Mother Infant Research Institute at Tufts Medical Center

Boston, MA, United States

Mother Infant Research Institute at Tufts Medical Center

Boston, MA, United States

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Maron J.L.,Mother Infant Research Institute at Tufts Medical Center
Clinical Therapeutics | Year: 2015

Premature newborns present unique challenges for the caregiver. Their clinical fragility and immature immune system places them at increased risk for bacterial and viral infections. Current clinical standard of care mandates invasive phlebotomy to assess an infant for an infection. However, serial blood draws can lead to blood transfusions and the infliction of noxious stimuli to this vulnerable population. Salivary screening for common neonatal morbidities, such as infections, could vastly improve the care for these infants and positively affect their long-term clinical outcomes. Recent technological advancements have improved our ability to detect thousands of proteins and/or microbes from a single salivary sample, making noninvasive assessment in neonates a possibility. This article reviews the clinical applications and challenges associated with integrating salivary analysis for infectious surveillance into the neonatal population. © 2015 Elsevier HS Journals, Inc.


Maron J.L.,Floating Hospital for Children at Tufts Medical Center | Maron J.L.,Mother Infant Research Institute at Tufts Medical Center | Dietz J.A.,Floating Hospital for Children at Tufts Medical Center | Parkin C.,Institute for Clinical Research and Health Policy Studies | And 3 more authors.
Journal of Maternal-Fetal and Neonatal Medicine | Year: 2012

Objective: To perform discovery-driven research on the neonatal salivary and cord blood transcriptomes. Methods: Two separate cohorts of infants were enrolled in this study. In one, cord blood (n = 10) and in the other, saliva samples (n = 10) were collected at term gestation. Total RNA was extracted, amplified and hybridized onto Affymetrix HG U133a gene expression microarrays. Following normalization, genes expressed in the highest quintile (≥ 80%) across all subjects in each biofluid were analyzed with Ingenuity Pathway Analysis. Over-represented pathways relating to organ specific development and physiological functions in the newborn were explored. Results: There were 303 genes in neonatal saliva and 282 genes in umbilical cord blood that met statistical criteria. Of these, 114 were common to both biofluids. Pathway analyses revealed the important roles of redox balance, cellular proliferation, and smooth muscle relaxation. In blood, hematopoiesis and immune response pathways predominated. In saliva, pathways associated with the gastrointestinal system were highlighted. Conclusions: Neonatal cord blood and saliva provide a wealth of transcriptomic information. These normally discarded biofluids should be considered an important source of real-time gene expression data that may elucidate key pathways in neonatal physiology and pathology. © 2012 Informa UK, Ltd.


Maron J.L.,Floating Hospital for Children at Tufts Medical Center | Maron J.L.,Mother Infant Research Institute at Tufts Medical Center | Johnson K.L.,Floating Hospital for Children at Tufts Medical Center | Johnson K.L.,Mother Infant Research Institute at Tufts Medical Center | And 4 more authors.
PLoS ONE | Year: 2012

Background: The current practice in newborn medicine is to subjectively assess when a premature infant is ready to feed by mouth. When the assessment is inaccurate, the resulting feeding morbidities may be significant, resulting in long-term health consequences and millions of health care dollars annually. We hypothesized that the developmental maturation of hypothalamic regulation of feeding behavior is a predictor of successful oral feeding in the premature infant. To test this hypothesis, we analyzed the gene expression of neuropeptide Y2 receptor (NPY2R), a known hypothalamic regulator of feeding behavior, in neonatal saliva to determine its role as a biomarker in predicting oral feeding success in the neonate. Methodology/Principal Findings: Salivary samples (n = 116), were prospectively collected from 63 preterm and 13 term neonates (post-conceptual age (PCA) 26 4/7 to 41 4/7 weeks) from five predefined feeding stages. Expression of NPY2R in neonatal saliva was determined by multiplex RT-qPCR amplification. Expression results were retrospectively correlated with feeding status at time of sample collection. Statistical analysis revealed that expression of NPY2R had a 95% positive predictive value for feeding immaturity. NPY2R expression statistically significantly decreased with advancing PCA (Wilcoxon test p value<0.01), and was associated with feeding status (chi square p value = 0.013). Conclusions/Significance: Developmental maturation of hypothalamic regulation of feeding behavior is an essential component of oral feeding success in the newborn. NPY2R expression in neonatal saliva is predictive of an immature feeding pattern. It is a clinically relevant biomarker that may be monitored in saliva to improve clinical care and reduce significant feeding-associated morbidities that affect the premature neonate. © 2012 Maron et al.


