Donald Peebles

Delayed ("secondary") cerebral energy failure after acute hypoxia-ischemia in the newborn piglet: continuous 48-hour studies by phosphorus magnetic resonance spectroscopy

ABSTRACT: Phosphorus (31P) spectra from the brains of severely birth-asphyxiated human infants are commonly normal on the first day of life. Later, cerebral energy failure develops, which carries a serious prognosis. The main purpose of this study was to test the hypothesis that this delayed (“secondary”) energy failure could be reproduced in the newborn piglet after a severe acute reversed cerebral hypoxicischemic insult. Twelve piglets were subjected to temporary occlusion of the common carotid arteries and hypoxemia [mean arterial Po2 3.1 (SD 0.6) kPa]. Mean cerebral phosphocreatine concentration [PCr]/inorganic orthophosphate concentration [Pi] decreased from 1.40 (SD 0.29) to 0.01 (SD 0.02), and nucleotide triphosphate concentration [NTP]/exchangeable phosphate pool concentration [EPP] decreased from 0.19 (SD 0.02) to 0.06 (SD 0.04) (p<0.001 for each decrease). On reperfusion and reoxygenation of the brain, mean [PCr]/[Pi] and [NTP]/[EPP] returned to baseline. Observations continuing for the next 48 h showed that [PCr]/[Pi] again decreased, in spite of normal arterial Po2, mean arterial blood pressure, and blood glucose, to 0.62 (SD 0.61) at 24 h (p<0.01) and 0.49 (SD 0.37) at 48 h (p<0.001). [NTP]/[EPP] also decreased, but to a lesser degree. Intracellular pH remained unchanged. These findings appeared identical with those seen in birth-asphyxiated human infants. No changes in cerebral metabolite concentrations took place in six control piglets. The severity of secondary energy failure, as judged by the lowest [PCr]/[Pi] recorded at 24-48 h, was directly related to the extent of acute energy depletion, obtained as the time integral of reduction in [NTP]/[EPP] (p<0.0001). This animal model of secondary energy failure may prove useful for testing cerebroprotective strategies.

White matter injury following systemic endotoxemia or asphyxia in the fetal sheep

White matter injury is the most frequently observed brain lesion in preterm infants. The etiology remains unclear, however, both cerebral hypoperfusion and intrauterine infections have been suggested as risk factors. We compared the neuropathological outcome, including the effect on oligodendrocytes, astrocytes, and microglia, following either systemic asphyxia or endotoxemia in fetal sheep at midgestation. Fetal sheep were subjected to either 25 minutes of umbilical cord occlusion or systemic endotoxemia by administration of Escherichia coli lipopolysaccharide (LPS O111:B4, 100 ng/kg, IV). Periventricular white matter lesions were observed in 2 of 6 asphyxiated fetuses, whereas the remaining animals showed diffuse injury throughout the subcortical white matter and neuronal necrosis in subcortical regions, including the striatum and hippocampus. LPS-treatment resulted in focal inflammatory infiltrates and cystic lesions in periventricular white matter in 2 of 5 animals, but with no neuron specific injury. Both experimental paradigms resulted in microglia activation in the white matter, damaged astrocytes, and loss of oligodendrocytes. These results show that the white matter at midgestation is sensitive to injury following both systemic asphyxia and endotoxemia. Asphyxia induced lesions in both white and subcortical grey matter in association with microglia activation, and endotoxemia resulted in selective white matter damage and inflammation.

Risk of preterm birth after treatment for cervical intraepithelial neoplasia among women attending colposcopy in England: retrospective-prospective cohort study

Objective To explore the association between preterm delivery and treatment at colposcopy. Design Retrospective-prospective cohort study using record linkage. Setting 12 National Health Service hospitals in England. Participants Women who had a cervical histology sample taken between 1987 and 2009. These women were linked by hospital episode statistics to hospital obstetric records between 1998 and 2009 for the whole of England to identify singleton live births between 20-43 gestational weeks before or after cervical histology. Main outcome measures Proportion of preterm births (<37 weeks); the relative risk for the strength of association between preterm births and treatment for cervical intraepithelial neoplasia. Results 18 441 singleton births occurred: 4176 before histology and 14 265 after histology. Of the singleton births after histology, 9.0% (n=1284) were preterm compared with 6.7% of all births in England over the same period (excess risk 2.3 per 100 births, 95% confidence interval 1.8% to 2.8%). Among first births after histology, the adjusted relative risk associated with previous treatment was 1.19 (95% confidence interval 1.01 to 1.41); among first births before histology the relative risk associated with subsequent treatment was 1.47 (1.05 to 2.05). Combining these, the relative risk associated with treatment adjusted for timing relative to histology was 0.91 (0.66 to 1.26) corresponding to an absolute difference of −0.25 (−2.61 to 2.11) per 100 singleton births. Among 372 women who gave birth both before and after treatment, there were 30 preterm births after treatment and 32 before treatment (relative risk 0.94, 0.62 to 1.43). Conclusion The risk of preterm delivery in women treated by colposcopy in England was substantially less than that in many other studies, predominantly from Nordic countries. The increased risk may be a consequence of confounding and not caused by treatment. Although this study is reassuring for large loop excision of the transformation zone overall, it is possible that deep conisation or repeated treatment leads to an increased risk of preterm delivery.

