Nahla Zaghloul
- Associate Professor, Pediatrics - (Clinical Scholar Track)
- Member of the Graduate Faculty
Contact
- (520) 626-3858
- Arizona Health Sciences Center, Rm. 4341B
- Tucson, AZ 85724
- nzaghloul@arizona.edu
Degrees
- M.D.
- University of Cairo, Cairo, Egypt
Awards
- Arizona Health Sciences Center Career Development Award
- UAHS, Spring 2020
Licensure & Certification
- Arizona medical license (2019)
- ECFMG (2006)
Interests
Research
Neonatal neurology Neonatal brain injury mechanism and treatment
Teaching
Neonatal neurologyPoint of care ultrasound
Courses
2023-24 Courses
-
Advanced Neonatology
PED 840B (Fall 2023)
2022-23 Courses
-
Advanced Neonatology
PED 840B (Fall 2022)
2020-21 Courses
-
Advanced Neonatology
PED 840B (Spring 2021)
Scholarly Contributions
Journals/Publications
- Ahmed, M., Casanova, N. G., Zaghloul, N., Gupta, A., Rodriguez, M., Robbins, I. R., Kempf, C. L., Sun, X., Song, J. H., Hernon, V. R., Sammani, S., Camp, S. M., Moreira, A., Hsu, C. D., & Garcia, J. G. (2023). The eNAMPT/TLR4 inflammatory cascade drives the severity of intra-amniotic inflammation in pregnancy and predicts infant outcomes. Frontiers in physiology, 14, 1129413.More infoIntra-amniotic inflammation (IAI) or chorioamnionitis is a common complication of pregnancy producing significant maternal morbidity/mortality, premature birth and neonatal risk of chronic lung diseases such as bronchopulmonary dysplasia (BPD). We examined eNAMPT (extracellular nicotinamide phosphoribosyltransferase), a critical inflammatory DAMP and TLR4 ligand, as a potential therapeutic target to reduce IAI severity and improve adverse fetal/neonatal outcomes. Blood/tissue samples were examined in: 1) women with histologically-proven chorioamnionitis, 2) very low birth weight (VLBW) neonates, and 3) a preclinical murine pregnancy model of IAI. Groups of pregnant IAI-exposed mice and pups were treated with an eNAMPT-neutralizing mAb. Human placentas from women with histologically-proven chorioamnionitis exhibited dramatic NAMPT expression compared to placentas without chorioamnionitis. Increased expression in whole blood from VLBW neonates (day 5) significantly predicted BPD development. Compared to untreated LPS-challenged murine dams (gestational day 15), pups born to eNAMPT mAb-treated dams (gestational days 15/16) exhibited a > 3-fold improved survival, reduced neonate lung eNAMPT/cytokine levels, and reduced development and severity of BPD and pulmonary hypertension (PH) following postnatal exposure to 100% hyperoxia days 1-14. Genome-wide gene expression studies of maternal uterine and neonatal cardiac tissues corroborated eNAMPT mAb-induced reductions in inflammatory pathway genes. The eNAMPT/TLR4 inflammatory pathway is a highly druggable contributor to IAI pathobiology during pregnancy with the eNAMPT-neutralizing mAb a novel therapeutic strategy to decrease premature delivery and improve short- and long-term neonatal outcomes. eNAMPT blood expression is a potential biomarker for early prediction of chronic lung disease among premature neonates.
- Welfley, H., Kylat, R., Zaghloul, N., Halonen, M., Martinez, F. D., Ahmed, M., & Cusanovich, D. A. (2023). Single-Cell Profiling of Premature Neonate Airways Reveals a Continuum of Myeloid Differentiation. American journal of respiratory cell and molecular biology, 69(6), 689-697.More infoSingle-cell genomic technologies hold great potential to advance our understanding of lung development and disease. A major limitation lies in accessing intact cells from primary lung tissues for profiling human airway health. Sampling methods such as endotracheal aspiration that are compatible with clinical interventions could enable longitudinal studies, the enrollment of large cohorts, and the development of novel diagnostics. To explore single-cell RNA sequencing profiling of the cell types present at birth in the airway lumen of extremely premature neonates (
- Zaghloul, N., Cohen, N. S., Ayasolla, K. R., Li, H. L., Kurepa, D., & Ahmed, M. N. (2023). Galantamine ameliorates hyperoxia-induced brain injury in neonatal mice. Frontiers in neuroscience, 17, 890015.More infoProlonged oxygen therapy in preterm infants often leads to cognitive impairment. Hyperoxia leads to excess free radical production with subsequent neuroinflammation, astrogliosis, microgliosis and apoptosis. We hypothesized that Galantamine, an acetyl choline esterase inhibitor and an FDA approved treatment of Alzheimer's disease, will reduce hyperoxic brain injury in neonatal mice and will improve learning and memory.
