Background and AimsInfants with Down syndrome (DS) or Trisomy 21, are at high risk for developing pulmonary arterial hypertension (PAH), but mechanisms that increase susceptibility are poorly understood. Laboratory studies have shown that early disruption of angiogenesis during development impairs vascular and alveolar growth and causes PAH. Human chromosome 21 encodes known anti-angiogenic factors, including collagen18a1 (endostatin, ES), ß-amyloid peptide (BAP) and Down Syndrome Critical Region 1 (DSCR-1). Therefore, we hypothesized that fetal lungs from subjects with DS are characterized by early over-expression of anti-angiogenic factors and have abnormal lung vascular growth in utero.MethodsHuman fetal lung tissue from DS and non-DS subjects were obtained from a biorepository. Quantitative reverse transcriptase PCR (qRT-PCR) was performed to assay 84 angiogenesis-associated genes and individual qRT-PCR was performed for ES, amyloid protein precursor (APP) and DSCR1. Western blot analysis (WBA) was used to assay lung ES, APP and DSCR-1 protein contents. Lung vessel density and wall thickness were determined by morphometric analysis.ResultsThe angiogenesis array identified up-regulation of three anti-angiogenic genes: COL18A1 (ES), COL4A3 (tumstatin) and TIMP3 (tissue inhibitor of metallopeptidase 3) in DS lungs. Single qRT-PCR and WBA showed striking elevations of ES and APP mRNA (p = 0.022 and p = 0.001) and protein (p = 0.040 and p = 0.002; respectively). Vessel density was reduced (p = 0.041) and vessel wall thickness was increased in DS lung tissue (p = 0.033) when compared to non-DS subjects.ConclusionsWe conclude that lung anti-angiogenic factors, including COL18A1 (ES), COL4A3, TIMP3 and APP are over-expressed and fetal lung vessel growth is decreased in subjects with DS. We speculate that increased fetal lung anti-angiogenic factor expression due to trisomy 21 impairs lung vascular growth and signaling, which impairs alveolarization and contributes to high risk for PAH during infancy.

SRS affords a reasonable rate of endocrine remission in patients with acromegaly and generally does so with a low rate of adverse effects.

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Stereotactic radiosurgery (SRS) is not only effective for the prevention of arteriovenous malformation (AVM)-associated hemorrhage, 3,4,6,7,15,16,23,26 but is also effective in the treatment of AVM-associated epilepsy, with estimates ranging from 55% to 80% of patients who are seizure free after SRS (Table 1). 8,9,14,22,23,25 However, detailed seizure outcomes are lacking in the majority of AVM series. Many studies, including a previous one from our Gamma Knife center, 23 outline clinical seizure outcomes broadly without a thorough analysis of factors related to outcome. Additionally, the potentially long-term antiepileptic effects of SRS are not accounted for by most previous studies due to their relatively short follow-up durations.In the current study, we evaluated a cohort of patients with AVM-related epilepsy who were treated with SRS at our institution. Our aims were to classify long-term postoperative seizure outcomes, determine antiepileptic drug abbreviatioNs AED = antiepileptic drug; AVM = arteriovenous malformation; CI = confidence interval; DSA = digital subtraction angiography; GKRS = Gamma Knife radiosurgery; OR = odds ratio; RIC = radiation-induced change; SRS = stereotactic radiosurgery. submitted June 20, 2014. accepted November 25, 2014. iNclude wheN citiNg Published online January 23, 2015; DOI: 10.3171/2014.11.JNS141388. disclosure The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper. Departments of 1 Neurological Surgery, 2 Neurology, and 3 Radiation Oncology, University of Virginia Health System, Charlottesville, Virginia obJect Epilepsy associated with arteriovenous malformations (AVMs) has an unclear course after stereotactic radiosurgery (SRS). Neither the risks of persistent seizures nor the requirement for postoperative antiepileptic drugs (AEDs) are well defined. methods The authors performed a retrospective review of all patients with AVMs who underwent SRS at the University of Virginia Health System from 1989 to 2012. Seizure status was categorized according to a modified Engel classification. The effects of demographic, AVM-related, and SRS treatment factors on seizure outcomes were evaluated with logistic regression analysis. Changes in AED status were evaluated using McNemar's test. results Of the AVM patients with pre- or post-SRS seizures, 73 with pre-SRS epilepsy had evaluable data for subsequent analysis. The median patient age was 37 years (range 5-69 years), and the median follow-up period was 65.6 months (range 12-221 months). Sixty-five patients (89%) achieved seizure remission (Engel Class IA or IB outcome). Patients presenting with simple partial or secondarily generalized seizures were more likely to achieve Engel Class I outcome (p = 0.045). Twenty-one (33%) of 63 patients tapered off of pre-SRS AEDs. The incidence of freedom from AED therapy increased significantly after SRS (p < 0.001, McNemar's test). Of the Engel Class IA patients who continued AED therapy, 54% had patent AVM nidi...