The Clinical Significance of Extreme Leukocytosis among Newborns: A Retrospective Cohort Study.

OBJECTIVE: The aim of the study is to examine the clinical significance of extreme leukocytosis (>40,000 cells/µL) at birth among neonates. STUDY DESIGN: Data were retrospectively collected on 208 infants with leukocytosis >40,000 cells/µL and on matched normal controls as determined in complete blood counts obtained on the first day of life. RESULTS: There were no significant group differences in birth weight, Apgar's score, timing of respiratory support, hospitalization in special care units or rehospitalization during the first month of life. All neonates with leukocytosis received antibiotics. The blood cultures of both groups were negative. A multivariate analysis showed that leukocytosis did not predict either the presence of symptoms associated with sepsis among neonates or hospitalization in a neonatal special care unit. CONCLUSION: Extreme leukocytosis on the first day of life is a poor predictor of infection. Clinicians should decide upon treatment according to risk factors and symptoms but not according to the degree of leukocytosis. KEY POINTS: · Extreme leukocytosis on the first day of life is a poor predictor of infection.. · Clinicians should decide upon treatment according to risk factors and symptoms.. · Leukocytosis was not predictive of a higher risk of morbidity in neonates..

In-utero treatment of prenatal thoracic abnormalities by thoraco-amniotic shunts, short and long term neuro developmental outcome: A single center experience.

BACKGROUND: Severe primary fetal hydrothorax (PFH) and fetal lung lesions (FLL) such as congenital pulmonary airway malformation (CPAM) and Bronchopulmonary sequestration (BPS) are often treated by thoraco-amniotic shunt (TAS). OBJECTIVES: To compare short and long-term outcome of fetuses treated by TAS due to FLL to those treated due to PFH. METHOD: A retrospective analysis was performed for all fetuses treated by TAS, between the years 2004-2015, evaluating the short and long term neurodevelopmental outcome. Long term neurodevelopment was additionally analyzed prospectively by Vineland adaptive behavioral scale (VABS) standardized questionnaires. RESULTS: 38 fetuses were treated by 52 TAS insertions; of which 13 (35%) due to FLL and 25 due to PFH. Perinatal survival was high (87.9%) with 3 neonatal death and one termination of pregnancy (TOP). High survival rate persisted even in cases requiring recurrent shunt insertion (80% survival). There was no significant difference in short or long term outcome including perinatal survival (84% Vs 90%, P = 0.64) and hydrops resolution (91% Vs 63%, p = 0.19). Long term outcome, including rate of neurodevelopmental abnormalities (23.5% Vs 20%) and VABS score (91.3 ± 13.3 Vs 96.4 ± 14.7), were similar for both groups. CONCLUSION: TAS insertion is effective and resulting in high perinatal survival even in cases when sequential insertion is needed. Short and long- term outcome of neonates with FLL treated by TAS are comparable to neonates treated due to PFH.

Fetal and neonatal brain lesions following laser ablation for twin-to-twin-transfusion-syndrome as detected by pre- and post-natal brain imaging.

OBJECTIVE: To determine the rate of and risk factors for fetal and neonatal brain lesions following laser ablation for twin-to-twin transfusion syndrome (TTTS). METHODS: A retrospective cohort study of 83 women with monochorionic twin pregnancies who underwent ablation for TTTS at a single tertiary hospital. Post-laser survivors were followed-up with fetal neurosonogram every 2 weeks and fetal brain MRI at 28-32 weeks of gestation; post-natal brain imaging included neurosonogram. Cases with pre- and post-natal brain lesions were compared to those without. RESULTS: 153 fetuses survived the immediate post-laser period and underwent brain imaging. Of these, 17 (11.11%) exhibited brain lesions on prenatal imaging studies, and 36 (32.4%) on post-natal ultrasound. Later gestational age (GA) at the time of ablation (23.0 vs. 21.4 weeks, p = 0.0244), post-laser twin-anemia-polycythemia-sequence (TAPS) (29.41% vs. 9.56%, p = 0.035) and birthweight discordancy (30% vs. 9%, p = 0.0025) were associated with prenatal brain lesions. Earlier GA at delivery (31.0 weeks vs. 32.2, p = 0.0002) and post-laser TAPS (25% vs. 9.33%, p = 0.038) were associated with post-natal brain lesions. CONCLUSIONS: Survivors of ablation for TTTS are at risk for brain lesions, which can be detected prenatally. Incorporation of neurosonogram and fetal brain MRI into the routine surveillance of such pregnancies should be considered.

