Biomedical subjects

Michael Obladen

Publications and source records attributed to Michael Obladen.

29 records · Page 2Linked to original sources

PubMed2002

Erythropoietin improves synaptic transmission during and following ischemia in rat hippocampal slice cultures.

Erythropoietin (EPO) prevents neuronal damage following ischemic, metabolic, and excitotoxic stress. In this study evoked extracellular field potentials (FP) were used to investigate the effect of EPO on synaptic transmission in hippocampal slice cultures. EPO treated cultured slices (40 units/ml for 48 h) showed significantly increased FP during and following oxygen and glucose deprivation compared with untreated control slices. The addition of the Jak2 inhibitor AG490 (50 microM for 48 h) blocked the EPO effect. These data suggest that EPO improves synaptic transmission during and following ischemia in hippocampal slice cultures.

Animals↗

PubMed2002

Acute neuronal injury after hypoxia is influenced by the reoxygenation mode in juvenile hippocampal slice cultures.

In neonates asphyxia is usually followed by hyperoxia due to resuscitation procedures. In order to study whether hyperoxic reoxygenation might cause additional cell injury we subjected organotypic hippocampal slice cultures of juvenile rats to normoxic or hyperoxic reoxygenation (19 or 85% oxygen, respectively) following hypoxia (3% oxygen) for 30, 60, and 120 min. Cell injury was quantified by lactate dehydrogenase (LDH) release and propidium iodide (PI) fluorescence 1 h after end of the reoxygenation period. In both experimental groups, LDH activity was significantly enhanced by hypoxia as compared to normoxic controls. However, hyperoxic reoxygenation caused a larger increase in LDH activity than normoxic reoxygenation (e.g., by a factor of 1.60 vs. 1.29 following 120 min hypoxia). PI fluorescence increased after hypoxia in all principal cell layers of the hippocampus but again showed a larger enhancement after hyperoxic reoxygenation as compared to normoxic reoxygenation (e.g., by a factor of 3.9 vs. 1.7 for CA1 and 120 min of hypoxia). After normoxic reoxygenation, PI fluorescence intensity was lower in the dentate gyrus as compared to CA1 and CA3, while it reached similar values like CA1 after high oxygen supply. In conclusion, juvenile hippocampal slice cultures subjected to hyperoxic reoxygenation display a greater amount of acute neuronal injury than slice cultures undergoing normoxic reoxygenation.

Age Factors↗

PubMed2002

A comparison of two mortality risk scores for very low birthweight infants: clinical risk index for babies and Berlin score.

OBJECTIVE: To compare the performance of two mortality risk scores for very low birthweight (VLBW) infants. DESIGN AND SETTING: Cohort study in two university-associated neonatal tertiary care units. PATIENTS: . The clinical risk index for babies and the Berlin score were assessed in 343 VLBW infants (below 1500 g) admitted to one center and 257 infants admitted to a second center between 1992 and 1996. An additional 572 VLBW infants admitted at the former center during 1978-1987 and 294 during 1988-1991 were studied for changes in risk-adjusted mortality over time. MEASUREMENTS AND RESULTS: Goodness of fit was excellent for both scores in both centers. Ability of discrimination was similarly high for both scores. The area under the receiver operating characteristic curves for all 600 infants was 0.84 for the clinical risk index for babies, 0.82 for the Berlin score, and 0.77 for birthweight alone. Both scores discriminated less well in the present samples than they did in the populations in which they were developed. Applying the Berlin score in three periods revealed a continuous decrease in risk-adjusted mortality from 1978 to 1996, indicating improvement in neonatal care. CONCLUSIONS: Both scores predicted death in hospital with high accuracy and interhospital reliability. Decreasing mortality in VLBW infants during the past 20 years requires regular reevaluation of existing scoring systems to avoid overestimation of mortality risk.

Berlin↗

PubMed2002

Hypoxia-induced cell death and changes in hypoxia-inducible factor-1 activity in PC12 cells upon exposure to nerve growth factor.

