摘要:

N-Methyl-D-aspartate (NMDA) receptors are a calcium-conducting class of excitatory amino acid receptors that are involved in neuronal development and migration. Certain well known teratogens (e.g.homocysteine, ethanol, and chloroform) that induce congenital neural tube and neural crest defects also have the capacity to act as NMDA receptor antagonists. We hypothesized that teratogenicity was a general property of NMDA receptor antagonists, and that high affinity NMDA receptor antagonists would induce neural tube and neural crest defects. Chicken embryos were given 5, 50, or 500 nmol/d of selected NMDA receptor antagonists for 3 consecutive days during the process of neural tube closure, beginning 4 h after the beginning of incubation. Selected NMDA receptor antagonists represented three classes of antagonists: ion channel blockers, glycine site antagonists, and glutamate site agonists and antagonists. All classes of NMDA receptor antagonists induced embryonic death and congenital defects of the neural crest and neural tube; however, the channel blockers were the most potent teratogens. Dextromethorphan at 500 nmol/embryo/d killed more than half the embryos and induced congenital defects in about one-eighth of the survivors; dextromethorphan was also highly lethal at 50 nmol/embryo/d. Glutamate site NMDA receptor agonists (NMDA and homoquinolinic acid) displayed weak toxicity relative to their known NMDA receptor potency. Taken together, these data indicate that NMDA receptor antagonists, particularly channel blockers, are potent teratogens in the chicken embryo model. Because dextromethorphan is a widely used nonprescription antitussive, its strong teratogeneticity using this model is particularly noteworthy.Abbreviations: MK-801,(5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine;NMDA,N-methyl-D-aspartate;HQ,homoquinolinic acid;CPP,DL-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid;AP5,D-2-amino-5-phosphopentanoic acid

ISSN:0031-3998    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

The effect of creatine (Cr) on the response of the respiratory center to anoxia was analyzed at different postnatal stages in a brainstem slice preparation of mice. Spontaneous rhythmic activity was recorded from hypoglossal rootlets (XII) and from identified neurons within the preBötzinger complex using the whole cell patch clamp technique. The hypoxic response was evaluated in slices from animals (n= 46), which received normal nutrition (controls,n= 16), from litters of animals fed with Cr (2 g/kg/day; nutrition group,n= 8), or after incubating slices for 3 h in Cr (200 μM) (incubation group,n= 22). ATP was measured in slices from controls and Cr-incubated slices which underwent 30-min anoxia. In neonatal animals (P0-5), amplitudes of hypoglossal bursts increased initially during anoxia by 14% in controls and by 41% in Cr-supplemented animals when compared with preanoxic values. Hypoglossal burst duration increased by 3% in controls, but by 18% in the Cr-nutrition group. In brainstem slices, the initial increase of amplitudes changed from 14%(controls) to 59% (Cr incubation) and prolongation of bursts from 3%(controls) to 37% (Cr incubation) compared with preanoxic values. In juvenile controls (P6-13), burst amplitude and duration increased by 12 and 14% during early anoxia when referred to preanoxic values. In slices from Cr-pretreated animals, increases of 48% (amplitude) and 21% (burst duration) occurred. The ATP levels remained constant during a 30-min anoxic period in the Cr-pretreated group compared with a decrease of 44% in slices from controls. Our data suggest that Cr can ameliorate hypoxic energy failure. Further studies will examine the neuroprotective potential in humans.Abbreviations: aCSF,artificial cerebrospinal fluid;Cr,creatine;PCr,phosphocreatine;XII,hypoglossal rootlets;NMDA,N-methyl-D-aspartate;preBÖTc,preBötzinger complex

ISSN:0031-3998    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

The aim of this study is to better understand the relationship between placental pathology and risk of intraventricular hemorrhage (IVH). We address two specific hypotheses.1) Morphologic correlates of pregnancy-induced hypertension (PIH) are associated with a decreased risk of IVH.2) Morphologic correlates of amniotic sac inflammation (ASI) are associated with an increased risk of IVH. Maternal, neonatal, and placental data were analyzed by univariate and multivariate methods in this prospective cohort study of 1095 very low birth weight infants. A cluster analysis model was used to categorize the placental pathologic features into clusters, the two main ones being PIH and ASI. Deliveries were subdivided by the interval between membrane rupture and delivery as an index of preexisting infection (<1 h) and ascending infection (≥1 h). Univariate analysis supports both hypotheses. However, in multivariate models that adjusted for such potential confounders as gestational age, labor, and route of delivery, the only associations that persisted were the increased risk of IVH associated with the presence of chorionic or umbilical vasculitis in infants born within 1 h of membrane rupture. Placental correlates of PIH do not provide additional information about IVH risk independent of the presence of other components of the PIH and ASI clusters, and confounders such as gestational age, labor, and route of delivery. Placental correlates of ASI, specifically the fetal responses of chorionic and umbilical vasculitis to preexisting infection, are associated with an increased risk of IVH independent of confounders. Cytokines may provide the link between placental inflammation and fetal/neonatal brain hemorrhage.Abbreviations: IVH,intraventricular hemorrhage;MDAP,maternal decidual arteriolar pathology;PIH,pregnancy-induced hypertension;ASI,amniotic sac inflammation;OR,odds ratio;CI,confidence interval