ASL expression in ALDH1A1+ neurons in the substantia nigra metabolically contributes to neurodegenerative phenotype.

Argininosuccinate lyase (ASL) is essential for the NO-dependent regulation of tyrosine hydroxylase (TH) and thus for catecholamine production. Using a conditional mouse model with loss of ASL in catecholamine neurons, we demonstrate that ASL is expressed in dopaminergic neurons in the substantia nigra pars compacta, including the ALDH1A1 + subpopulation that is pivotal for the pathogenesis of Parkinson disease (PD). Neuronal loss of ASL results in catecholamine deficiency, in accumulation and formation of tyrosine aggregates, in elevation of α-synuclein, and phenotypically in motor and cognitive deficits. NO supplementation rescues the formation of aggregates as well as the motor deficiencies. Our data point to a potential metabolic link between accumulations of tyrosine and seeding of pathological aggregates in neurons as initiators for the pathological processes involved in neurodegeneration. Hence, interventions in tyrosine metabolism via regulation of NO levels may be therapeutic beneficial for the treatment of catecholamine-related neurodegenerative disorders.

Which Patient in the Neonatal Intensive Care Unit should Receive Antifungal Prophylaxis Therapy?

BACKGROUND: Extremely preterm infants are at high risk for mortality and morbidity including neurodevelopmental impairment from invasive Candida infections. Prophylactic antifungal therapy has been shown to reduce both colonization and invasive candidemia in high-risk preterm infants. Prophylactic treatment should be started in the first 48 to 72 hours after birth to extremely low birth weight (ELBW) infants (weighing ≤ 1000 grams at birth) or below 27 weeks gestation age with risk factors, or in any NICU with moderate (5-10%) or high (≥ 10%) rates of invasive candidiasis. Studies demonstrated the benefits of fluconazole prophylaxis regarding its safety of the short-term and long-term without the development of fungal resistance. Empiric antifungal therapy may lower mortality and improve outcomes.

Retinopathy of prematurity in discordant twins: is the small twin at increased risk?

PURPOSE: To examine the effect of birth weight (BW) independent of gestational age (GA) on Retinopathy of prematurity (ROP) in preterm discordant twins. METHODS: A retrospective cohort study of 45 preterm twin pairs born at < 34 weeks of gestation with BW discordance of ≥ 20%. The twin pairs were divided into two groups based on BW - small or large. Rates of ROP, stage, treatment, and prognosis were compared between the two groups. Other neonatal outcomes related to prematurity were also compared between groups. RESULTS: The mean gestation age at delivery was 31.1 weeks of gestation. The rate of ROP was significantly higher among the smaller twins compared to the larger twins (8.9% vs 0% respectively, p = 0.04). All smaller twins with ROP had stage 2 disease, and all cases of ROP had resolved without treatment. Regarding neonatal morbidities, the smaller twins had longer hospitalization length (53.8 vs 39.4 days respectively, p < 0.01) and a higher rate of hypoglycemia (55.6% vs 24.4% respectively, p = 0.003), whereas the larger twins were more commonly affected by respiratory distress syndrome (59.1% vs 26.7% respectively, p = 0.002). CONCLUSION: The rate of ROP was higher among the small twins in preterm discordant twins. This may indicate that low BW rather than early GA is the main factor contributing to the development of ROP.

ASL Metabolically Regulates Tyrosine Hydroxylase in the Nucleus Locus Coeruleus.

Patients with germline mutations in the urea-cycle enzyme argininosuccinate lyase (ASL) are at risk for developing neurobehavioral and cognitive deficits. We find that ASL is prominently expressed in the nucleus locus coeruleus (LC), the central source of norepinephrine. Using natural history data, we show that individuals with ASL deficiency are at risk for developing attention deficits. By generating LC-ASL-conditional knockout (cKO) mice, we further demonstrate altered response to stressful stimuli with increased seizure reactivity in LC-ASL-cKO mice. Depletion of ASL in LC neurons leads to reduced amount and activity of tyrosine hydroxylase (TH) and to decreased catecholamines synthesis, due to decreased nitric oxide (NO) signaling. NO donors normalize catecholamine levels in the LC, seizure sensitivity, and the stress response in LC-ASL-cKO mice. Our data emphasize ASL importance for the metabolic regulation of LC function with translational relevance for ASL deficiency (ASLD) patients as well as for LC-related pathologies.

Short-Term Neonatal Outcome among Term Infants after In-Utero Exposure to Beta Blockers.