Dietz J.A.,Floating Hospital for Children at Tufts Medical Center | Johnson K.L.,Floating Hospital for Children at Tufts Medical Center | Johnson K.L.,Mother Infant Research Institute at Tufts Medical Center | Wick H.C.,Tufts University | And 4 more authors.
Neonatology | Year: 2012

Background: Gene expression profiling of the salivary supernatant is emerging as a new and important source of real-time, systemic, biological information. However, existing technologies prevent RNA extraction of small quantities found in neonatal salivary supernatant. Objective: The aim of this study was to develop techniques to enhance extraction of cell-free RNA from neonatal salivary supernatant. Methods: Two saliva samples (10-100 μl) were serially collected from newborns (36-41 weeks' gestation) (n = 13) and stabilized. Total RNA was extracted from salivary supernatant with the use of two modified extraction techniques: Qiagen RNAprotect® Saliva Mini Kit (method 1) and the QIAamp Viral RNA Mini Kit (method 2). Quantitative RT-PCR amplification for GAPDH was performed on extracted salivary samples. Statistical analyses were performed on mean threshold cycle (Ct) levels to compare RNA yield from each protocol. Paired microarray analyses were made between neonatal whole saliva and supernatant (n = 3) to discern gene expression differences between these biolayers. Results: mRNA was successfully extracted and amplified from all salivary supernatant samples. Extraction with method 2 yielded more RNA than with method 1 (p = 0.008). There was a 7.5% discordance between paired gene expression analyses for whole saliva and supernatant. Genes that were statistically significantly upregulated in supernatant highlighted 16 distinct biological functions not seen in whole saliva. Conversely, only two biological functions were unique to whole saliva. Conclusion: Neonatal cell-free salivary supernatant mRNA may be readily extracted and utilized on downstream applications. These technical enhancements allow for further exploration of the diagnostic potential of the neonatal salivary transcriptome. Copyright © 2011 S. Karger AG, Basel.


Dao M.C.,U.S. Department of Agriculture | Sen S.,U.S. Department of Agriculture | Sen S.,Mother Infant Research Institute at Tufts Medical Center | Sen S.,Floating Hospital for Children at Tufts Medical Center | And 4 more authors.
Journal of Perinatology | Year: 2013

Objective: To ascertain the effect of obesity-related inflammation on maternal and fetal iron status. We hypothesized that obese (Ob) pregnant women would have increased inflammation, hepcidin levels, and that their infants would have impaired iron status compared with lean (Lc) controls. Study Design: Fifteen Ob and fifteen Lc women were recruited in their second trimester of pregnancy. Markers of iron status, inflammation and hepcidin were measured in maternal and cord blood. Student's t-test was used to compare Ob and Lc groups, and Pearson's correlation coefficients were determined between maternal and cord blood values. Result: Maternal C-reactive protein (P<0.01) and hepcidin (P<0.01) were higher, and cord blood iron (P<0.01) was lower in the Ob group. Maternal body mass index (P<0.01) and hepcidin (P<0.05) were negatively correlated with cord blood iron status. Conclusion: Maternal obesity is associated with impaired maternal-fetal iron transfer, potentially through hepcidin upregulation. Copyright © 2013 Nature America, Inc.


PubMed | Leiden University, Beth Israel Deaconess Medical Center, Mother Infant Research Institute at Tufts Medical Center and University Medicine of Berlin
Type: | Journal: Journal of reproductive immunology | Year: 2014

In oocyte donation (OD) pregnancies, there is a higher level of antigenic dissimilarity between mother and fetus compared with naturally conceived (NC) pregnancies. We hypothesize that a higher degree and/or a different type of immunoregulation is necessary to maintain an uncomplicated OD pregnancy. Different immunological aspects of successful OD pregnancies (n=28) were compared with those of NC pregnancies (n=51), and non-donor IVF (n=20) pregnancies. Maternal peripheral blood mononuclear cells (mPBMCs) were characterized by flow cytometry; the outcome correlated with the number of mother-child HLA mismatches. The fetus-specific alloreactivity of mPBMCs was measured in a mixed lymphocyte reaction. The percentages of CD4(+)CD25(bright) and CD4(+)CD25(dim) cells were higher in mPBMCs of OD and IVF pregnancies compared with NC pregnancies. The percentage of CD4(+)CD25(dim) cells in mPBMCs of OD pregnancies correlated positively with the number of HLA mismatches. Functional studies showed a lower proliferative response to umbilical cord blood by mPBMCs in OD pregnancies. In conclusion, we found a higher degree of peripheral immunoregulation in OD and IVF pregnancies compared with NC pregnancies. A higher number of HLA mismatches in successful OD pregnancies leads to increased percentages of activated T cells in peripheral blood, but not to a higher alloreactivity to the fetus. These studies show that immunoregulation in OD pregnancy is different from that in NC pregnancies. The antigenic dissimilarity in OD pregnancies may play a role in the pathophysiology of preeclampsia.