ISSN:0031-3998    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Segments of basilar and middle cerebral arteries of eight human preterm and early postnatal infants have been examined using the resistance artery myograph technique for wire-mounted segments and the pressure perfusion arteriograph. Myographmounted segments spontaneously developed tone of varying duration and time course. Perfused segments showed maintained tone levels of approximately 40% of maximum possible constriction when the intraluminal pressure was 60 mm Hg. This level is not different from that found in adult human pial arteries of similar lumen diameter. Indomethacin (10-5M) either initiated tone increase or potentiated existing tone in the isometrically mounted segments. After washout of vasoconstrictors norepinephrine (10-6M) and angiotensin II (10-8M), indomethacin caused a pronounced, long lasting increase in basal tone. Spontaneous tone was reversed by acetylcholine (10-6M), isoproterenol(10-8to 10-5M), histamine (10-8to 10-5M), and papaverine (10-5M). Low levels of tone were increased and higher levels decreased by intraluminal flow. The pressure/diameter curves of these vessels were of similar shape as those of the equivalent size in the adult. It is concluded that intrinsic tone is a prominent feature of these large cerebral arteries, and it is modified by an endogenous indomethacin-sensitive process.Abbreviations: PSS,Physiologic saline solution;PG,prostaglandin

ISSN:0031-3998    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Disturbances in cerebral blood flow (CBF) are a major factor in the etiology and pathogenesis of cerebral damage in the neonate. As most animals are more mature at birth than man, extrapolation from animal studies to the human is questionable. Therefore, we have measured regional CBF (rCBF) in preterm infants. rCBF flow was measured in 12 normotensive and normoxic preterm infants [mean birth weight 915 g (range 550 to 2680 g), mean gestational age 27.7 wk (25 to 32 wk)]. All infants had a normal cerebral ultrasound examination. rCBF was measured using a mobile brain dedicated fast-rotating four-head multidetector system specially designed for neonatal studies. The tracer was99mTc-labeled D,L-hexamethylpropylenamine oxime in a dose of 4 Mbq/kg. rCBF of the subcortical white matter was 0.53(0.48-0.58) of the global CBF. After correction for scattered radiation, the estimate of rCBF to the white matter was reduced to 0.39 (0.36-0.42). The flow to the basal ganglia was 2.33 (2.08-2.59) times the global CBF. After correction for partial volume effect, the cortical flow was higher than the flow to the basal ganglia and highest in the frontotemporal cortex (motor cortex). The flow to the cerebellum was of the same magnitude as the flow to the basal ganglia, but with a significantly higher variation. rCBF in 12 preterm infants showed a flow distribution similar to flow in other newborn mammals. The gray-white matter contrast, however, was greater. This new information, combined with existing data showing low global CBF, suggests that blood flow to the white matter in the preterm human neonate is extremely low.Abbreviations: CBF,cerebral blood flow;rCBF,regional cerebral blood flow;SPECT,single photon emission computer tomography;FWHM,full-width at half-maximum;HMPAO,D,L-hexamethylpropylenamine oxime;ROI,region of interest

ISSN:0031-3998    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Cerebral blood flow (CBF) measurement by near infrared spectroscopy (NIRS) using oxyhemoglobin (Hbo2) as a tracer (CBF-Hbo2) needs rapid changes in arterial oxygen saturation (Sao2) which often cannot be achieved in many sick infants. An alternative method based on the same adaptation of the Fick principle using i.v. injection of the dye indocyanine green (ICG) is described (CBF-ICG). Six mechanically ventilated infants (age 26-38 wk, birth weight 0.885-3.730 kg) requiring supplementary oxygen therapy were studied within 72 h of birth. For CBF-ICG measurements, ICG (0.1 mg·kg-1was injected via an umbilical venous catheter, and blood ICG concentration was measured by an optical umbilical artery catheter and brain ICG concentration was measured by NIRS. For CBF-HbO2measurements the inspired oxygen concentration was rapidly increased, blood Hbo2concentration was calculated from Sao2measured by pulse oximetry, and brain Hbo2concentration was measured by NIRS. A series of CBF measurements were performed using each method before and after altering the arterial carbon dioxide tension (Paco2). Mean CBF values from repeated measurements by each method at any given Paco2were used to compare the methods. The SD of single measurements within an individual subject by CBF-ICG was 15%, and by CBF-HbO2, 24%. The relationship between the methods was mean CBF-ICG = (1.13. mean CBF-HbO2) - 2.76 mL·100 g-1·min-1Hbo2(r= 0.93,p< 0.001). The mean difference between the methods (CBF-ICG - CBF-Hbo2) was -0.25 mL·100 g-1·min-1(95% confidence interval 6.30 to -6.80). The methods were in good agreement, and the use of i.v. ICG permitted rapid and repeated CBF measurements in the sickest infants at greatest risk of cerebral injury.Abbreviations: CBF,cerebral blood flow;Hb,deoxyhemoglobin;Hbo2,oxyhemoglobin;ICG,indocyanine green;CBF-ICG,CBF measured using ICG;CBF-Hbo2,CBF measured using Hbo2;CI,confidence interval;NIRS,near infrared spectroscopy;Paco2,arterial carbon dioxide tension;Sao2,arterial oxygen saturation.