BACKGROUND: The need for postnatal monitoring of infants exposed to intrauterine beta blockers (BBs) has not been clearly defined. OBJECTIVES: To evaluate infants exposed to intrauterine BBs in order to estimate the need for postnatal monitoring. METHODS: This retrospective case-control study comprised 153 term infants born to mothers who had been treated with BBs during pregnancy. Treatment indications included hypertension 76 mothers (49.7%), cardiac arrhythmias 48 (31.4%), rheumatic heart disease 14 (9.1%), cardiomyopathy 11 (7.2%) and migraine 4 (2.6%). The controls were infants of mothers with hypertension not exposed to BBs who were born at the same gestational age and born closest (before or after) to the matched infant in the study group. RESULTS: Compared to the control group, the infants in the study group had a higher prevalence of early asymptomatic hypoglycemia (study 30.7% vs. control 18.3%, P = 0.016), short symptomatic bradycardia events, other cardiac manifestations (P = 0.016), and longer hospitalization (P < 0.001). No life-threatening medical conditions were documented. The birth weight was significantly lower for the high-dose subgroup compared to the low-dose subgroup (P = 0.03), and the high-dose subgroup had a higher incidence of small-for-gestational-age (P = 0.02). CONCLUSIONS: No alarming or life-threatening medical conditions were observed among term infants born to BB treated mothers. These infants can be safely observed for 48 hours after birth close to their mothers in the maternity ward. Glucose follow-up is needed, especially in the first hours of life.

"Golden Hour" quality improvement intervention and short-term outcome among preterm infants.

OBJECTIVE: To evaluate the impact of a quality improvement intervention during the first hour of life ("Golden Hour") on short-term preterm neonatal outcome. STUDY DESIGN: A comprehensive protocol designed for initial stabilization and treatment of preterm infants that included cord blood sampling, use of a dedicated resuscitation room and improved team communication using Crew Resource Management tools. The infants admitted before and after implementation of the protocol were retrospectively compared in a matched case-control design. RESULTS: There were 194 infants in the intervention group and 194 controls. Admission temperatures improved significantly from a mean of 35.26 °C to 36.26 °C (P < 0.001), and late-onset sepsis and bronchopulmonary dysplasia rates lowered significantly (P = 0.035 and P = 0.028, respectively) in the intervention group. There was trend towards reduction in early blood transfusion and ventilation duration. CONCLUSIONS: A "Golden Hour" quality improvement intervention was of significant benefit for preterm neonates. Further follow-up to assess long-term effects is warranted.

Internal and External Resources and the Adjustment of Parents of Premature Infants.

Studies have shown premature birth and infant hospitalization to be associated with increased levels of parental distress. Internal and external psychological resources have been found to mitigate distress among persons coping with stressful medical events. The current study evaluated psychological resources and distress in 87 parents (57 mothers and 30 fathers) to whom an infant was born prematurely and hospitalized in the NICU of a large tertiary medical center. Parents were administered standardized measures of internal (problem-solving skills) and external (total spousal support, adequacy of spousal support) psychological resources and of psychological distress (depression, posttraumatic symptoms, and mood). Findings indicated that higher levels of problem-solving skills and more adequate spousal support, but not total spousal support, were related to lower levels of parental distress. Adequacy of spousal support and parents' problem-solving skills accounted for 18% of the variance in overall mood and 13.8% of the variance in posttraumatic stress symptoms. A significant two-way interaction was found between adequacy of spousal support and problem-solving skills such that individuals with better problem-solving skills reported better overall mood independent of the adequacy of spousal support they receive. However, for individuals with poor problem-solving skills, the adequacy of the spousal support they receive was a significant factor in determining their overall mood. The theoretical and clinical implications of these findings are discussed in terms of the accessibility of these resources to assessment and their potential for change via existing intervention approaches.

Induction of Nitric-Oxide Metabolism in Enterocytes Alleviates Colitis and Inflammation-Associated Colon Cancer.

Nitric oxide (NO) plays an established role in numerous physiological and pathological processes, but the specific cellular sources of NO in disease pathogenesis remain unclear, preventing the implementation of NO-related therapy. Argininosuccinate lyase (ASL) is the only enzyme able to produce arginine, the substrate for NO generation by nitric oxide synthase (NOS) isoforms. Here, we generated cell-specific conditional ASL knockout mice in combination with genetic and chemical colitis models. We demonstrate that NO derived from enterocytes alleviates colitis by decreasing macrophage infiltration and tissue damage, whereas immune cell-derived NO is associated with macrophage activation, resulting in increased severity of inflammation. We find that induction of endogenous NO production by enterocytes with supplements that upregulate ASL expression and complement its substrates results in improved epithelial integrity and alleviation of colitis and of inflammation-associated colon cancer.