- Ahmed, M., Zaghloul, N., Zimmerman, P., Casanova, N. G., Sun, X., Song, J. H., Hernon, V. R., Sammani, S., Rischard, F., Rafikova, O., Rafikov, R., Makino, A., Kempf, C. L., Camp, S. M., Wang, J., Desai, A. A., Lussier, Y., Yuan, J. X., & Garcia, J. G. (2022). Endothelial eNAMPT drives EndMT and preclinical PH: rescue by an eNAMPT-neutralizing mAb. Pulmonary circulation, 11(4), 20458940211059712.More infoPharmacologic interventions to halt/reverse the vascular remodeling and right ventricular dysfunction in pulmonary arterial hypertension (PAH) remains an unmet need. We previously demonstrated extracellular nicotinamide phosphoribosyltransferase (eNAMPT) as a DAMP (damage-associated molecular pattern protein) contributing to PAH pathobiology via TLR4 ligation. We examined the role of endothelial cell (EC)-specific eNAMPT in experimental PH and an eNAMPT-neutralizing mAb as a therapeutic strategy to reverse established PH. Hemodynamic/echocardiographic measurements and tissue analyses were performed in Sprague Dawley rats exposed to 10% hypoxia/Sugen (three weeks) followed by return to normoxia and weekly intraperitoneal delivery of the eNAMPT mAb (1 mg/kg). WT C57BL/6J mice and conditional EC-cNAMPT mice were exposed to 10% hypoxia (three weeks). Biochemical and RNA sequencing studies were performed on rat PH lung tissues and human PAH PBMCs. Hypoxia/Sugen-exposed rats exhibited multiple indices of severe PH (right ventricular systolic pressure, Fulton index), including severe vascular remodeling, compared to control rats. PH severity indices and plasma levels of eNAMPT, IL-6, and TNF- were all significantly attenuated by eNAMPT mAb neutralization. Compared to hypoxia-exposed WT mice, cNAMPT KO mice exhibited significantly reduced PH severity and evidence of EC to mesenchymal transition (EndMT). Finally, biochemical and RNAseq analyses revealed eNAMPT mAb-mediated rectification of dysregulated inflammatory signaling pathways (TLR/NF-κB, MAP kinase, Akt/mTOR) and EndMT in rat PH lung tissues and human PAH PBMCs. These studies underscore EC-derived eNAMPT as a key contributor to PAH pathobiology and support the eNAMPT/TLR4 inflammatory pathway as a highly druggable therapeutic target to reduce PH severity and reverse PAH.
- Zaghloul, N., Oatmen, K., & Camelo-piragua, S. (2022). Novel mutation in the MYH2 gene in a symptomatic neonate with a hereditary myosin myopathy.. Journal of neonatal-perinatal medicine, 15(1), 63-68. doi:10.3233/npm-210780More infoHereditary myosin myopathies are muscle disorders caused by mutations in myosin heavy chain genes. The MYH2 gene encodes the fast 2A skeletal muscle isoform, and mutations manifest as joint contractures, muscle weakness, and external ophthalmoplegia. Muscle biopsy shows decreased type 2A fibers, and vacuoles are sometimes present in adults with progressive disease..This case describes a full term baby boy with hypotonia, dysmorphic features, dysphagia, and aspiration. Whole genome sequencing detected a novel heterozygous variant in the MYH2 gene. Muscle biopsy showed decreased type 2A fibers and vacuoles in myofibers..Hypotonia and dysphagia are common in infants with a MYH2 myopathy. However, dysmorphic features and vacuoles on biopsy have not previous been described in infants with MYH2 myopathies..This case reports an unusual phenotype of a rare neonatal-onset congenital myopathy associated with a novel heterozygous variant in MYH2.
