Compensatory fetal membrane mechanisms between biglycan and decorin in inflammation.

Preterm premature rupture of fetal membranes (PPROM) is associated with infection, and is one of the most common causes of preterm birth. Abnormal expression of biglycan and decorin, two extracellular matrix proteoglycans, leads to preterm birth and aberrant fetal membrane morphology and signaling in the mouse. In humans and mice, decorin dysregulation is associated with inflammation in PPROM. We therefore investigated the link between biglycan and decorin and inflammation in fetal membranes using mouse models of intraperitoneal Escherichia coli injections superimposed on genetic biglycan and decorin deficiencies. We assessed outcomes in vivo as well as in vitro using quantitative PCR, Western blotting, and enzyme-linked immunosorbent assays. Our results suggest that biglycan and decorin compensate for each other in the fetal membranes, but lose the ability to do so under inflammation, leading to decreased latency to preterm birth. Furthermore, our findings suggest that biglycan and decorin play discrete roles in fetal membrane signaling pathways during inflammation, leading to changes in the abundance of MMP8 and collagen α1VI, two components of the fetal membrane extracellular matrix that influence the pathophysiology of PPROM. In summary, these findings underline the importance of biglycan and decorin as targets for the manipulation of fetal membrane extracellular matrix stability in the context of inflammation

Uterine Dysfunction in Biglycan and Decorin Deficient Mice Leads to Dystocia during Parturition

Cesarean birth rates are rising. Uterine dysfunction, the exact mechanism of which is unknown, is a common indication for Cesarean delivery. Biglycan and decorin are two small leucine-rich proteoglycans expressed in the extracellular matrix of reproductive tissues and muscle. Mice deficient in biglycan display a mild muscular dystrophy, and, along with mice deficient in decorin, are models of Ehlers-Danlos Syndrome, a connective tissue anomaly associated with uterine rupture. As a variant of Ehlers-Danlos Syndrome is caused by a genetic mutation resulting in abnormal biglycan and decorin secretion, we hypothesized that biglycan and decorin play a role in uterine function. Thus, we assessed wild-type, biglycan, decorin and double knockout pregnancies for timing of birth and uterine function. Uteri were harvested at embryonic days 12, 15 and 18. Nonpregnant uterine samples of the same genotypes were assessed for tissue failure rate and spontaneous and oxytocin-induced contractility. We discovered that biglycan/decorin mixed double-knockout dams displayed dystocia, were at increased risk of delayed labor onset, and showed increased tissue failure in a predominantly decorin-dependent manner. In vitro spontaneous uterine contractile amplitude and oxytocin-induced contractile force were decreased in all biglycan and decorin knockout genotypes compared to wild-type. Notably, we found no significant compensation between biglycan and decorin using quantitative real time PCR or immunohistochemistry. We conclude that the biglycan/decorin mixed double knockout mouse is a model of dystocia and delayed labor onset. Moreover, decorin is necessary for uterine function in a dose-dependent manner, while biglycan exhibits partial compensatory mechanisms in vivo. Thus, this model is poised for use as a model for testing novel targets for preventive or therapeutic manipulation of uterine dysfunction

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis

Compensatory fetal membrane mechanisms between biglycan and decorin in inflammation.

Preterm premature rupture of fetal membranes (PPROM) is associated with infection, and is one of the most common causes of preterm birth. Abnormal expression of biglycan and decorin, two extracellular matrix proteoglycans, leads to preterm birth and aberrant fetal membrane morphology and signaling in the mouse. In humans and mice, decorin dysregulation is associated with inflammation in PPROM. We therefore investigated the link between biglycan and decorin and inflammation in fetal membranes using mouse models of intraperitoneal Escherichia coli injections superimposed on genetic biglycan and decorin deficiencies. We assessed outcomes in vivo as well as in vitro using quantitative PCR, Western blotting, and enzyme-linked immunosorbent assays. Our results suggest that biglycan and decorin compensate for each other in the fetal membranes, but lose the ability to do so under inflammation, leading to decreased latency to preterm birth. Furthermore, our findings suggest that biglycan and decorin play discrete roles in fetal membrane signaling pathways during inflammation, leading to changes in the abundance of MMP8 and collagen α1VI, two components of the fetal membrane extracellular matrix that influence the pathophysiology of PPROM. In summary, these findings underline the importance of biglycan and decorin as targets for the manipulation of fetal membrane extracellular matrix stability in the context of inflammation

A simulation based difficult conversations intervention for neonatal intensive care unit nurse practitioners: A randomized controlled trial.