Hui L.,Mother Infant Research Institute at Tufts Medical Center | Hui L.,University of Sydney | Bianchi D.W.,Mother Infant Research Institute at Tufts Medical Center
Human Reproduction Update | Year: 2011

Background: Research into cell-free fetal (cff) nucleic acids has primarily focused on maternal plasma; however, cff DNA and RNA are also detectable in other body fluids such as amniotic fluid (AF). In AF, cff DNA is present in much greater concentrations than in maternal plasma and represents a pure fetal sample uncontaminated by maternal- and trophoblast-derived nucleic acids. The aim of this review was to summarize the current knowledge on cff nucleic acids in AF and to outline future research directions. Methods: MEDLINE and PREMEDLINE were searched up to August 2010 for original investigations of cell-free RNA or DNA in AF. Sixteen studies were included in the review. Results: AF cff DNA represents a physiologically separate pool from cff DNA in maternal plasma. The placenta is not a major source of nucleic acids in AF. It is feasible to isolate cff nucleic acids from small volumes of discarded AF supernatant in sufficient quality and quantity to perform microarray studies and downstream applications such as pathway analysis. This 'discovery-driven approach' has resulted in new information on the pathogenesis of Down syndrome and polyhydramnios. There is otherwise a paucity of information relating to the basic biology and clinical applications of cff nucleic acids in AF. Conclusions: AF supernatant is a valuable and widely available but under-utilized biological resource. Further studies of cff nucleic acids in AF may lead to new insights into human fetal development and ultimately new approaches to antenatal treatment of human disease. © The Author 2010. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.


PubMed | Mother Infant Research Institute at Tufts Medical Center and Tufts Medical Center
Type: Journal Article | Journal: Clinical therapeutics | Year: 2015

Premature newborns present unique challenges for the caregiver. Their clinical fragility and immature immune system places them at increased risk for bacterial and viral infections. Current clinical standard of care mandates invasive phlebotomy to assess an infant for an infection. However, serial blood draws can lead to blood transfusions and the infliction of noxious stimuli to this vulnerable population. Salivary screening for common neonatal morbidities, such as infections, could vastly improve the care for these infants and positively affect their long-term clinical outcomes. Recent technological advancements have improved our ability to detect thousands of proteins and/or microbes from a single salivary sample, making noninvasive assessment in neonates a possibility. This article reviews the clinical applications and challenges associated with integrating salivary analysis for infectious surveillance into the neonatal population.


PubMed | Mother Infant Research Institute at Tufts Medical Center
Type: Journal Article | Journal: Stem cells and development | Year: 2012

The transfer of fetal cells to maternal organs occurs in mouse and human pregnancy. Techniques such as polymerase chain reaction and flow cytometry do not permit study of fetal cell morphology or anatomic location. Using a green fluorescent protein (GFP) transgenic mouse model, our objective was to determine whether GFP+ signal emanates from intact or degraded fetal cells, and whether they have a characteristic appearance and location within maternal lung. Four wild-type female mice were mated to males homozygous for the Gfp transgene and studied at days e16-18. Controls were 2 females mated to wild-type males. Morphologic appearance and anatomic position of each GFP+ object within maternal lung was recorded. GFP signals were sufficiently bright to be visualized without anti-GFP antibody and were confirmed by confocal microscopy to be separate from fluorescent artifact. Of 438 GFP+ objects detected, 375 (85.6%) were from intact cells, and 63 (14.4%) were acellular. Four distinct categories of intact cells were observed. Of these, 23.2% had mononuclear morphology with a relatively large nucleus and GFP+ cytoplasm (Group A). An additional group of cells (10.1%) had mononuclear morphology and podocyte extensions (Group B). The remainder of cells had fragmented nuclei or cytoplasm. Both intact cells and acellular fragments were predominantly localized to the maternal alveolar septum (P<0.0001). This study demonstrates that fetal GFP+ cells are predominantly located in the alveolar septum and have characteristic morphologies, although it remains unclear whether these represent distinct categories of cells or degrading cells. Nevertheless, this naturally acquired population of fetal cells in maternal lung should be considered in studies of lung biology and repair.


PubMed | Mother Infant Research Institute at Tufts Medical Center
Type: Journal Article | Journal: Trends in genetics : TIG | Year: 2013

The amount of genetic and genomic information obtainable from the human fetus during pregnancy is accelerating at an unprecedented rate. Two themes have dominated recent technological advances in prenatal diagnosis: interrogation of the fetal genome in increasingly high resolution and the development of non-invasive methods of fetal testing using cell-free DNA in maternal plasma. These two areas of advancement have now converged with several recent reports of non-invasive assessment of the entire fetal genome from maternal blood. However, technological progress is outpacing the ability of the healthcare providers and patients to incorporate these new tests into existing clinical care, and further complicates many of the economic and ethical dilemmas in prenatal diagnosis. This review summarizes recent work in this field and discusses the integration of these new technologies into the clinic and society.

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