Infants Born with Esophageal Atresia with or without Tracheo-Esophageal Fistula: Short- and Long-Term Outcomes.

BACKGROUND: The estimated incidence of esophageal atresia (EA) with or without tracheo-esophageal fistula (TEF) is 1:3500 live births. During childhood these patients have various co-morbidities, but the overall quality of life among adults is similar to that of the general population. OBJECTIVES: To evaluate short- and long-term co-morbidities and quality of life among infants born with EA ± TEF at a large single medical center. METHODS: Medical records of 65 children born over a 21 year period were reviewed for short- and long-term medical data. Telephone interviews were conducted with 46 of their parents regarding medical problems and quality of life after home discharge. RESULTS: The main long-term co-morbidities during the first 2 years of life, 4-6 years of age, and during adolescence (12-16 years) included gastro-esophageal reflux disease (GERD) in 56.5%, 35.8%, and 18.7%, respectively; stridor in 84.8%, 45.2%, and 12.5%, respectively; hyper-reactive airway disease (HRAD) in 43.5%, 35.5%, and 36.5%, respectively; recurrent pneumonia in 43.5%, 32.3%, and 18.8%, respectively; and overall recurrent hospitalizations in 87%, 41.9%, and 25%, respectively. The quality of life was reportedly affected among 100%, 75%, and 33.3% respectively. CONCLUSIONS: Long-term follow-up of patients with EA ± TEF indicates a high burden of co-morbidities during the first 6 years of life, with a gradual decrease in symptoms thereafter. Nevertheless, HRAD continued to impact the daily life of about one-third of the older adolescents, and GERD one-fifth. A long-term multidisciplinary follow-up should be conducted to prevent late onset complications that may affect the quality of life.

Risk factors for brain damage among preterm twins.

AIM: To evaluate the perinatal and postnatal risk factors for various brain pathologies among preterm twins. METHODS: Retrospective data of 104 twin pairs of which one of the siblings had evidence of abnormal head ultrasound (HUS) and its co-twin with normal HUS served as control. RESULTS: Abnormal HUS consisted of periventricular echodensities among 69 infants, intraventricular hemorrhage among 28 infants, cystic periventricular leukomalacia among 10 infants, and other parenchymal brain pathologies among 5 infants. Perinatal and postnatal complications were similar between study and controls. Siblings with severe brain pathologies were ventilated for longer time over their co-twins. In 10 out of 11 cases of discordant twins (≥20%) with severe brain pathology, the severe pathology was recorded in the larger sibling. CONCLUSIONS: Our study results, which included matched preterm twin pairs for study/control groups to evaluate risk factors for the overall evidence of brain injury, could not determine specific risk factors for these brain pathologies. The finding that severe brain pathologies were more common among the larger co-twin requires further study of and attention to short- and long-term outcomes and the potential conflicts that may arise.

Does antenatal steroids treatment prior to elective cesarean section at 34-37 weeks of gestation reduce neonatal morbidity? Evidence from a case control study.

OBJECTIVE: To determine whether antenatal corticosteroids administration prior to an elective cesarean section (ECS) at 34-37 weeks gestation is associated with improved neonatal outcome. MATERIALS AND METHODS: A case control study of women with singleton pregnancies who underwent ECS between 34 and 37 weeks of gestation including two groups: (1) study group in which patients were treated with betamethasone prior to ECS (n = 58) and (2) control group matched for gestational age at delivery in which patients did not receive betamethasone (n = 107). Neonatal measures including respiratory distress syndrome (RDS), transient tachypnea of the newborn (TTN), oxygen requirement, admission to the special care unit, hypoglycemia, hyperbilirubinemia and length of hospitalization were determined in both groups. Composite respiratory morbidity was defined as the presence of either RDS, TTN, mechanical ventilation or oxygen requirement. RESULTS: There was no significant difference in the rate of composite respiratory morbidity nor its components between patients with and without betamethasone treatment (25.9 vs. 25.2%, respectively, p = 0.9). CONCLUSION: Antenatal treatment with corticosteroids prior to ECS at 34-37 weeks of gestation did not result in significant reduction in neonatal respiratory morbidity in our cohort of patients.

Neonatal outcome of late preterm uncomplicated monochorionic twins: what is the optimal time for delivery?