- Bader, M. Y., Zaghloul, N., Repholz, A., Nagy, N., Ahmed, M. N., Thompson, L., & Kylat, R. I. (2021). A Retrospective Review Following the Addition of Clonidine to a Neonatal Abstinence Syndrome Treatment Algorithm. Frontiers in pediatrics, 9, 632836.More infoTo investigate the outcomes associated with the implementation of a neonatal abstinence syndrome (NAS) treatment algorithm utilizing dual therapy with morphine sulfate and clonidine in a level four neonatal intensive care unit (NICU). A cohort of neonates (≥35 weeks gestation) born at an academic tertiary medical center between January 1, 2015 and December 31, 2018 who were diagnosed with NAS were retrospectively evaluated following the implementation of a new NAS treatment algorithm. Neonates were categorized in two groups based on if they were treated pre- or post-implementation of the protocol. The primary efficacy outcome was length of hospital stay. Secondary outcomes included the incidence of adverse drug reactions, length of treatment for NAS, and maximum as well as total cumulative dose of each medication used to treat NAS. The implementation of this NAS treatment algorithm significantly reduced the length of hospital stay (30 days vs. 20 days, = 0.001). In addition, there was a significant decrease in duration of morphine sulfate exposure as well as cumulative dose of morphine required to successfully treat a neonate with NAS in the post-implementation group (26 days vs. 15 days, = 0.002 and 6.9 mg/kg vs. 3.4 mg/kg, = 0.031). Addition of clonidine to morphine sulfate as initial therapy for NAS significantly reduced the cumulative exposure as well as duration of exposure to morphine sulfate compared to morphine monotherapy and decrease length of hospital stay.
- Bhasin, N., Roe, D., Stephens, L., Zaghloul, N., Sola-visner, M., Smith, J., Feldman, H., & Cui, H. (2021). Retrospective Review of Transfusion Practices in a Single Neonatal Intensive Care Unit (NICU) Compared to Recent Transfusion Guidelines. Blood, 138(Supplement 1), 2145-2145. doi:10.1182/blood-2021-154475More infoAbstract Background Platelet and packed red blood cell (pRBC) transfusion practices for preterm infants vary significantly worldwide. Recent randomized trials of preterm infants receiving platelet or pRBC transfusions have not shown any benefit with higher compared to lower transfusion thresholds. In the recent PlaNeT2 study published in January 2019, infants receiving platelets at higher thresholds had significantly higher rates of death and major bleeding. These findings raise concern about transfusing adult platelets into a delicately balanced neonatal hemostatic system with relatively hypofunctional platelets as a potential etiology of this multifactorial outcome. In this retrospective review, we aimed to review transfusion practices and outcomes, including thrombosis, in the neonatal intensive care unit (NICU) at the University of Arizona, Tucson in comparison to the PlaNeT2 study. Methods After Institutional Review Board approval, we reviewed the electronic medical records of all neonates born at < 32 weeks gestation in the NICU or transferred to the NICU within 48 hours of birth between January 1, 2018 and December 31, 2019, corresponding to one year pre- and one year post-publication of the PlaNet2 study. For each patient record reviewed, we collected demographics, reviewed whether transfusions occurred, and documented pre-transfusion hemoglobin, platelet count, international normalized ratio, fibrinogen activity level, and clinical outcomes. We recorded the number of transfusions of each product, clinical central lines placed, and imaging studies performed to detect thrombosis. These data were analyzed using descriptive analysis. Results There were 127 neonates born
- Kurepa, D., Boyar, V., Zaghloul, N., Beachy, J., Zaytseva, A., Teng, D., Cooper, R., Klewer, S., & Amodio, J. (2021). Structured Neonatal Point-of-Care Ultrasound Training Program. American journal of perinatology.More infoPoint-of-care ultrasound (POC US) has been increasingly used by intensive care physicians. Growing use of POC US necessitates defining distinct clinical indications for its application, as well as structured POC US training programs. Homogeneous approach to POC US education combined with rigorous quality assurance should further enable POC US to become standard-of-care clinical tool. This study aimed to present the first, innovative, and structured POC US program in neonatal-perinatal medicine field. In addition, we reviewed the availability of the POC US training programs across different medical specialties.