BACKGROUND:Neonatal nurse practitioners are often the front line providers in discussing unexpected news with parents. This study seeks to evaluate whether a simulation based Difficult Conversations Workshop for neonatal nurse practitioners leads to improved skills in conducting difficult conversations. METHODS:We performed a randomized controlled study of a simulation based Difficult Conversations Workshop for neonatal nurse practitioners (n = 13) in a regional level IV neonatal intensive care unit to test the hypothesis that this intervention would improve communication skills. A simulated test conversation was performed after the workshop by the intervention group and before the workshop by the control group. Two independent blinded content experts scored each conversation using a quantitative communication skills performance checklist and by assigning an empathy score. Standard statistical analysis was performed. RESULTS:Randomization occurred as follows: n = 5 to the intervention group, n = 7 to the control group. All participants were analyzed in each group. Participation in the simulation based Difficult Conversations Workshop increases participants' empathy score (p = 0.015) and the use of communication skills (p = 0.013) in a simulated clinical encounter. CONCLUSIONS:Our study demonstrates that a lecture and simulation based Difficult Conversations Workshop for neonatal nurse practitioners improves objective communication skills and empathy in conducting difficult conversations

Mortality, morbidity and clinical care in a referral neonatal intensive care unit in Haiti.

BackgroundNeonatal mortality rates in Haiti are among the highest in the Western hemisphere. Few mothers deliver with a skilled birth attendant present, and there is a significant lack of pediatricians. The neonatal intensive care unit (NICU) at St. Damien Pediatric Hospital, a national referral center, is one of only five neonatology departments in Haiti. In order to target limited resources toward improving outcomes, this study seeks to describe clinical care in the St. Damien NICU.MethodsA retrospective medical record review was performed on available medical records on all admissions to the NICU between April 2016 and April 2017.Results220 neonates were admitted to the NICU within the study epoch. The mortality rate was 14.5%. Death was associated with a maternal diagnosis of hypertension (p = 0.03) and neonatal diagnoses of lower gestational age (pConclusionsThis study demonstrates that preterm birth, sepsis, RDS and kernicterus are key contributors to neonatal mortality in a Haitian national pediatric referral center NICU and as such are promising interventional targets for reducing the neonatal mortality rate in Haiti

Altered TGF-β expression in biglycan knockout mice.

<p><b>A:</b> TGF-β expression was evaluated in uterine samples of pregnant dams at E18. Western blotting was performed on wild-type, <i>Bgn−/−Dcn+/+</i> and <i>Bgn+/+Dcn−/−</i> uteri. GAPDH was used as an internal standard. <b>B:</b> TGF-β is decreased in the absence of biglycan. Digitally scanned and densitometrically analyzed Western blots from three experiments from three individual mouse uteri are expressed as a ratio of TGF-β over GAPDH and normalized to the wild-type ratio. Student's t-test. <i>P</i> = 0.004 for biglycan knockout; <i>P</i> = 0.46 for decorin knockout. Error bars = SD.</p

Lack of a significant compensatory mechanism at the gene level between biglycan and decorin in the knockout mice.

<p>Levels of biglycan mRNA in wild-type and <i>Bgn+/+Dcn−/−</i> mouse uterus, as well as decorin mRNA in wild-type and <i>Bgn−/−Dcn+/+</i> mouse uterus were determined using qPCR at progressive gestational ages. Biglycan and decorin are not developmentally regulated in the pregnant uterus, nor do they compensate for each other at the transcript level in the <i>Bgn−/−Dcn+/+</i> or the <i>Bgn+/+Dcn−/−</i> (<i>P</i> = 0.271 and <i>P</i> = 0.351 respectively). Two-way ANOVA Holm-Sidak. n = 4−6 samples from 4–6 pregnant dams per condition. E = embryonic day. Error bars = SD.</p