Use of high intensity adjusted dose low molecular weight heparin in women with mechanical heart valves during pregnancy: a single-center experience.

This report describes the successful use of dose-escalating low molecular weight heparin thrombo-profylaxis in pregnant women with prosthetic heart valves. The use of standard dose low molecular weight heparin (LMWH) to anticoagulate women with mechanical valves in pregnancy is associated with morbidity and mortality. We conducted a prospective audit of the use of adjusted dose high intensity LMWH in 12 pregnancies in 11 women with prosthetic heart valves. LMWH ± low-dose aspirin was started at therapeutic-dose with monitoring of anti-Xa levels to achieve a target level of 1.0–1.2 IU/mL (0.8–1.2 in the first 3/12 pregnancies). This necessitated a mean increase in the dose of LMWH of 54.4% (SD±33.2) over initial dose. Eleven of 12 pregnancies resulted in live births, with one intrauterine fetal death at 37 weeks. One non-fatal valve thrombosis occurred at 26 weeks gestation associated with subtherapeutic anti-Xa levels. Three patients experienced major bleeding. This regime provides a therapeutic option for women with mechanical heart valves during pregnancy, provided anti-Xa levels are kept within the target range. These patients require close surveillance for bleeding and thrombotic complications within a multi-disciplinary setting.

CHANGES IN HUMAN FETAL CEREBRAL HEMOGLOBIN CONCENTRATION AND OXYGENATION DURING LABOR MEASURED BY NEAR-INFRARED SPECTROSCOPY

OBJECTIVE The purpose of this study was to measure by near-infrared spectroscopy changes in human fetal cerebral oxyhemoglobin, deoxyhemoglobin, and cerebral blood volume during labor and to calculate mean cerebral hemoglobin oxygen saturation. STUDY DESIGN The effects of uterine contractions with and without fetal heart rate decelerations were compared in eight singleton term fetuses. Results were analyzed by analysis of variance. RESULTS In six of eight fetuses normal uterine contractions were associated with proportional decreases in both oxyhemoglobin and deoxyhemoglobin and a fall in cerebral blood volume without desaturation of cerebral hemoglobin. Contractions with fetal heart rate decelerations produced different results in that oxyhemoglobin fell but deoxyhemoglobin rose, indicating cerebral desaturation. In two of the eight fetuses normal contractions were associated with increases in oxyhemoglobin, deoxyhemoglobin, and cerebral blood volume; no decelerations were seen in either fetus. Mean cerebral hemoglobin oxygen saturation calculated during normal contractions was 43% +/- 10% (SD). CONCLUSION Uterine contractions were associated with detectable changes from baseline in cerebral oxyhemoglobin, deoxyhemoglobin, and cerebral blood volume.

Differing Prevalence and Diversity of Bacterial Species in Fetal Membranes from Very Preterm and Term Labor

Background Intrauterine infection may play a role in preterm delivery due to spontaneous preterm labor (PTL) and preterm prolonged rupture of membranes (PPROM). Because bacteria previously associated with preterm delivery are often difficult to culture, a molecular biology approach was used to identify bacterial DNA in placenta and fetal membranes. Methodology/Principal findings We used broad-range 16S rDNA PCR and species-specific, real-time assays to amplify bacterial DNA from fetal membranes and placenta. 74 women were recruited to the following groups: PPROM <32 weeks (n = 26; 11 caesarean); PTL with intact membranes <32 weeks (n = 19; all vaginal birth); indicated preterm delivery <32 weeks (n = 8; all caesarean); term (n = 21; 11 caesarean). 50% (5/10) of term vaginal deliveries were positive for bacterial DNA. However, little spread was observed through tissues and species diversity was restricted. Minimal bacteria were detected in term elective section or indicated preterm deliveries. Bacterial prevalence was significantly increased in samples from PTL with intact membranes [89% (17/19) versus 50% (5/10) in term vaginal delivery p = 0.03] and PPROM (CS) [55% (6/11) versus 0% (0/11) in term elective CS, p = 0.01]. In addition, bacterial spread and diversity was greater in the preterm groups with 68% (13/19) PTL group having 3 or more positive samples and over 60% (12/19) showing two or more bacterial species (versus 20% (2/10) in term vaginal deliveries). Blood monocytes from women with PTL with intact membranes and PPROM who were 16S bacterial positive showed greater level of immune paresis (p = 0.03). A positive PCR result was associated with histological chorioamnionitis in preterm deliveries. Conclusion/Significance Bacteria are found in both preterm and term fetal membranes. A greater spread and diversity of bacterial species were found in tissues of women who had very preterm births. It is unclear to what extent the greater bacterial prevalence observed in all vaginal delivery groups reflects bacterial contamination or colonization of membranes during labor. Bacteria positive preterm tissues are associated with histological chorioamnionitis and a pronounced maternal immune paresis.