ISSN:0031-3998    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

We have previously shown the presence of erythropoietin (Epo) within the spinal fluid of normal preterm and term infants, and the presence of Epo receptor (Epo-R) in the spinal cords of human fetuses. It is not known, however:1) whether cells within the fetal central nervous system(CNS) express Epo;2) if so, whether this expression changes with development;3) which cells within the CNS express Epo-R;4) whether Epo-R expression within the CNS changes with development; and5) whether Epo-R within the fetal CNS are functional. Expression of mRNA for Epo and Epo-R was sought by reverse transcription-PCR in mixed primary cultures of fetal spinal cords as well as NT2 and hNT cells, human cell lines of neuronal precursors and mature neurons, respectively. Epo was measured by ELISA in spent media from primary cell culture, and immunohistochemistry was used to identify Epo-R on neurons and glia in cell culture, and in brain sections. Developmental changes in Epo and Epo-R expression were sought in spinal cords and brains from fetuses of 7-24 wk postconception by semiquantitative PCR. To assess Epo-R function, NT2 cells were exposed to conditions which stimulate programmed cell death, and rescue from apoptosis by the addition of recombinant Epo was evaluated by nuclear matrix protein ELISA, cell counts, and by Klenow labeling of DNA fragments. Epo and Epo-R mRNA were expressed in mixed primary cultures of neural tissues and NT2 and hNT cells. Epo was detected by ELISA in media removed from mixed cell cultures, and immunohistochemical staining confirmed the presence of Epo-R on neurons and their supporting cells. Semiquantitative PCR revealed no significant change in expression of either Epo or Epo-R in spinal cords between 7 and 16 wk of gestation, with increased expression of Epo and Epo-R in brains from 8 to 24 wk of gestation. Epo mRNA expression from neurons doubled under conditions of hypoxia. Recombinant Epo decreased apoptotic cell death of neurons under conditions of hypoxia. Protein and mRNA for Epo and its receptor are expressed by human neurons and glial cells in spinal cord and brain during fetal development. These receptors appear to have a neuroprotective effect in conditions of hypoxia.Abbreviations: ARA-C,cytosine β-D-arabino furanoside;CNS,central nervous system;DMEM,Delbecco's modified Eagle's medium;Epo,erythropoietin;Epo-R,erythropoietin receptor;rEpo,recombinant erythropoietin;FBS,fetal bovine serum;GFAP,glial fibrillary acidic protein antibody;MAP,microtubule-associated protein;RT,reverse transcription

ISSN:0031-3998    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Fetal head compression during labor may increase intracranial pressure(ICP) and decrease cerebral perfusion pressure (CPP). An increase in mean arterial pressure (MAP) associated with the Cushing response normally acts to mitigate an ischemic insult when the increase in ICP approaches MAP. However, the premature fetus may be limited in its ability to increase MAP. We compared the efficacy of the pressor response in sustaining CPP, cerebral blood flow(CBF), and cerebral O2consumption (CMRo2) in chronically catheterized fetal sheep at 0.6 gestation (92 d;n= 7) and 0.9 gestation (133 d;n= 7). When fetal ICP was increased to baseline MAP (41 ± 3 mm Hg; ±SEM) in 92-d fetuses, MAP increased by 7± 2 mm Hg and remained stable during 30 min of constant ICP elevation; CBF decreased by 72% and CMRo2decreased by 46%. In 133-d fetuses, MAP increased from 53 ± 2 to 65 ± 4 mm Hg at 3 min of elevated ICP; CBF decreased by 62% and CMRo2decreased 30%. However, MAP continued to increase after 3 min and reached a stable level of 75 ± 3 mm Hg at 30 min in 133-d fetuses. The additional increase in MAP restored CBF and CMRo2to baseline values. Plasma epinephrine and vasopressin concentrations increased between 6 and 33 min of elevated ICP to levels, exceeding those in 92-d fetuses. We conclude that the arterial pressure response to intracranial hypertension is present at 0.6 gestation but is less well developed than at 0.9 gestation in fetal sheep, possibly due to immaturity of the sympathoadrenal and vasopressin systems. Consequently, CBF and CMRo2are not as well defended at mid-gestation against elevated ICP as might occur during difficult labor.Abbreviations: CBF,cerebral blood flow;CMRo2,cerebral metabolic rate of oxygen;CPP,cerebral perfusion pressure;ICP,intracranial pressure;MAP,mean arterial pressure;P50,Po2at 50% O2saturation

