Low Rate of Spontaneous Closure in Premature Infants Discharged with a Patent Ductus Arteriosus: A Multicenter Prospective Study.

OBJECTIVES: To assess the rate of spontaneous closure and the incidence of adverse events in infants discharged home with a patent ductus arteriosus. STUDY DESIGN: In a prospective multicenter study, we enrolled 201 premature infants (gestational age of 23-32 weeks at birth) discharged home with a persistently patent ductus arteriosus (PDA) and followed their PDA status at 6-month intervals through 18 months of age. The primary study outcome was the rate and timing of spontaneous ductal closure. Secondary outcomes included rate of assisted closure and the incidence of serious adverse events. RESULTS: Spontaneous ductal closure occurred in 95 infants (47%) at 12 months and 117 infants (58%) by 18 months. Seventeen infants (8.4%) received assisted closure with surgical ligation or device assisted occlusion. Three infants died (1.5%). Although infants with spontaneous closure had a higher mean birth weight and gestational age compared with infants with a persistent PDA or assisted closure, we did not identify other factors predictive of spontaneous closure. CONCLUSIONS: Spontaneous closure of the PDA occurred in slightly less than one-half of premature infants discharged with a patent ductus by 1 year, lower than prior published reports. The high rate of assisted closure and/or adverse events in this population warrants close surveillance following discharge. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02750228.

P2Y12 Receptor Function and Response to Cangrelor in Neonates With Cyanotic Congenital Heart Disease.

Shunt thrombosis remains a major cause of morbidity and mortality, especially during the initial palliation for single-ventricle physiology. The authors present evidence that the P2Y12 inhibitor cangrelor may fill a therapeutic void in thromboprophylaxis. They base this theory on results showing that platelets from neonatal patients with cyanotic congenital heart disease have a robust response to adenosine diphosphate and are amenable to P2Y12 inhibition with cangrelor. Unique to this study was their ability to establish drug efficacy in an avatar mouse model that permits the in vivo evaluation of human platelet-mediated thrombus formation illustrating that this P2Y12 inhibitor yields the intended biological response.

Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation.

BACKGROUND: Marrow stromal cells (MSC) can differentiate into multiple mesenchymal tissues. To assess the feasibility of human MSC transplantation, we evaluated the in vitro immunogenicity of MSC and their ability to function as alloantigen presenting cells (APC). METHODS: Human MSC were derived and used in mixed cell cultures with allogeneic peripheral blood mononuclear cells (PBMC). Expression of immunoregulatory molecules on MSC was analyzed by flow cytometry. An MSC-associated suppressive activity was analyzed using cell-proliferation assays and enzyme-linked immunoassays. RESULTS: MSC failed to elicit a proliferative response when cocultured with allogeneic PBMC, despite provision of a costimulatory signal delivered by an anti-CD28 antibody and pretreatment of MSC with gamma-interferon. MSC express major histocompatibility complex (MHC) class I and lymphocyte function-associated antigen (LFA)-3 antigens constitutively and MHC class II and intercellular adhesion molecule (ICAM)-1 antigens upon gamma-interferon treatment but do not express CD80, CD86, or CD40 costimulatory molecules. MSC actively suppressed proliferation of responder PBMC stimulated by third-party allogeneic PBMC as well as T cells stimulated by anti-CD3 and anti-CD28 antibodies. Separation of MSC and PBMC by a semipermeable membrane did not abrogate the suppression. The suppressive activity could not be accounted for by MSC production of interleukin-10, transforming growth factor-beta1, or prostaglandin E2, nor by tryptophan depletion of the culture medium. CONCLUSIONS: Human MSC fail to stimulate allogeneic PBMC or T-cell proliferation in mixed cell cultures. Unlike other nonprofessional APC, this failure of function is not reversed by provision of CD28-mediated costimulation nor gamma-interferon pretreatment. Rather, MSC actively inhibit T-cell proliferation, suggesting that allogeneic MSC transplantation might be accomplished without the need for significant host immunosuppression.

Stem cell plasticity and blood and marrow transplantation: a clinical strategy.

The newly described phenomenon of stem cell plasticity raises interesting biological questions and offers exciting opportunities in clinical application. This review uses the well-established practice of blood and marrow transplantation as a paradigm to explore the clinical consequences of this finding. Recently proposed non-myeloablative conditioning regimens have shown that mixed donor-host hematolymphoid chimerism can be established with relatively low toxicity in both animal studies and human trials. Hematopoietic growth factor treatment of transplanted patients can mobilize a large number of donor stem cells to migrate from marrow to non-hematopoietic organs. We propose that these advances, in conjunction with the developmental plasticity of stem cells, can constitute components of a clinical strategy to use blood and marrow transplantation as a platform to treat systemic diseases involving non-hematopoietic tissues.