- Lussier, Y., Desai, A. A., Wang, J., Makino, A., Rafikov, R., Rafikova, O., Rischard, F., Sammani, S., Song, J. H., Sun, X., Casanova, N. G., Zaghloul, N., Ahmed, M., Zimmerman, P., Hernon, V. R., Kempf, C. L., Camp, S. M., Yuan, J. X., & Garcia, J. G. (2021). Endothelial eNAMPT drives EndMT and preclinical PH: rescue by an eNAMPT‐neutralizing mAb. Pulmonary Circulation, 11(4), 1-14. doi:10.1177/20458940211059712
- Rajgarhia, A., Ayasolla, K. R., Zaghloul, N., Lopez Da Re, J. M., Miller, E. J., & Ahmed, M. (2021). Extracellular Superoxide Dismutase (EC-SOD) Regulates Gene Methylation and Cardiac Fibrosis During Chronic Hypoxic Stress. Frontiers in cardiovascular medicine, 8, 669975.More infoChronic hypoxic stress induces epigenetic modifications mainly DNA methylation in cardiac fibroblasts, inactivating tumor suppressor genes (RASSF1A) and activating kinases (ERK1/2) leading to fibroblast proliferation and cardiac fibrosis. The Ras/ERK signaling pathway is an intracellular signal transduction critically involved in fibroblast proliferation. RASSF1A functions through its effect on downstream ERK1/2. The antioxidant enzyme, extracellular superoxide dismutase (EC-SOD), decreases oxidative stress from chronic hypoxia, but its effects on these epigenetic changes have not been fully explored. To test our hypothesis, we used an model: wild-type C57B6 male mice (WT) and transgenic males with an extra copy of human hEC-SOD (TG). The studied animals were housed in hypoxia (10% O) for 21 days. The right ventricular tissue was studied for cardiac fibrosis markers using RT-PCR and Western blot analyses. Primary C57BL6 mouse cardiac fibroblast tissue culture was used to study the model, the downstream effects of RASSF-1 expression and methylation, and its relation to ERK1/2. Our findings showed a significant increase in cardiac fibrosis markers: Collagen 1, alpha smooth muscle actin (ASMA), and SNAIL, in the WT hypoxic animals as compared to the TG hypoxic group ( < 0.05). The expression of DNA methylation enzymes (DNMT 1&3b) was significantly increased in the WT hypoxic mice as compared to the hypoxic TG mice ( < 0.001). RASSF1A expression was significantly lower and ERK1/2 was significantly higher in hypoxia WT compared to the hypoxic TG group ( < 0.05). Use of SiRNA to block RASSF1A gene expression in murine cardiac fibroblast tissue culture led to increased fibroblast proliferation ( < 0.05). Methylation of the RASSF1A promoter region was significantly reduced in the TG hypoxic group compared to the WT hypoxic group (0.59 vs. 0.75, respectively). Based on our findings, we can speculate that EC-SOD significantly attenuates RASSF1A gene methylation and can alleviate cardiac fibrosis induced by hypoxia.
- Ahmed, M., Zaghloul, N., Rajgarhia, A., Ayyasola, K., Re, J. M., & Miller, E. J. (2020). Extracellular Superoxide Dismutase (EC-SOD) Regulates Gene Methylation and Cardiac Fibrosis During Chronic Hypoxic Stress. front cardiovascular medicine. doi:10.21203/rs.3.rs-96228/v1
- Zaghloul, N., Kurepa, D., Bader, M. Y., Nagy, N., & Ahmed, M. N. (2020). Prophylactic inhibition of NF-κB expression in microglia leads to attenuation of hypoxic ischemic injury of the immature brain. Journal of neuroinflammation, 17(1), 365.More infoPeriventricular leukomalacia (PVL), a devastating brain injury affecting premature infants, is the most common cause of cerebral palsy. PVL is caused by hypoxia ischemia (HI) and is characterized by white matter necrotic lesions, microglial activation, upregulation of NF-κB, and neuronal death. The microglia is the main cell involved in PVL pathogenesis. The goal of this study was to investigate the role of microglial NF-κB activity and its prophylactic inhibition in a neonate mouse model of HI.
- Cohen, N., Ahmed, M. N., Goldfischer, R., & Zaghloul, N. (2019). Persistent cloaca and caudal duplication in a monovular twin, a rare case report. International journal of surgery case reports, 60, 137-140.More infoA cloaca occurs when genitourinary tract and bowel converge into a common channel. We report a case of partial caudal duplication, persistent cloaca and vestigial appendage in a monovular female twin infant.
- Li, H. L., Zaghloul, N., Ahmed, I., Omelchenko, A., Firestein, B. L., Huang, H., & Collins, L. (2019). Caffeine inhibits hypoxia-induced nuclear accumulation in HIF-1α and promotes neonatal neuronal survival. Experimental neurology, 317, 66-77.More infoApnea of prematurity (AOP) defined as cessation of breathing for 15-20 s, is commonly seen in preterm infants. Caffeine is widely used to treat AOP due to its safety and effectiveness. Caffeine releases respiratory arrest by competing with adenosine for binding to adenosine A and A receptors (AR and AR). Long before its use in treating AOP, caffeine has been used as a psychostimulant in adult brains. However, the effect of caffeine on developing brains remains unclear. We found that AR proteins for caffeine binding were expressed in the brains of neonatal rodents and preterm infants (26-27 weeks). Neonatal AR proteins colocalized with PSD-95, suggesting its synaptic localization. In contrast, our finding on AR expression in neonatal neurons was restricted to the mRNA level as detected by single cell RT/PCR due to the lack of specific AR antibody. Furthermore, caffeine (200 μM) at a dose twice higher than the clinically relevant dose (36-130 μM) had minor or no effects on several basic neuronal functions, such as neurite outgrowth, synapse formation, expression of AR and transcription of CREB-1 and c-Fos, further supporting the safety of caffeine for clinical use. We found that treatment with CoCl (125 μM), a hypoxia mimetic agent, for 24 h triggered neuronal death and nuclear accumulation of HIF-1α in primary neuronal cultures. Subsequent treatment with caffeine at a concentration of 100 μM alleviated CoCl-induced cell death and prevented nuclear accumulation of HIF-1α. Consistently, caffeine treatment in early postnatal life of neonatal mice (P4-P7) also prevented subsequent hypoxia-induced nuclear increase of HIF-1α. Together, our data support the utility of caffeine in alleviating hypoxia-induced damages in developing neurons.