ISSN:0031-3998    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Inasmuch as smooth muscle contractile protein abnormalities may account for the maintenance of a high pulmonary vascular resistance, we evaluated the pulmonary arterial myosin light chain kinase (MLCK) and phosphatase (MLCP) in normal and pulmonary hypertensive (PH) fetal sheep. In addition, aorta and vena cava MLCP and MLCK activities were also measured. The MLCK activity(nanomoles/min/mg) was determined by the incorporation of[32P]PO4-3to the 20-kD smooth muscle myosin light chains and the MLCP activity by assaying for the dephosphorylation of the 20-kD myosin light chain (MLCP-light chain) and heavy meromyosin (MLCP-HMM). The MLCP content was determined by Western blot analysis. PH was characterized by a significant increase in the right-to-left ventricular wall weight ratio from 0.99 ± 0.04 in the control to 1.52 ± 0.12 in the experimental group (p< 0.01). The pulmonary MLCP-light chain and MLCP-HMM activities in the experimental group were 2.0 ± 0.2 and 1.3 ± 0.2 and significantly lower than in the control group values (3.8 ± 0.5 and 2.5 ± 0.3;p< 0.01). The MLCK activity was 9.6± 1.2 in the control and 7.8 ± 0.7 in the experimental fetal pulmonary artery (p= NS). The activities of both enzymes in the aorta and vena cava samples were not altered by PH. The MLCP content in experimental animals (0.50 ± 0.09 OD × mm2) was significantly lower than that for the control pulmonary tissue (1.72 ± 0.42;p< 0.01), suggesting that PH down-regulates pulmonary vascular MLCP expression. In conclusion, the maintenance of a high pulmonary vascular resistance in PH may be secondary to abnormalities in tissue content and/or activity of MLCP.Abbreviations: PPHN,persistent pulmonary hypertension syndrome of newborn;MLCK,myosin light chain kinase;MLCP,myosin light chain phosphatase;HMM,heavy meromyosin;PP1,PP2, protein phosphatase types 1 and 2;PP1M,myosin protein phosphatase;SMP,smooth muscle phosphatase

ISSN:0031-3998    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

The incidence of venous thromboembolic disease is reduced in children compared with adults. Thromboprotective mechanisms, some of which have already been identified in plasma, must be present in children. Blood vessel walls have important antithrombotic properties that maintain blood fluidity. This is in part due to proteoglycan (PG)-related glycosaminoglycan (GAG) molecules within vessel walls. PGs are macromolecules with covalently attached GAG chains, either chondroitin, dermatan, heparan, or keratan sulfate. The influence of age on the concentration and anticoagulant activities of PGs and GAGs, within vein walls before puberty has not been previously investigated. We hypothesized that developmental differences in vein walls may contribute to the reduced risk of thrombosis in children. We used a rabbit model to examine morphologic and biochemical features of inferior venae cavae (IVCs). We assessed IVC wall morphology, PG distribution, GAG mass, and GAG antithrombin activity. Morphologically, there were only minor differences between pups and adult rabbits' IVCs. However, there was a significant increase in GAGs by mass in IVCs from pups compared with adult rabbits (p= 0.012). In addition the total antithrombin activity (p= 0.04), and especially that of heparan sulfate (p= 0.01) was significantly increased in pups compared with adult rabbits. These results demonstrate important differences in the antithrombotic properties of IVC walls in pups and adult rabbits. In summary, developmental differences in vein wall PG content and activity exist which may contribute to the reduced risk of venous thromboembolism in children. Further characterization of these differences is required.Abbreviations: PG,proteoglycan;GAG,glycosaminoglycan;IVC,inferior vena cava;TEM,transmission electron microscopy;SEM,scanning electron microscopy;SMC,smooth muscle cell;ECM,extracellular matrix;CS,chondroitin sulfate;DS,dermatan sulfate;HS,heparan sulfate;α2M,α2-macroglobulin;TM,thrombomodulin

ISSN:0031-3998    

出版商:OVID    

年代:1998

数据来源: OVID