The transcription factor hypoxia-inducible factor-1 (HIF-1) strongly contributes to the expression of adaptive genes under hypoxic conditions. In addition, HIF-1 has been implicated in the regulation of delayed neuronal cell death. Suspension-grown and adherent PC12 cells treated with NGF were used as an experimental model for studying the relationship between hypoxia-induced cell death and activation of HIF-1. Cell damage was assessed by flow cytometry of double-stained (Annexin V and propidiumiodide) cells, and by analysis of the overall death parameters LDH and mitochondrial dehydrogenase. In parallel, cells were transfected with a control and a three-hypoxia-responsive-elements (HRE)-containing vector and HIF-1-driven luciferase activity was determined. Exposure of NGF-treated PC12 cells to hypoxia resulted in a higher cell death rate when compared to untreated controls. PC12 cells exposed for 2 days to NGF exhibited a decrease of HIF-1 activity up to a factor of ten. This decrease may contribute to the enhanced hypoxia-induced cell death via reduced expression of HIF-1alpha-regulated genes responsible for adaptation to hypoxia, like those for glucose transport proteins and enzymes of the glycolytic chain. The decrease in HIF-1 activity and the increase in hypoxia sensitivity may suggest that NGF act as an hierarchically organized signaling molecule.

Animals↗

PubMed2002

Preconceptional factors associated with very low birthweight delivery in East and West Berlin: a case control study.

BACKGROUND: Very low birthweight, i.e. a birthweight < 1500 g, is among the strongest determinants of infant mortality and childhood morbidity. To develop primary prevention approaches to VLBW birth and its sequelae, information is needed on the causes of preterm birth, their personal and social antecedents, and on conditions associated with very low birthweight. Despite the growing body of evidence linking sociodemographic variables with preterm delivery, little is known as to how this may be extrapolated to the risk of very low birthweight. METHODS: In 1992, two years after the German unification, we started to recruit two cohorts of very low birthweight infants and controls in East and West Berlin for a long-term neurodevelopmental study. The present analysis was undertaken to compare potential preconceptional risk factors for very low birthweight delivery in a case-control design including 166 mothers (82 East vs. 84 West Berlin) with very low birthweight delivery and 341 control mothers (166 East vs. 175 West). RESULTS: Multivariate logistic regression analysis was used to assess the effects of various dichotomous parental covariates and their interaction with living in East or West Berlin. After backward variable selection, short maternal school education, maternal unemployment, single-room apartment, smoking, previous preterm delivery, and fetal loss emerged as significant main effect variables, together with living in West Berlin as positive effect modificator for single-mother status. CONCLUSION: Very low birthweight has been differentially associated with obstetrical history and indicators of maternal socioeconomic status in East and West Berlin. The ranking of these risk factors is under the influence of the political framework.

Berlin↗

PubMed2002

Vascular endothelial growth factor and erythropoietin concentrations in cerebrospinal fluid of children with hydrocephalus.

INTRODUCTION: Hypoxia induces transcription of vascular endothelial growth factor (VEGF) and erythropoietin (EPO) genes. We set up the hypothesis that elevated intracranial pressure in patients with hydrocephalus triggers release of VEGF and EPO into cerebrospinal fluid (CSF). METHODS AND RESULTS: VEGF and EPO concentrations, measured in 57 CSF aliquots obtained from infants and children with hydrocephalus undergoing surgery or therapeutic taps, were significantly elevated compared with those in 41 CSF aliquots of sex- and age-matched children undergoing routine diagnostic lumbar puncture for unrelated reasons ( P<0.001 and P=0.015, respectively). In hydrocephalus samples, median (interquartile range) VEGF concentrations were 135 (35-410) pg/ml, and 4 of 57 hydrocephalus samples had a VEGF concentration below the detection limit (1 pg/ml), compared with 38 of 41 control samples. Erythropoietin was undetectable (<0.1 pg/ml) in 34 of 57 hydrocephalus samples and in 34 of 41 controls. CONCLUSION: We conclude that conditions necessitating surgical intervention in hydrocephalus patients result in increased CSF concentrations of VEGF and EPO.