- Perveen, S., Ayasolla, K., Zagloul, N., Patel, H., Ochani, K., Orner, D., Benveniste, H., Salerno, M., Vaska, P., Zuo, Z., Alabed, Y., Nasim, M., Miller, E. J., & Ahmed, M. (2019). Correction: MIF inhibition enhances pulmonary angiogenesis and lung development in congenital diaphragmatic hernia. Pediatric research, 85(5), 735.More infoIn the original version of this article, the name of the author "Kamesh Ayasolla" was incorrectly given as "Kamesh Ayyasola". This has now been corrected to "Kamesh Ayasolla" in both the PDF and HTML versions of the article.
- Zaghloul, N. (2019). MIF inhibition enhances pulmonary angiogenesis and lung development in congenital diaphragmatic hernia.. Pediatric research.
- Zaghloul, N., Watkins, L., Choi-Rosen, J., Perveen, S., & Kurepa, D. (2019). The superiority of point of care ultrasound in localizing central venous line tip position over time. European journal of pediatrics, 178(2), 173-179.More infoThe primary objective was to study agreement between X-rays and point of care ultrasound (POC-US) in determining central venous line (CVL) tip position. The secondary objective was to examine malposition rates over time using POC-US. Fifty-six neonates were enrolled who had a CVL placed. Initial X-rays and POC-US were obtained. POC-US was performed daily thereafter for the total of 6 days. US video clips were acquired in four standard echocardiographic views: subcostal, four-chamber, and short- and long-axis parasternal views. Gwet's agreement coefficient (AC1) for agreement measured inter-rater reliability of X-rays and POC-US (correct position/malposition). A generalized linear mixed model for binary clustered data estimated malposition rate over time. All analyses were conducted using SAS version 9.4 and Agree Stat. The study included 108 "pairs" of X-rays and POC-US images. Agreement coefficient (AC1), with respect to correct position/malposition of CVL tip, was high AC1 = 0.872 (UVC-AC1 = 0.814, PICC-AC1 = 0.94). Among birth weight (BW) 1500 g, AC1 values were 0.922, 0.774, and 0.873, respectively. CVL tip malposition rate decreased over time.Conclusions: Agreement between POC-US and X-rays for CVL tip position was high, with the highest in BW
- Kurepa, D., Zaghloul, N., Watkins, L., & Liu, J. (2018). Neonatal lung ultrasound exam guidelines. Journal of perinatology : official journal of the California Perinatal Association, 38(1), 11-22.More infoPoint-of-care ultrasound (POC-US) is increasingly used especially in emergency and critical-care medicine. It is focused, quick and does not expose patients to ionizing radiation. It encompasses all organ systems and has well-defined indications. Lung ultrasound (LUS) represents one of the most exciting applications in the field of POC-US. It is particularly important to emphasize the role of LUS in neonatology due to the specific pathology inherent in lung immaturity as well as in the particular sensitivity of neonates to repeated radiation exposure. One of the main barriers to the more extensive use of the ultrasound technology is a lack of efficient and attractive training solutions followed by the structured quality-check assurance. In an effort to help bridge this gap, based on the most current literature, we developed creative and intuitive neonatal LUS algorithms. We hope they can serve as a clinical imaging guidelines and a valuable complement to the history and physical exam.
- Patel, H., Zaghloul, N., Lin, K., Liu, S. F., Miller, E. J., & Ahmed, M. (2017). Hypoxia-induced activation of specific members of the NF-kB family and its relevance to pulmonary vascular remodeling. The international journal of biochemistry & cell biology, 92, 141-147.More infoPulmonary Hypertension (pH) is a chronic progressive disease. Endothelial cells (EC) play a central and critical role in the initiation and progression of pH. The NF-κB family (NF-κB1 (p50/p105), NF-κB2 (p52/p100), RelA (p65), RelB, and C-Rel) regulates a wide array of genes involved in inflammatory responses, cell proliferation, and survival. The involvement of specific NF-κB family members in the pathogenesis of hypoxia-induced pH remains to be determined. The objective of this study was to assess the specific role of individual NF-κB family members in mediating endothelial cell responses to hypoxia and its downstream effect on smooth muscle cell proliferation.
