DUF1220 protein domains drive proliferation in human neural stem cells and are associated with increased cortical volume in anthropoid primates.

Genome sequences encoding DUF1220 protein domains show a burst in copy number among anthropoid species and especially humans, where they have undergone the greatest human lineage-specific copy number expansion of any protein coding sequence in the genome. While DUF1220 copy number shows a dosage-related association with brain size in both normal populations and in 1q21.1-associated microcephaly and macrocephaly, a function for these domains has not yet been described. Here we provide multiple lines of evidence supporting the view that DUF1220 domains function as drivers of neural stem cell proliferation among anthropoid species including humans. First, we show that brain MRI data from 131 individuals across 7 anthropoid species shows a strong correlation between DUF1220 copy number and multiple brain size-related measures. Using in situ hybridization analyses of human fetal brain, we also show that DUF1220 domains are expressed in the ventricular zone and primarily during human cortical neurogenesis, and are therefore expressed at the right time and place to be affecting cortical brain development. Finally, we demonstrate that in vitro expression of DUF1220 sequences in neural stem cells strongly promotes proliferation. Taken together, these data provide the strongest evidence so far reported implicating DUF1220 dosage in anthropoid and human brain expansion through mechanisms involving increasing neural stem cell proliferation.

Patterns of placental pathology in preterm premature rupture of membranes.

Inflammation is associated with preterm premature rupture of membranes (PPROM) and adverse neonatal outcomes. Subchorionic thrombi, with or without inflammation, may also be a significant pathological finding in PPROM. Patterns of inflammation and thrombosis may give insight into mechanisms of adverse neonatal outcomes associated with PPROM. To characterize histologic findings of placentas from pregnancies complicated by PPROM at altitude, 44 placentas were evaluated for gross and histological indicators of inflammation and thrombosis. Student's t-test (or Mann-Whitney U-test), χ 2 analysis (or Fisher's exact test), mean square contingency and logistic regression were used when appropriate. The prevalence of histologic acute chorioamnionitis (HCA) was 59%. Fetal-derived inflammation (funisitis and chorionic plate vasculitis) was seen at lower frequency (30% and 45%, respectively) and not always in association with HCA. There was a trend for Hispanic women to have higher odds of funisitis (OR = 5.9; P = 0.05). Subchorionic thrombi were seen in 34% of all placentas. The odds of subchorionic thrombi without HCA was 6.3 times greater that the odds of subchorionic thrombi with HCA (P = 0.02). There was no difference in gestational age or rupture-to-delivery interval, with the presence or absence of inflammatory or thrombotic lesions. These findings suggest that PPROM is caused by or can result in fetal inflammation, placental malperfusion, or both, independent of gestational age or rupture-to-delivery interval; maternal ethnicity and altitude may contribute to these findings. Future studies focused on this constellation of PPROM placental findings, genetic polymorphisms and neonatal outcomes are needed.

Criteria for polycystic ovarian morphology in polycystic ovary syndrome as a function of age.

CONCEPT: Ovaries meeting criteria for polycystic ovary morphology during peak reproductive years may no longer meet the criteria with age. OBJECTIVE: Ovarian volume and follicle number decrease with age in women with polycystic ovary syndrome (PCOS), permitting age-dependent criteria for PCOM. DESIGN AND SETTING: We conducted longitudinal (7-15 year interval) and cross-sectional studies to examine polycystic ovarian morphology over time at an outpatient clinic and pathology laboratory in a tertiary care hospital. PATIENTS: Subjects included those with PCOS defined by the National Institutes of Health criteria (n = 11 and 483 for longitudinal and cross-sectional, respectively) and control women with regular menstrual cycles and no hyperandrogenism (n = 15 and 367), age 18-64 yr. INTERVENTIONS: Subjects underwent an ovarian ultrasound by a single observer. MAIN OUTCOME MEASURES: Ovarian volume and follicle number were measured and ultrasound findings confirmed by a pathologist in a subset (n = 9). RESULTS: Ovarian volume (15.2 +/- 7.4 vs. 7.1 +/- 3.7 ml; P < 0.01) and follicle number (12.8 +/- 3.2 vs. 8.1 +/- 3.9; P < 0.05) decreased longitudinally in PCOS and control women (volume 11.6 +/- 4.4 vs. 5.4 +/- 2.2 ml and follicle number 8.3 +/- 1.9 vs. 6.3 +/- 1.8; both P < 0.005). Using cross-sectional data, log ovarian volume and follicle number decreased in both groups, but the decrease in log ovarian volume was less pronounced in women with PCOS than in controls (P < 0.01). A combination of age, log ovarian volume, follicle number, and testosterone distinguished PCOS subjects from controls with a receiver operator characteristic curve area of 0.90. CONCLUSIONS: Ovarian volume and follicle number decrease with age in women with PCOS and controls necessitating age-based criteria to define polycystic ovarian morphology. It is possible to use these criteria to distinguish PCOS in women over age 40 yr.

The placenta in pre-eclampsia and intrauterine growth restriction.

Placental examination in pregnancies with complications such as pre-eclampsia/toxaemia of pregnancy (PET) or intrauterine growth restriction (IUGR) can provide insight into specific diagnoses, recurrence risk and chronicity. Placental findings have clinical significance as they can identify the aetiology of the IUGR (as in inborn errors of metabolism) and predict recurrence (as in maternal floor infarcts). Evaluation of obstetric pathology in such pregnancies should be an integral part of clinical care. This review will highlight the placental findings in IUGR and PET.