Brain Neoplasms↗

PubMed2002

Early treatment with erythropoietin beta ameliorates anemia and reduces transfusion requirements in infants with birth weights below 1000 g.

OBJECTIVE: To investigate whether recombinant erythropoietin (rhEPO) reduces the need for transfusion in extremely low birth weight (ELBW) infants (birth weight 500-999 g) and to determine the optimal time for treatment. METHODS: In a blinded multicenter trial, 219 ELBW infants were randomized on day 3 to one of 3 groups: early rhEPO group (rhEPO from the first week for 9 weeks, n = 74), late rhEPO group (rhEPO from the fourth week for 6 weeks, n = 74), or control group (no rhEPO, n = 71). All infants received enteral iron (3-9 mg/kg/day) from the first week. The rhEPO beta dose was 750 IU/kg/week. Success was defined as no transfusion and hematocrit levels never below 30%. RESULTS: Success rate was 13% in the early rhEPO group, 11% in the late rhEPO group, and 4% in the control group (P =.026 for early rhEPO versus control group). Median transfusion volume was 0.4 versus 0.5 versus 0.7 mL/kg/day (P =.02) and median donor exposure was 1.0 versus 1.0 versus 2.0 (P =.05) in the early rhEPO group, the late rhEPO group, and the control group, respectively. Infection risk was not increased and weight gain was not delayed with rhEPO beta. CONCLUSION: Early rhEPO beta treatment effectively reduces the need for transfusion in ELBW infants.

Anemia, Neonatal↗

PubMed2002

Complement activation by in vivo neonatal and in vitro extracorporeal membrane oxygenation.

Complment activation during extracorporeal membrane oxygenation (ECMO) in newborns can be caused by both the underlying disease processes and by blood contact with the ECMO circuit. We investigated the relative importance of these mechanisms by measuring C3a, C5a and sC5b-9 before, during and after neonatal ECMO in six consecutive newborn patients using enzyme-linked immunoassay. In addition complement activation during in vitro ECMO with repeated flow of the same blood volume was measured using blood from healthy adult donors. C3a increased significantly in vivo after 1 h (from 1035+/-193 to 1865+/-419 microg/l) and in vitro ECMO (from 314+/-75 to 1962+/-1062 microg/l). C5a increased during ECMO without significant differences between in vivo and in vitro activation. In neonatal patients, sC5b-9 rose faster than in vitro, but the rapid increase was also significant for in vitro experiments (in vivo: from 328+/-63 to 1623+/-387 microg/l after 2 h; and in vitro: from 78+/-32 to 453+/-179 microg/l after 8 h). After this initial peak at 1-2 h, complement activation decreased gradually until 2-3 days after the initiation of ECMO. We conclude that in newborns the rapid activation of the complement system after the start of ECMO is predominantly caused by contact with artificial surfaces rather than the patient's underlying disease.

Complement Activation↗

PubMed2002

Soluble intercellular cell adhesion molecule-1 and L-selectin plasma concentrations and response to surfactant in preterm infants.

