Halting the Canadian STRIDER randomised controlled trial of sildenafil for severe, early-onset fetal growth restriction: ethical, methodological, and pragmatic considerations.

OBJECTIVES: To determine the efficacy and safety of sildenafil citrate to improve outcomes in pregnancies complicated by early-onset, dismal prognosis, fetal growth restriction (FGR). Eligibility: women ≥ 18 years, singleton, 18 + 0-27 + 6 weeks' gestation, estimated fetal weight < 700 g, low PLFG, and ≥ 1 of (i) abdominal circumference < 10th percentile for gestational age (GA); or (ii) reduced growth velocity and either abnormal uterine artery Doppler or prior early-onset FGR with adverse outcome. Ineligibility criteria included: planned termination or reversed umbilical artery end-diastolic flow. Eligibility confirmed by placental growth factor (PLGF) < 5 th percentile for GA measured post randomization. Women randomly received (1:1) either sildenafil 25 mg three times daily or matched placebo until either delivery or 31 + 6 weeks. PRIMARY OUTCOME: delivery GA. The trial stopped early when Dutch STRIDER signalled potential harm; despite distinct eligibility criteria and IRB and DSMB support to continue, because of futility. NCT02442492 [registered 13/05/2015]. RESULTS: Between May 2017 and June 2018, 21 (90 planned) women were randomised [10 sildenafil; 11 placebo (1 withdrawal)]. Baseline characteristics, PLGF levels, maternal and perinatal outcomes, and adverse events did not differ. Delivery GA: 26 + 6 weeks (sildenafil) vs 29 + 2 weeks (placebo); p = 0.200. Data will contribute to an individual participant data meta-analysis.

Collagenosis of the Deep Medullary Veins: An Underrecognized Pathologic Correlate of White Matter Hyperintensities and Periventricular Infarction?

White matter hyperintensities (WMH) are prevalent. Although arteriolar disease has been implicated in their pathogenesis, venous pathology warrants consideration. We investigated relationships of WMH with histologic venous, arteriolar and white matter abnormalities and correlated findings with premortem neuroimaging. Three regions of periventricular white matter were sampled from archived autopsy brains of 24 pathologically confirmed Alzheimer disease (AD) and 18 age-matched nonAD patients. Using trichrome staining, venous collagenosis (VC) of periventricular veins (<150 µm in diameter) was scored for severity of wall thickening and occlusion; percent stenosis by collagenosis of large caliber (>200 µm) veins (laVS) was measured. Correlations were made between WMH in premortem neuroimaging and vascular and white matter pathology. We found greater VC (U(114) = 2092.5, p = 0.005 and U(114) = 2121.5, p = 0.002 for small and medium caliber veins, respectively) and greater laVS (t(110) = 3.46, p = 0.001) in patients with higher WMH scores; WMH scores correlated with VC (rs(114) = 0.27, p = 0.004) and laVS (rs(110) = 0.38, p < 0.001). By multiple linear regression analysis, the strongest predictor of WMH score was laVS (ß = 0.338, p < 0.0001). VC was frequent in patients with periventricular infarcts identified on imaging. We conclude that periventricular VC is associated with WMH in both AD and nonAD patients and the potential roles of VC in WMH pathogenesis merit further study.

The role of dorsal root ganglia activation and brain-derived neurotrophic factor in multiple sclerosis.

Multiple sclerosis (MS) is characterized by focal destruction of the white matter of the brain and spinal cord. The exact mechanisms underlying the pathophysiology of the disease are unknown. Many studies have shown that MS is predominantly an autoimmune disease with an inflammatory phase followed by a demyelinating phase. Recent studies alongside current treatment strategies, including glatiramer acetate, have revealed a potential role for brain-derived neurotrophic factor (BDNF) in MS. However, the exact role of BDNF is not fully understood. We used the experimental autoimmune encephalomyelitis (EAE) model of MS in adolescent female Lewis rats to identify the role of BDNF in disease progression. Dorsal root ganglia (DRG) and spinal cords were harvested for protein and gene expression analysis every 3 days post-disease induction (pdi) up to 15 days. We show significant increases in BDNF protein and gene expression in the DRG of EAE animals at 12 dpi, which correlates with peak neurological disability. BDNF protein expression in the spinal cord was significantly increased at 12 dpi, and maintained at 15 dpi. However, there was no significant change in mRNA levels. We show evidence for the anterograde transport of BDNF protein from the DRG to the dorsal horn of the spinal cord via the dorsal roots. Increased levels of BDNF within the DRG and spinal cord in EAE may facilitate myelin repair and neuroprotection in the CNS. The anterograde transport of DRG-derived BDNF to the spinal cord may have potential implications in facilitating central myelin repair and neuroprotection.