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The dystrophin associated protein complex (DAPC) provides a linkage between the cytoskeleton and the extracellular matrix and is also a scaffold for a host of signaling molecules. The constituents of the DAPC must be targeted to the sarcolemma in order to properly function. Biglycan is an extracellular matrix molecule that associates with the DAPC. Here, we show that biglycan null mice exhibit a mild dystrophic phenotype and display a selective reduction in the localization of α-dystrobrevin -1 and -2, α-and β1-syntrophin, and nNOS at the sarcolemma. Purified biglycan induces nNOS redistribution to the plasma membrane in cultured muscle cells. Biglycan protein injected into muscle becomes stably associated with the sarcolemma and extracellular matrix for at least two weeks. This injected biglycan restores the sarcolemmal expression of α-dystrobrevin-1 and -2, and β1-and β2-syntrophin in biglycan null mice. We conclude that biglycan is important for the maintenance of muscle cell integrity and plays a direct role in regulating the expression and sarcolemmal localization of the intracellular signaling proteins dystrobrevin-1 and -2, α-and β1-syntrophin and nNOS.

Preterm birth is the leading cause of newborn mortality in the United States and about one third of cases are caused by preterm premature rupture of fetal membranes, a complication that is frequently observed in patients with Ehlers-Danlos Syndrome. Notably, a subtype of Ehlers-Danlos Syndrome is caused by expression of abnormal biglycan and decorin proteoglycans. As compound deficiency of these two small leucine-rich proteoglycans is a model of preterm birth, we investigated the fetal membranes of Bgn−/−;Dcn−/− double-null and single-null mice. Our results showed that biglycan signaling supported fetal membrane remodeling during early gestation in the absence of concomitant changes in TGFβ levels. In late gestation, biglycan signaling acted in a TGFβ–dependent manner to aid in membrane stabilization. In contrast, decorin signaling supported fetal membrane remodeling at early stages of gestation in a TGFβ–dependent manner, and fetal membrane stabilization at later stages of gestation without changes in TGFβ levels. Furthermore, exogenous soluble decorin was capable of rescuing the TGFβ signaling pathway in fetal membrane mesenchymal cells. Collectively, these findings provide novel targets for manipulation of fetal membrane extracellular matrix stability and could represent novel targets for research on preventive strategies for preterm premature rupture of fetal membranes.

The receptor tyrosine kinase MuSK is indispensable for nerve-muscle synapse formation and maintenance. MuSK is necessary for pre-patterning of the endplate zone anlage and as a signaling receptor for agrin-mediated postsynaptic differentiation. MuSK-associated proteins such as Dok7, LRP4, and Wnt11r are involved in these early events in neuromuscular junction formation. However, the mechanisms regulating synapse stability are poorly understood. Here we examine a novel role for the extracellular matrix protein biglycan in synapse stability. Synaptic development in fetal and early postnatal biglycan null (bgn-/o) muscle is indistinguishable from wild type controls. However, by 5 wks after birth nerve-muscle synapses in bgn-/o mice are abnormal as judged by the presence of perijunctional folds, increased segmentation and focal misalignment of acetylcholinesterase and AChRs. These observations indicate that previously occupied pre- and post- synaptic territory has been vacated. Biglycan binds MuSK and the levels of this receptor tyrosine kinase are selectively reduced at bgn-/o synapses. In bgn-/o myotubes, the initial stages of agrin-induced MuSK phosphorylation and AChR clustering are normal, but the AChR clusters are unstable. This stability defect can be substantially rescued by the addition of purified biglycan. Together, these results indicate that biglycan is an extracellular ligand for MuSK that is important for synapse stability.

Preterm premature rupture of membranes is responsible for one third of preterm births. Ehlers-Danlos syndrome (EDS) is associated with preterm premature rupture of membranes in humans. Notably, an EDS variant is caused by a genetic mutation resulting in abnormal secretion of biglycan and decorin, two small leucine-rich proteoglycans highly expressed in reproductive tissues. Because biglycan/decorin null mutant (Bgn−/−Dcn−/−) mice demonstrate phenotypic changes similar to EDS, we utilized this model to test whether either or both biglycan and decorin play a role in the attainment of successful term gestation. Wild-type, biglycan null mutant, decorin null mutant and biglycan/decorin null mutant pregnancies were assessed for length of gestation, pup and placenta weight and litter size. Quantitative real-time polymerase chain reaction was performed to measure biglycan and decorin gene expression and immunohistochemistry was performed to assess protein expression in placenta and fetal membranes at embryonic day E12, E15 and E18. Bgn−/−Dcn−/− dams displayed preterm birth, whereas the possession of at least two biglycan or decorin wild-type alleles was protective of preterm birth. Bgn−/−Dcn−/− pups were decreased at postnatal day P1 but not at E18. Biglycan and decorin were upregulated in the placenta in each other’s absence and were developmentally regulated in fetal membranes, suggesting that these two proteoglycans demonstrate genetic complementation and contribute to gestational success in a dose dependent manner. Thus, the biglycan/decorin null mutant mouse is a model of genetically induced preterm birth and perinatal loss. This model presents novel targets for preventive or therapeutic manipulation of preterm birth.

The implementation of a neonatal palliative care initiative was associated with increases in palliative interventions for neonates in their final 48 h of life, suggesting that such an initiative may enhance end-of-life care.

BackgroundThe death of a newborn is a traumatic life changing event in the lives of parents. We hypothesized that bereaved parents of newborn infants want to have choices in the personal care of their infant at the end of life.MethodsParents who had suffered a perinatal or neonatal loss between 1 and 6 years before the survey in a regional level IV neonatal intensive care unit (NICU) and associated labor and delivery room were invited to participate. Parents chose between an online survey, paper survey or telephone interview. The survey included multiple choice and open ended questions.ResultsParents prefer multiple options for the personal care of their infant at the end of life. Emergent themes were need for guidance by the medical team, memory making, feeling cared for and respected by staff, and regrets related to missed opportunities.ConclusionWhile parents differ in their preferences in utilizing specific personal care options for their infant’s end of life, they share a common preference for being presented with multiple options to choose from and in being guided and supported by healthcare providers, while being afforded the opportunity to make memories with their infant by bonding with and parenting them.Electronic supplementary materialThe online version of this article (doi:10.1186/s12904-015-0063-6) contains supplementary material, which is available to authorized users.

Biglycan is an extracellular ligand for the dystrophin-associated protein complex (DAPC) that is upregulated in both dystrophic and regenerating muscle. Biglycan also binds to collagen VI, mutations of which cause a congenital muscular dystrophy (Ullrich's; UCMD) that is also characterized by connective tissue abnormalities. The expression of biglycan in early development and postnatal ages has not been well characterized. Here we show that biglycan transcript levels peak at approximately 21 weeks' gestation in human fetal muscle. Immunocytochemical analysis of developing mouse muscle shows that biglycan can be detected in muscle as early as embryonic day (E)16 and is most abundant between postnatal day (P)1 and P7. Biglycan is also highly expressed in developing tendon, with maximal levels observed at E16-18. This robust tendon expression is correlated with a sharp peak in biglycan transcript levels in the hindlimb. Finally, at E18 collagen VI colocalizes with biglycan in tendon. These results suggest that biglycan has a particularly important function during muscle and connective tissue development. Moreover, biglycan may play a role in the pathogenesis of collagen VI-associated congenital muscular dystrophies.