OBJECTIVE: To investigate whether plasma concentrations of soluble intercellular cell adhesion molecule (ICAM)-1 and L-selectin at 24 hrs of life are related to good or poor response to exogenous surfactant in preterm infants. DESIGN: Prospective study of markers of inflammation in circulating blood at 24 hrs of life. SETTING: Level III neonatal intensive care unit. PATIENTS: Twenty-nine preterm newborns suffering from severe respiratory distress syndrome (Fio(2) > 0.4) without signs of infection or fetal acidosis, and 17 healthy preterm newborns of similar gestational age serving as controls. INTERVENTIONS: Infants with respiratory distress were treated with natural surfactant at 0.3-5 hrs of life. A response to surfactant, defined as a decrease of Fio(2) >50% within 6 hrs after surfactant, was seen in 21 infants. MEASUREMENTS AND MAIN RESULTS: Soluble ICAM-1 and L-selectin concentrations were determined in plasma samples taken at 24 hrs of age. ICAM-1 was elevated (p <.001) in infants who responded poorly to surfactant (median, 392 ng/mL; range, 58.26-4884.24 ng/mL) compared with good responders (20.52 ng/mL, 2.32-138.58 ng/mL) or controls (21.91 ng/mL, 2.61-65.73 ng/mL), without differences between controls and good responders. L-selectin was lower (p =.004) in surfactant-treated infants (4.45 nmol/L, 2.0-10.4 ng/mL) than in controls (6.0/2.35-10.25 nmol/L) without differences between surfactant good and poor responders. However, infants requiring supplemental oxygen at 36 wks of gestational age had reduced L-selectin at 24 hrs of age (3.2/2.0-3.45 vs. 5.0/2.35-10.4 nmol/L, p =.004), whereas there was no difference in ICAM-1. CONCLUSIONS: In preterm infants with respiratory distress, a poor response to surfactant within 6 hrs of administration is associated with elevated circulating ICAM-1 concentrations at 24 hrs of age. Low plasma L-selectin at 24 hrs of age predicts prolonged requirement for supplemental oxygen.

Journal Article↗

PubMed2002

Severe spinal muscular atrophy variant associated with congenital bone fractures.

Infantile autosomal recessive spinal muscular atrophy (type I) represents a lethal disorder leading to progressive symmetric muscular atrophy of limb and trunk muscles. Ninety-six percent cases of spinal muscular atrophy type I are caused by deletions or mutations in the survival motoneuron gene (SMNI) on chromosome 5q11.2-13.3. However, a number of chromosome 5q-negative patients with additional clinical features (respiratory distress, cerebellar hypoplasia) have been designated in the literature as infantile spinal muscular atrophy plus forms. In addition, the combination of severe spinal muscular atrophy and neurogenic arthrogryposis has been described. We present clinical, molecular, and autopsy findings of a newborn boy presenting with generalized muscular atrophy in combination with congenital bone fractures and extremely thin ribs but without contractures.

Bone and Bones↗

PubMed2002

Fas (CD95/Apo-1)/Fas ligand expression in neonates with pontosubicular neuron necrosis.

Pontosubicular neuron necrosis (PSN) represents an age-specific response to severe hypoxic-ischemic injury occurring in human neonates but not in older children or adults. Histologically, PSN is characterized by acute neuronal death in the pontine nuclei and the hippocampal subiculum bearing the hallmarks of apoptosis. In animal models of hypoxic-ischemic injury, induction of neuronal apoptosis can be triggered by Fas (CD95/Apo-1), a cell surface receptor of the tumor necrosis factor-alpha superfamily, which transduces apoptotic death signals when cross-linked by its natural ligand. Here, we have investigated the expression of Fas/Fas ligand in human autopsy material consisting of 13 PSN cases and 10 age-matched cases without PSN. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling, immunohistochemistry, and double labeling for Fas/Fas ligand and the astrocyte marker glial fibrillary acid protein, the microglia/macrophage specific marker KiM1P, and the neuronal marker NeuN were performed on formalin-fixed brain specimens. Although mainly neurons of both PSN and controls expressed Fas receptor, expression was significantly increased (p = 0.001) in PSN cases in which predominantly degenerating cells with signs of early apoptosis showed Fas expression. In contrast, Fas ligand expression was found mainly on astrocytes and microglial cells. There was no significant difference between cases with and without PSN. We conclude that in the developing human brain, cells expressing the Fas receptor may be susceptible to undergoing apoptosis in response to hypoxic-ischemic injury.

Adult↗