Cerebral hemodynamic effects of treatment with modified natural surfactant investigated by near infrared spectroscopy.

The purpose of this study was to investigate the effects on cerebral hemodynamics of administering modified natural surfactant (Curosurf, 200 mg · kg-1) to infants requiring mechanical ventilation for hyaline membrane disease. Observations were made using near infrared spectroscopy on 20 infants for between 26 and 109 (median 57) min before and 22 to 112 (median 46) min after surfactant instillation. Changes in cerebral oxyhemoglobin concentration and cerebral blood volume (CBV) were monitored continuously; cerebral blood flow, oxygen delivery, and the response of CBV to changes in arterial carbon dioxide tension were measured while the infants were stable shortly before and after surfactant was given. Cerebral oxyhemoglobin concentration fell transiently in all infants immediately after surfactant by a median of −0.21 (range −0.46 to 0.05) mL · 100 g-1, but quickly recovered so that the median change during the 10 min after surfactant was 0.01 (-0.46 to 0.46) mL · 100 g-1. Alterations in CBV also occurred ranging from −0.44 to 0.40 (median 0) mL · 100 g-1, which represented −12 to 16% of total CBV; these changes rapidly resolved. When the infants were stable before and after surfactant, the values for mean (SD) cerebral blood flow were 20.5 (7.5) and 23.1 (5.2) mL · 100 g-1 · min-1, respectively (n = 9); for mean cerebral oxygen delivery, values were 2.71 (0.89) and 3.15 (0.73) mL · 100 g-1 · min-1 (n = 9); and for response of CBV to changes in arterial carbon dioxide tension, they were 0.14 (0.09) and 0.11 (0.11) mL · 100 g-1 · kPa-1 (n = 16); these changes were not statistically significant. We conclude that (1) surfactant administration caused small, transient perturbations in cerebral oxyhemoglobin concentration and CBV, and (2) no important alterations in cerebral blood flow, cerebral oxygen delivery, or response of CBV to changes in arterial carbon dioxide tension were detected.

Activation and deactivation of periventricular white matter phagocytes during postnatal mouse development

Brain microglia are related to peripheral macrophages but undergo a highly specific process of regional maturation and differentiation inside the brain. Here, we examined this deactivation and morphological differentiation in cerebral cortex and periventricular subcortical white matter, the main “fountain of microglia” site, during postnatal mouse development, 0–28 days after birth (P0–P28). Only macrophages in subcortical white matter but not cortical microglia exhibited strong expression of typical activation markers alpha5, alpha6, alphaM, alphaX, and beta2 integrin subunits and B7.2 at any postnatal time point studied. White matter phagocyte activation was maximal at P0, decreased linearly over P3 and P7 and disappeared at P10. P7 white matter phagocytes also expressed high levels of IGF1 and MCSF, but not TNFalpha mRNA; this expression disappeared at P14. This process of deactivation followed the presence of ingested phagocytic material but correlated only moderately with ramification, and not with the extent of TUNEL+ death in neighboring cells, their ingestion or microglial proliferation. Intravenous fluosphere labeling revealed postnatal recruitment and transformation of circulating leukocytes into meningeal and perivascular macrophages as well as into ramified cortical microglia, but bypassing the white matter areas. In conclusion, this study describes strong and selective activation of postnatally resident phagocytes in the P0–P7 subcortical white matter, roughly equivalent to mid 3rd trimester human fetal development. This presence of highly active and IGF1‐ and MCSF‐expressing phagocytes in the neighborhood of vulnerable white matter could play an important role in the genesis of or protection against axonal damage in the fetus and premature neonate.

The newborn brain: Neuroscience and clinical applications

The new edition of this highly respected work presents a comprehensive review of thebasic mechanisms of brain development and the pathophysiology of disorders ...

Relation between frequency of uterine contractions and human fetal cerebral oxygen saturation studied during labour by near infrared spectroscopy

Objective To investigate the effect of the frequency of uterine contractions on fetal cerebral oxygenation, using near infrared spectroscopy.