OBJECTIVE: To determine the neonatal outcome at late prematurity of uncomplicated monochorionic (MC) twin pregnancies. METHODS: A retrospective cohort study of 166 patients with uncomplicated MC diamniotic twins delivered between 34 and 37 weeks of gestation at a single tertiary center. The study population was classified into four groups according to the gestational age at delivery: (1) 34 weeks, (2) 35 weeks, (3) 36 weeks and (4) 37 weeks. Neonatal outcome measures were compared between the groups. RESULTS: Neonatal morbidity was significantly higher at 34 weeks of gestation compared to the other three groups including respiratory distress syndrome, oxygen requirement, hypothermia and hyperbilirubinemia. Moreover, the rate of admission to the special care unit and need for phototherapy were significantly higher in newborns born at 36 weeks compared to 37 weeks of gestation (p = 0.02 and 0.03 respectively). Multiple regression analysis revealed that the risk for adverse neonatal outcome was significantly associated with gestational age at delivery. Of note, there were no fetal or neonatal deaths in our cohort. CONCLUSIONS: The risk of neonatal morbidity of uncomplicated MC twins delivered at 34-37 weeks of gestation significantly decreases with advanced gestation. Therefore, under close fetal surveillance, uncomplicated MC twin pregnancies should be delivered at 37 weeks of gestation.

Mode of delivery of twin gestation with very low birthweight: is vaginal delivery safe?

OBJECTIVE: The purpose of this study was to determine whether planned vaginal delivery is associated with increased risk of perinatal death and morbidity in twin pregnancies that are complicated by a very low birthweight of the second twin. STUDY DESIGN: We conducted a retrospective cohort study of twin pregnancies in which the second twin's birthweight was ≤1500 g. One hundred ninety-three twin gestations met the study criteria; patients were classified into 2 groups according to the planned mode of delivery: (1) cesarean delivery (n = 142) and (2) vaginal delivery (n = 51). In the vaginal delivery group, 21 pairs were in cephalic-cephalic presentation at the time of delivery; 28 pairs were cephalic-noncephalic, and 2 pairs were noncephalic-noncephalic. Composite adverse neonatal outcome was defined as the presence of neonatal death, respiratory distress syndrome, sepsis, necrotizing enterocolitis, or intraventricular hemorrhage grade 3-4. RESULTS: Trial of vaginal delivery was successful for both twins in 90.5% of cephalic-cephalic twins and 96.4% in cephalic-noncephalic twins. The rate of intraventricular hemorrhage was significantly higher in the vaginal delivery group (29.4% vs 8.5%, respectively; P = .013; adjusted odds ratio [OR], 3.65; 95% confidence interval [CI], 1.32-10.1). The increased risk of intraventricular hemorrhage in the vaginal delivery groups was evident in both twin A (17.6% vs 7.0%; P = .029) and twin B (15.7% vs 4.9%; P = .014); however, these differences were not significant after adjustment for possible confounders (twin A: adjusted OR, 1.79; 95% CI, 0.58-5.55; twin B: adjusted OR, 2.13; 95% CI, 0.63-7.25). In addition, subgroup analysis revealed that both cephalic-cephalic and cephalic-noncephalic twins who were delivered vaginally had increased risk for intraventricular hemorrhage. There were no significant differences between the cesarean and vaginal delivery groups in the rates of Apgar score <7 at 5 minutes, arterial cord pH <7.1, composite adverse neonatal outcome, and neonatal mortality rate. However, the rate of respiratory distress syndrome was significantly lower in the vaginal delivery group (66.7% vs 69%; P = .042; OR, 0.34; 95% CI, 0.12-0.96). CONCLUSION: Vaginal delivery of very low birthweight twins is associated with an increased risk of intraventricular hemorrhage, regardless of presentation. Because of the small sample size and the retrospective cohort design, large prospective randomized studies are needed.

Growth parameters of discordant preterm twins during the first year of life.

OBJECTIVE: To evaluate and compare growth parameters (weight, length and head circumference) of discordant preterm twins during the first year of life. METHODS: Retrospective data were collected on 78 pairs of >10% discordant preterm twins. Data regarding short-term neonatal outcome were recorded. Growth parameters were recorded at birth and again at 1 year of age, as collected by phone interview. RESULTS: At 1 year of age, the gap was significantly reduced between the group of smaller twins and the group of larger twins on all the parameters studied. Discordance in weight decreased from a mean of 22% at birth (calculated from the weight of the larger twin) to 8.9%, in length from 6.5% to 2.5% and in head circumference from 5.5% to 1.3% at 1 year of age. While length and head circumference (HC) z-scores improved in both the large and the small siblings, weight z-score decreased significantly among the large twins and decreased mildly among the small twins. CONCLUSIONS: The gaps in growth parameters between the smaller twins of preterm discordant twins and their larger siblings are significantly reduced during the first year of life. The impact of the differential growth patterns between the two siblings should be further evaluated.