- Zaghloul, N., & Ahmed, M. (2017). Pathophysiology of periventricular leukomalacia: What we learned from animal models. Neural regeneration research, 12(11), 1795-1796.
- Zaghloul, N., Addorisio, M. E., Silverman, H. A., Patel, H. L., Valdés-Ferrer, S. I., Ayasolla, K. R., Lehner, K. R., Olofsson, P. S., Nasim, M., Metz, C. N., Wang, P., Ahmed, M., Chavan, S. S., Diamond, B., Tracey, K. J., & Pavlov, V. A. (2017). Forebrain Cholinergic Dysfunction and Systemic and Brain Inflammation in Murine Sepsis Survivors. Frontiers in immunology, 8, 1673.More infoSepsis, a complex disorder characterized by immune, metabolic, and neurological dysregulation, is the number one killer in the intensive care unit. Mortality remains alarmingly high even in among discharged from the hospital. There is no clear strategy for managing this lethal chronic sepsis illness, which is associated with severe functional disabilities and cognitive deterioration. Providing insight into the underlying pathophysiology is desperately needed to direct new therapeutic approaches. Previous studies have shown that brain cholinergic signaling importantly regulates cognition and inflammation. Here, we studied the relationship between peripheral immunometabolic alterations and brain cholinergic and inflammatory states in mouse survivors of cecal ligation and puncture (CLP)-induced sepsis. Within 6 days, CLP resulted in 50% mortality vs. 100% survival in sham-operated controls. As compared to sham controls, sepsis survivors had significantly lower body weight, higher serum TNF, interleukin (IL)-1β, IL-6, CXCL1, IL-10, and HMGB1 levels, a lower TNF response to LPS challenge, and lower serum insulin, leptin, and plasminogen activator inhibitor-1 levels on day 14. In the basal forebrain of mouse sepsis survivors, the number of cholinergic [choline acetyltransferase (ChAT)-positive] neurons was significantly reduced. In the hippocampus and the cortex of mouse sepsis survivors, the activity of acetylcholinesterase (AChE), the enzyme that degrades acetylcholine, as well as the expression of its encoding gene were significantly increased. In addition, the expression of the gene encoding the M1 muscarinic acetylcholine receptor was decreased in the hippocampus. In parallel with these forebrain cholinergic alterations, microglial activation (in the cortex) and increased and gene expression (in the cortex), and gene expression (in the hippocampus) were observed in mouse sepsis survivors. Furthermore, microglial activation was linked to decreased cortical ChAT protein expression and increased AChE activity. These results reinforce the notion of in sepsis survivors and characterize a previously unrecognized relationship between forebrain cholinergic dysfunction and neuroinflammation in sepsis survivors. This insight is of interest for new therapeutic approaches that focus on brain cholinergic signaling for patients with chronic sepsis illness, a problem with no specific treatment.
- Zaghloul, N., Patel, H., & Ahmed, M. N. (2017). A model of Periventricular Leukomalacia (PVL) in neonate mice with histopathological and neurodevelopmental outcomes mimicking human PVL in neonates. PloS one, 12(4), e0175438.More infoPeriventricular leukomalacia (PVL), a brain injury affecting premature infants is commonly associated with cerebral palsy. PVL results from hypoxia-ischemia (HI) with or without infection and is characterized by white matter necrotic lesions, hypomyelination, microglial activation, astrogliosis, and neuronal death. It is important to study a PVL mouse model that mimics human PVL in symptomatology, anatomic and molecular basis. In our neonate mice model, bilateral carotid arteries were temporary ligated at P5 followed by hypoxic exposure (FiO2 of 8% for 20 min.). At P5 in mice, the white matter is more vulnerable to HI injury than the grey matter. In our PVL model, mice suffer from significant hind limb paresis, incoordination and feeding difficulties. Histologically they present with ventriculomegally, white matter loss, microglial activation and neuronal apoptosis. HI injury increases proinflammtory cytokines, activates NF-kB, activates microglia and causes nitrative stress. All these inflammatory mediators lead to oligodendroglial injury and white matter loss. Neurobehavioral analysis in the PVL mice model at P60 showed that the HI group had a significant decrease in hind limb strength, worsening rotarod testing and worsening performance in the open field test. This new PVL model has great advantages far beyond just mimicking human PVL in clinical features and histopathology. Long term survival, the development of cerebral palsy and the ability of using this model in transgenic animals will increase our understanding of the mechanistic pathways underlying PVL and defining specific targets for the development of suitable therapeutics.
