Growth restriction in gastroschisis: quantification of its severity and exploration of a placental cause.

BACKGROUND: Gastroschisis patients are commonly small for gestational age (SGA, birth weight [BW] < 10th centile). However, the extent, symmetry and causes of that growth restriction remain controversial. METHODS: We compared BW, crown-heel length (LT), occipitofrontal circumference (OFC) and ponderal index (PI) in 179 gastroschisis cases and 895 matched controls by univariate and multiple regression. Fetal ultrasounds (N = 80) were reviewed to determine onset of growth restriction. Placental histology was examined in 31 gastroschisis patients whose placental tissue was available and in 29 controls. RESULTS: Gastroschisis cases weighed less than controls (BW = 2400 ± 502 g vs. 2750 ± 532 g, p < 0.001) and their BW frequency curve was shifted to the left, indicating lower BW as a group compared to controls (p < 0.001 by Kolmogorov-Smirnov test). BW differences varied from -148 g at 33 weeks to -616 g at 38 weeks gestation. Intrauterine growth restriction was symmetric with gastroschisis patients having a shorter LT (45.7 ± 3.3 vs. 48.4 ± 2.7 cm, p < 0.001), smaller OFC (31.9 ± 1.9 vs. 32.9 ± 1.6 cm, p < 0.001), but larger ponderal index (2.51 ± 0.37 vs. 2.40 ± 0.16, p < 0.001) compared to controls. Gastroschisis patients had a similar reduction in BW (-312 g, 95% confidence interval [CI] = -367, -258) compared to those with chromosomal abnormalities (-239 g, CI = -292, -187). Growth deficits appeared early in the second trimester and worsened as gestation increased. Placental chorangiosis was more common in gastroschisis patients than controls, even after removing all SGA patients (77% vs. 42%, p = 0.02). CONCLUSIONS: Marked, relatively symmetric intrauterine growth restriction is an intrinsic part of gastroschisis. It begins early in the second trimester, and is associated with placental chorangiosis.

Engineering of N. benthamiana L. plants for production of N-acetylgalactosamine-glycosylated proteins--towards development of a plant-based platform for production of protein therapeutics with mucin type O-glycosylation.

BACKGROUND: Mucin type O-glycosylation is one of the most common types of post-translational modifications that impacts stability and biological functions of many mammalian proteins. A large family of UDP-GalNAc polypeptide:N-acetyl-α-galactosaminyltransferases (GalNAc-Ts) catalyzes the first step of mucin type O-glycosylation by transferring GalNAc to serine and/or threonine residues of acceptor polypeptides. Plants do not have the enzyme machinery to perform this process, thus restricting their use as bioreactors for production of recombinant therapeutic proteins. RESULTS: The present study demonstrates that an isoform of the human GalNAc-Ts family, GalNAc-T2, retains its localization and functionality upon expression in N. benthamiana L. plants. The recombinant enzyme resides in the Golgi as evidenced by the fluorescence distribution pattern of the GalNAc-T2:GFP fusion and alteration of the fluorescence signature upon treatment with Brefeldin A. A GalNAc-T2-specific acceptor peptide, the 113-136 aa fragment of chorionic gonadotropin ß-subunit, is glycosylated in vitro by the plant-produced enzyme at the "native" GalNAc attachment sites, Ser-121 and Ser-127. Ectopic expression of GalNAc-T2 is sufficient to "arm" tobacco cells with the ability to perform GalNAc-glycosylation, as evidenced by the attachment of GalNAc to Thr-119 of the endogenous enzyme endochitinase. However, glycosylation of highly expressed recombinant glycoproteins, like magnICON-expressed E. coli enterotoxin B subunit:H. sapiens mucin 1 tandem repeat-derived peptide fusion protein (LTBMUC1), is limited by the low endogenous UDP-GalNAc substrate pool and the insufficient translocation of UDP-GalNAc to the Golgi lumen. Further genetic engineering of the GalNAc-T2 plants by co-expressing Y. enterocolitica UDP-GlcNAc 4-epimerase gene and C. elegans UDP-GlcNAc/UDP-GalNAc transporter gene overcomes these limitations as indicated by the expression of the model LTBMUC1 protein exclusively as a glycoform. CONCLUSION: Plant bioreactors can be engineered that are capable of producing Tn antigen-containing recombinant therapeutics.

NICU practices and outcomes associated with 9 years of quality improvement collaboratives.

OBJECTIVE: Quality improvement collaboratives (QICs) can improve short-term outcomes, but few have examined their long-term results. This study evaluated the changes in treatment practices and outcomes associated with participation in multiple sequential QICs. DESIGN AND METHODS: This retrospective, 9-year, pre-post study of very low birth weight infants, we assessed treatment and outcomes from the 8 NICUs of the Reduce Lung Injury (ReLI) group of a QIC sponsored by the Vermont Oxford Network (VON). We analyzed data from 1998 (pre-ReLI), 2001 (last ReLI year), and 2006 (5 years after ReLI) by using univariate and multiple regression. RESULTS: A total of 4065 very low birth weight infants were treated in ReLI NICUs in 1998, 2001, and 2006. From 1998 to 2006, the ReLI group decreased delivery room intubation (70% vs 52%; adjusted odds ratio [aOR]: 0.2 [95% confidence interval (CI): 0.2-0.3]; P < .001), conventional ventilation (75% vs 62%; aOR: 0.3 [95% CI: 0.2-0.4]; P < .001), and postnatal steroids for BPD (35% vs 10%; aOR: 0.09 [95% CI: 0.07-0.1]; P < .001). They increased the use of nasal continuous positive airway pressure (57% vs 78%; aOR: 3.3 [95% CI: 2.7-3.9]; P < .001). BPD-free survival remained unchanged (68% vs 66%; aOR: 0.9 [95% CI: 0.7-1.1]; P = .16), the BPD rate increased (25% vs 29%; aOR: 1.3 [95% CI: 1.1-1.6]; P = .017), survival to discharge increased (90% vs 93%; aOR: 1.5 [95% CI: 1.1-2.2]; P < .001), and nosocomial infections decreased (18% vs 15%; aOR: 0.8 [95% CI: 0.6-0.99]; P = .045). CONCLUSIONS: Participation in VON-sponsored QICs was associated with sustained implementation of potentially better respiratory practices, increased survival, and reduced nosocomial infections. The BPD-free survival rate did not change, and the BPD rate increased. Implemented changes endured for at least 5 years after the QIC.