Delivery room breastfeeding for prevention of hypoglycaemia in infants of diabetic mothers.

OBJECTIVE: To evaluate the effect of duration of early breastfeeding in the delivery room on blood glucose levels among term neonates of diabetic mothers. METHODS: Mothers with gestational diabetes were encouraged to breastfeed their infants immediately after birth in the delivery room. The breastfeeding duration was recorded by the midwife. RESULTS: The longer duration of breastfeeding subgroup (n = 39) demonstrated a lower rate of hypoglycaemia in the first 8 hours of life (< 40 mg/dl) compared to the shorter duration subgroup (n = 40), but this difference did not reach statistical significance (2.6% vs. 17.5% respectively, p = 0.057). Hypoglycaemia was mainly predicted by lower cord glucose for each decrease of 10 mg/dl (OR 2.11 [CI 1.1-4.03] p = 0.024. CONCLUSION: Longer duration of delivery room breastfeeding did not reduce the rate of hypoglycaemia, which was mainly influenced by lower cord blood glucose level.

Should patients with documented fetal lung immaturity after 34 weeks of gestation be treated with steroids?

OBJECTIVE: The purpose of this study was to determine whether corticosteroid administration after 34 weeks of gestation is associated with improved neonatal outcome in the presence of fetal lung immaturity. STUDY DESIGN: We conducted a retrospective cohort study of women who underwent amniocentesis to determine fetal lung maturity from 34-37 weeks of gestation. Patients with negative results (167 women) received steroids based on physician preference and were categorized into 2 groups: study group treated with betamethasone (n = 83 women) and control group in which patients did not receive betamethasone therapy (n = 84 women). The 2 groups were compared with respect to neonatal outcomes. Composite neonatal morbidity was defined as the presence of respiratory distress syndrome, transient tachypnea of the newborn infant, or the need for respiratory support. RESULTS: The rate of composite neonatal morbidity was significantly lower among infants who were exposed to steroids compared with the control group (8.4% vs 21%; P = .02). Multiple regression analysis revealed that corticosteroid administration was associated independently with the composite morbidity outcome. CONCLUSION: Antenatal steroid administration after 34 weeks of gestation is associated with improved neonatal outcome and should be considered when fetal lung immaturity is documented.

Ectopic PDX-1 expression directly reprograms human keratinocytes along pancreatic insulin-producing cells fate.

BACKGROUND: Cellular differentiation and lineage commitment have previously been considered irreversible processes. However, recent studies have indicated that differentiated adult cells can be reprogrammed to pluripotency and, in some cases, directly into alternate committed lineages. However, although pluripotent cells can be induced in numerous somatic cell sources, it was thought that inducing alternate committed lineages is primarily only possible in cells of developmentally related tissues. Here, we challenge this view and analyze whether direct adult cell reprogramming to alternate committed lineages can cross the boundaries of distinct developmental germ layers. METHODOLOGY/PRINCIPAL FINDINGS: We ectopically expressed non-integrating pancreatic differentiation factors in ectoderm-derived human keratinocytes to determine whether these factors could directly induce endoderm-derived pancreatic lineage and ß-cell-like function. We found that PDX-1 and to a lesser extent other pancreatic transcription factors, could rapidly and specifically activate pancreatic lineage and ß-cell-like functional characteristics in ectoderm-derived human keratinocytes. Human keratinocytes transdifferentiated along the ß cell lineage produced processed and secreted insulin in response to elevated glucose concentrations. Using irreversible lineage tracing for KRT-5 promoter activity, we present supporting evidence that insulin-positive cells induced by ectopic PDX-1 expression are generated in ectoderm derived keratinocytes. CONCLUSIONS/SIGNIFICANCE: These findings constitute the first demonstration of human ectoderm cells to endoderm derived pancreatic cells transdifferentiation. The study represents a proof of concept which suggests that transcription factors induced reprogramming is wider and more general developmental process than initially considered. These results expanded the arsenal of adult cells that can be used as a cell source for generating functional endocrine pancreatic cells. Directly reprogramming somatic cells into alternate desired tissues has important implications in developing patient-specific, regenerative medicine approaches.