- Hand, I., Zaghloul, N., Barash, L., Parris, R., Aden, U., & Li, H. L. (2016). Timing of Caffeine Therapy and Neonatal Outcomes in Preterm Infants: A Retrospective Study. International journal of pediatrics, 2016, 9478204.More infoBackground. Caffeine is widely used to treat apnea of prematurity. Here, we evaluated the efficacy of early caffeine (1-2 DOL) in decreasing the incidence of adverse neonatal outcomes. Methods. A retrospective cohort was used to compare the neonatal morbidity of 150 preterm neonates with gestational age ≤29 weeks. Infants were divided into 3 groups based on the initiation timing of caffeine therapy; (1) early caffeine (1-2 DOL), (2) late caffeine (3-7 DOL), and (3) very late caffeine (≥8 DOL). Results. The neonatal outcomes of early caffeine were comparable with those of the late caffeine group. Moreover, when comparing the neonatal morbidity of the very late caffeine group with that of the early caffeine group, multivariable logistic regression analyses were performed. We found that the timing of caffeine did not influence the risk of BPD (OR, 0.393; CI, 0.126-1.223; p = 0.107), but birthweight did (OR, 0.996; CI, 0.993-0.999; p = 0.018) in these infants. Conclusion. Neonatal outcomes of preterm infants were comparable whether caffeine was administered early or late in the first 7 DOL. The risk of BPD in infants receiving caffeine after 8 DOL was irrespective of delayed treatment with caffeine. Our results clearly demonstrate the need for further studies before caffeine prophylaxis can be universally recommended.
- Zaghloul, N., Patel, H., Codipilly, C., Marambaud, P., Dewey, S., Frattini, S., Huerta, P. T., Nasim, M., Miller, E. J., & Ahmed, M. (2014). Overexpression of extracellular superoxide dismutase protects against brain injury induced by chronic hypoxia. PloS one, 9(9), e108168.More infoExtracellular superoxide dismutase (EC-SOD) is an isoform of SOD normally found both intra- and extra-cellularly and accounting for most SOD activity in blood vessels. Here we explored the role of EC-SOD in protecting against brain damage induced by chronic hypoxia. EC-SOD Transgenic mice, were exposed to hypoxia (FiO2.1%) for 10 days (H-KI) and compared to transgenic animals housed in room air (RA-KI), wild type animals exposed to hypoxia (H-WT or wild type mice housed in room air (RA-WT). Overall brain metabolism evaluated by positron emission tomography (PET) showed that H-WT mice had significantly higher uptake of 18FDG in the brain particularly the hippocampus, hypothalamus, and cerebellum. H-KI mice had comparable uptake to the RA-KI and RA-WT groups. To investigate the functional state of the hippocampus, electrophysiological techniques in ex vivo hippocampal slices were performed and showed that H-KI had normal synaptic plasticity, whereas H-WT were severely affected. Markers of oxidative stress, GFAP, IBA1, MIF, and pAMPK showed similar values in the H-KI and RA-WT groups, but were significantly increased in the H-WT group. Caspase-3 assay and histopathological studies showed significant apoptosis/cell damage in the H-WT group, but no significant difference in the H-KI group compared to the RA groups. The data suggest that EC-SOD has potential prophylactic and therapeutic roles in diseases with compromised brain oxygenation.
- Ahmed, M. N., Zhang, Y., Codipilly, C., Zaghloul, N., Patel, D., Wolin, M., & Miller, E. J. (2012). Extracellular superoxide dismutase overexpression can reverse the course of hypoxia-induced pulmonary hypertension. Molecular medicine (Cambridge, Mass.), 18, 38-46.More infoHypoxia leads to free radical production, which has a pivotal role in the pathophysiology of pulmonary hypertension (PH). We hypothesized that treatment with extracellular superoxide dismutase (EC-SOD) could ameliorate the development of PH induced by hypoxia. In vitro studies using pulmonary microvascular endothelial cells showed that cells transfected with EC-SOD had significantly less accumulation of xanthine oxidase and reactive oxygen species than nontransfected cells after hypoxia exposure for 24 h. To study the prophylactic role of EC-SOD, adult male wild-type (WT) and transgenic (TG) mice, with lung-specific overexpression of human EC-SOD (hEC-SOD), were exposed to fraction of inspired oxygen (FiO(2)) 10% for 10 d. After exposure, right ventricular systolic pressure (RVSP), right ventricular mass (RV/S + LV), pulmonary vascular wall thickness (PVWT) and pulmonary artery contraction/relaxation were assessed. TG mice were protected against PH compared with WT mice with significantly lower RVSP (23.9 ± 1.24 versus 47.2 ± 3.4), RV/S + LV (0.287 ± 0.015 versus 0.335 ± 0.022) and vascular remodeling, indicated by PVWT (14.324 ± 1.107 versus 18.885 ± 1.529). Functional studies using pulmonary arteries isolated from mice indicated that EC-SOD prevents hypoxia-mediated attenuation of nitric oxide-induced relaxation. Therapeutic potential was assessed by exposing WT mice to FiO(2) 10% for 10 d. Half of the group was transfected with plasmid containing cDNA encoding human EC-SOD. The remaining animals were transfected with empty vector. Both groups were exposed to FiO(2) 10% for a further 10 d. Transfected mice had significantly reduced RVSP (18.97 ± 1.12 versus 41.3 ± 1.5), RV/S + LV (0.293 ± 0.012 versus 0.372 ± 0.014) and PVWT (12.51 ± 0.72 versus 18.98 ± 1.24). On the basis of these findings, we concluded that overexpression of EC-SOD prevents the development of PH and ameliorates established PH.
