= 24 hours (OR, 8.15; 95% CI, 5.98-11.10) were associated with EOS, but not antenatal steroids or gestational age., Conclusion: EOS was caused mainly by gram-negative bacteria. Prolonged rupture of membranes and amnionitis have an additive effect on EOS with an above 8-fold excess risk when both were present.

Mycophenolate mofetil (MFM) is an immunosuppressant agent used in organ transplantation, rheumatoid arthritis and lupus nephritis. Experimental data show that doses roughly equivalent to those used clinically in transplant patients may cause fetal resorption and malformations in pregnant rats and rabbits. There are limited data regarding the use of MFM in pregnant women. The human experience is based on 9 case reports, 1 case series, and 2 registry data. The most frequent structural anomalies described in 12 newborns exposed to MFM were as follows: microtia (11); auditory canal atresia (8); cleft lip and palate (6); micrognathia (4); hypertelorism (4); ocular coloboma (3); short fingers (2) and hypoplasic nails (2). The distinctive and unique phenotype associated with MFM exposure during pregnancy (EMFO tetrada: Ear, Mouth, Fingers, Ocular/Organ malformation) raised the hypothesis that MFM may be a real teratogenic drug. Appropriate recommendations to prevent this possible new embryopathy are given.

Background: Environmental physical activity is known to be associated with many factors of human homeostasis, such as fetal development, birth number, and some genetic abnormalities. This study sought to investigate possible temporal links between the occurrence of congenital heart disease and solar, geomagnetic, and cosmic ray activities., Patients and Methods: The study sample include 79,085 infants born live at a tertiary medical center in central Israel from 1995 to 2005, of whom 1739 were diagnosed with congenital heart disease, including 309 with patent ductus arteriosus (PDA). The number of infants with congenital heart disease (total and excluding PDA) was analyzed against the values of the physical parameters, as derived from international indices, by year of birth and 1 year before and by month of birth and 9 months before. Pearson correlation coefficients and their probabilities were calculated., Results: The number of cases of infantile congenital heart disease over the 132-month study period significantly correlated with solar activity (r=0.5, p<0.0001) and with cosmic ray activity (r=-0.45, p<0.0001). On analysis by year, correlations were as follows: with solar activity 1 year before delivery, r=0.71, p=0.014, n=11, and at time of delivery, r=0.66, p=0.026; with cosmic ray activity, 1 year before delivery, r=-0.66, p=0.03, and at time of delivery, r=-0.61, p=0.047, n=11. The levels of correlation and probability were higher for solar activity indices at conception (9 months or 1 year before delivery) than at birth. Significance was maintained when cases of PDA were excluded., Conclusion: The monthly number of infants born with congenital heart disease is directly correlated with the level of solar activity and inversely correlated with the level of cosmic ray activity during pregnancy, predominantly in the month of conception. The mechanism underlying the possible effect of solar activity on the occurrence of congenital heart disease warrants additional studies.

We deciphered constituent parts of a signal transduction cascade that is initiated by collagen II and results in the release of various pro-inflammatory cytokines, including interleukin-6 (IL-6), in primary human chondrocytes. This cascade represents a feed-forward mechanism whereby cartilage matrix degradation is exacerbated by the mutually inducing effect of released collagen II fragments and pro-inflammatory cytokines. We previously proposed discoidin domain receptor 2 as a central mediator in this event. Since this cascade plays a prominent role in the pathogenesis of osteoarthritis, our study further investigates the hypothesis that discoidin domain receptor 2 is a candidate receptor for collagen II, and that transcription factor NFkappaB, lipid kinase PI3K, and the MAP kinases are constituent parts of this very signal transduction cascade. To accomplish this, we selectively knocked down the molecules of interest in primary human chondrocytes, induced the specified cascade by incubating primary human chondrocytes with collagen II, and observed the outcome, specifically the changes in interleukin-6 release. Knockdown was performed by siRNA-mediated gene silencing in the case of discoidin domain receptor 2 (DDR2) or by using specific inhibitors for the remainder of the molecules. Results indicated that discoidin domain receptor 2 mediates the collagen II-dependent release of interleukin-6 in primary human chondrocytes and that MAP kinases p38, JNK and ERK, as well as transcription factor NFkappaB, are integral components of intracellular collagen II signalling. Given the detrimental role of these molecules in osteoarthritis, our findings provide new targets for more specific therapeutics, which may have fewer side effects than those currently applied.