Children with hypoplastic left heart syndrome (HLHS) have an increased prevalence of central nervous system (CNS) abnormalities. The extent to which this problem is due to CNS maldevelopment, prenatal ischemia, postnatal chronic cyanosis and/or multiple exposures to cardiopulmonary bypass is unknown. To better understand the etiology of CNS abnormalities in HLHS, we evaluated 68 neonates with HLHS; in 28 cases, both fetal ultrasound and echocardiogram data were available to assess head size, head growth and aortic valve anatomy (atresia or stenosis). In addition, we evaluated neuropathology in 11 electively aborted HLHS fetuses. The mean head circumference percentile in HLHS neonates was significantly smaller than HLHS fetuses (22 Ϯ 2% versus 40 Ϯ 4%, p Ͻ 0.001). A significant decrease in head growth, defined as a 50% reduction in head circumference percentile, was observed in half (14/28) of HLHS fetuses and nearly a quarter (6/28) were already growth restricted (Յ10%) at the time of initial evaluation. Brains from HLHS fetuses demonstrated chronic diffuse white matter injury of varying severity. These patterns of prenatal head growth and brain histopathology identify a spectrum of abnormal CNS development and/or injury in HLHS fetuses. remains a significant cause of infant mortality and long-term morbidity despite significant advances in diagnosis and treatment (1-4). HLHS patients have an increased prevalence of central nervous system (CNS) abnormalities, which have been attributed to chronic cyanosis and multiple exposures to cardiopulmonary bypass (5,6). However, results from several studies indicate that in approximately one half of cases, CNS abnormalities are present at birth (4,7-10) and may manifest as reduced head circumference or microcephaly in the neonate (10 -12). It is unknown at what stage of development these CNS abnormalities occur and whether this represents a primary CNS developmental abnormality or a secondary insult resulting from alterations in cerebral blood flow due to HLHS.Little is known of the etiology of HLHS. Evidence supporting both genetic (13-15) and epigenetic (16 -18) factors has been reported. A widely accepted hypothesis is that HLHS develops as a result of alterations in embryonic intracardiac blood flow, such as narrowing of the foramen ovale and aortic stenosis (AS) (16 -18). Longitudinal studies of the fetus have shown that AS is part of the in utero natural history of HLHS (19,20); for this reason, there has been considerable interest in developing indications for fetal intervention for AS (21,22). By adversely affecting antegrade aortic blood flow, early progression of aortic valve obstruction may reduce cerebral blood flow, thereby adversely impacting CNS development and subsequent head growth. This possibility is supported by identification of white matter injury, reminiscent of periventricular leukomalacia, in term neonates with HLHS before surgical intervention (23)(24)(25). Neuropathologic findings have also identified white matter injury in postoperativ...

Certain strains of mice display an increased frequency of fetal resorption, but little is known about the effector mechanisms involved. We have examined the events associated with lipopolysaccharide (LPS)-induced fetal resorption in mice. Administration of 25 micrograms LPS on Day 12 of gestation resulted in the appearance of tumour necrosis factor-alpha (TNF-alpha) in the amniotic fluid and fetal resorption. Levels of LPS-induced TNF-alpha were reduced by 90% after pretreatment with the TNF-alpha-suppressing drug pentoxifylline (PXF). Treatment of pregnant mice during early gestation with 0.1 micrograms LPS resulted in fetoplacental resorption which was maximal when the LPS was given on Day 8. Resorption induced by 0.1 micrograms LPS on Day 8 of gestation was significantly reduced by pretreatment with PXF. Infiltration of asialo-GM1-positive cells was observed in the decidual-ectoplacental cone area of embryonic units from LPS-treated mice. In addition, treatment with anti-AGM1 antiserum prevented the LPS-induced resorption. Our results suggest that TNF-alpha and asialo-GM1-positive cells are involved in LPS-induced fetal resorption.

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In humans, chromosome-number abnormalities have been associated with altered recombination and increased maternal age. Therefore, age-related effects on recombination are of major importance, especially in relation to the mechanisms involved in human trisomies. Here, we examine the relationship between maternal age and recombination rate in humans. We localized crossovers at high resolution by using over 600,000 markers genotyped in a panel of 69 French-Canadian pedigrees, revealing recombination events in 195 maternal meioses. Overall, we observed the general patterns of variation in fine-scale recombination rates previously reported in humans. However, we make the first observation of a significant decrease in recombination rates with advancing maternal age in humans, likely driven by chromosome-specific effects. The effect appears to be localized in the middle section of chromosomal arms and near subtelomeric regions. We postulate that, for some chromosomes, protection against non-disjunction provided by recombination becomes less efficient with advancing maternal age, which can be partly responsible for the higher rates of aneuploidy in older women. We propose a model that reconciles our findings with reported associations between maternal age and recombination in cases of trisomies.

Treatment of infants with infantile hemangioma with imiquimod up to seven times per week for 16 weeks was generally well tolerated with low systemic exposure. Improvement was observed in hemangioma coloration, but not lesion size, suggesting effects were limited to the superficial component.