- Zaghloul, N. (2012). Extracellular superoxide dismutase overexpression can reverse the course of hypoxia-induced pulmonary hypertension.. Molecular medicine.
- Zaghloul, N. (2012). Overexpression of extracellular superoxide dismutase has a protective role against hyperoxia-induced brain injury in neonatal mice.. FEBS.
- Zaghloul, N., Nasim, M., Patel, H., Codipilly, C., Marambaud, P., Dewey, S., Schiffer, W. K., & Ahmed, M. (2012). Overexpression of extracellular superoxide dismutase has a protective role against hyperoxia-induced brain injury in neonatal mice. The FEBS journal, 279(5), 871-81.More infoThere is increasing evidence that hyperoxia, particularly at the time of birth, may result in neurological injury, in particular to the susceptible vasculature of these tissues. This study was aimed at determining whether overexpression of extracellular superoxide dismutase (EC-SOD) is protective against brain injury induced by hyperoxia. Transgenic (TG) mice (with an extra copy of the human extracellular superoxide dismutase gene) and wild-type (WT) neonate mice were exposed to hyperoxia (95% of F(i) o(2) ) for 7 days after birth versus the control group in room air. Brain positron emission tomography (PET) scanning with fludeoxyglucose (FDG) isotope uptake was performed after exposure. To assess apoptosis induced by hyperoxia exposure, caspase 3 ELISA and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining were performed. Quantitative western blot for the following inflammatory markers was performed: glial fibrillary acidic protein, ionized calcium-binding adaptor molecule 1, macrophage-inhibiting factor, and phospho-AMP-activated protein kinase. PET scanning with FDG isotope uptake showed significantly higher uptake in the WT hyperoxia neonate brain group (0.14 ± 0.03) than in both the TG group (0.09 ± 0.01) and the control group (0.08 ± 0.02) (P< 0.05). Histopathological investigation showed more apoptosis and dead neurons in hippocampus and cerebellum brain sections of WT neonate mice after exposure to hyperoxia than in TG mice; this finding was also confirmed by TUNEL staining. The caspase 3 assay confirmed the finding of more apoptosis in WT hyperoxia neonates (0.814 ± 0.112) than in the TG hyperoxic group (0.579 ± 0.144) (P < 0.05); this finding was also confirmed by TUNEL staining. Quantitative western blotting for the inflammatory and metabolic markers showed significantly higher expression in the WT group than in the TG and control groups. Thus, overexpression of EC-SOD in the neonate brain offers significant protection against hyperoxia-induced brain damage.
Proceedings Publications
- Zaghloul, N. (2022). Mapping fetal myeloid differentiation in airway samples from premature neonates with single-cell profiling. In hematology conference.More infoSingle-cell genomic technologies hold great potential to advance our understanding of development and disease. A major limitation lies in isolating intact cells from primary tissues for profiling. Sampling methods compatible with current clinical interventions could enable longitudinal studies, the enrollment of large cohorts, and even the development of novel diagnostics. To explore single-cell RNA-seq (scRNA-seq) profiling of the cell types present at birth in the airway lumen of extremely premature (
- Zaghloul, N., Ahmed, M., Chester, A., McCormack, A., Ayyasola, K., Miller, E., & Yacoub, M. (2020). CD4+ ChAT+ T Cells (ChAT T Cells) as a New Vasodilator. In publication.
Poster Presentations
- Zaghloul, N. (2019, May). An Innovative Neuro-protective Role for Galantamine in a Neonatal Mouse model of white matter injury (WMI). PAS. Baltimore.
- Zaghloul, N. (2019, October). An Innovative Neuro-protective Role for Galantamine in a Neonatal Mouse model of white matter injury (WMI). Society of Neuroscience. chicago.