Lewis P. Rubin

Variations in Prevalence of Hypotension, Hypertension, and Vasopressor Use in NICUs

OBJECTIVE: Very low birth weight infants are vulnerable to hypotension and its associated complications. Vasopressors are used to raise blood pressure (BP), but indications for use are uncertain. Our objectives were (1) to study variations in BP stability among NICUs, (2) to investigate inter-NICU differences in vasopressor use, and (3) to address the association between intraventricular hemorrhage (IVH) and abnormal BPs.STUDY DESIGN: A total of 1288 infants with birth weight <1500 g were admitted to six NICUs in Massachusetts and Rhode Island over 21 months. The lowest and highest mean BPs were collected within the first 12 hours. Also recorded were the use of vasopressors within the first 24 hours and the occurrence of IVH. Logistic regressions were used to model outcomes, controlling for gestational age and illness severity using the Score for Neonatal Acute Physiology.RESULTS: Two of the six NICUs had significantly higher percentages of infants with at least one hypotensive BP, with prevalences of 24% to 45%. Percentages of infants treated with vasopressors ranged from 4% to 39%. This range of vasopressor use could not be explained by inter-NICU differences in birth weight, illness severity, or rates of hypotension. We found a borderline association between severe IVH and hypotension (odds ratio 1.6, p=0.055), but not between severe IVH and hypertension.CONCLUSION: Wide differences exist in the prevalence of hypotension, hypertension, and vasopressor use among NICUs. We also found an association between hypotension and IVH, but not between hypertension and IVH.

Variations in blood transfusions among newborn intensive care units

OBJECTIVES Very low birth weight (< 1500 g) infants frequently require packed red blood cell transfusions, and transfusion rates vary among neonatal intensive care units (NICUs). We analyzed transfusions and compared outcomes among NICUs. STUDY DESIGN In a 6-site prospective study, we abstracted all newborns weighing < 1500 g (total = 825) born between October 1994 and September 1995. Transfusion frequency and volume and phlebotomy number were analyzed by site and adjusted for birth weight and illness severity. We compared rates of intraventricular hemorrhage, necrotizing enterocolitis, bronchopulmonary dysplasia, growth, and length of stay between the high and low transfuser NICUs. RESULTS Sites differed significantly in mean birth weight, illness severity, number of transfusions, pretransfusion hematocrit, blood draws, and donor number. Multivariate adjustment for these risks showed that the highest transfusing NICU transfused an additional 24 cc/kg per baby during the first 14 days and 47 cc/kg per baby after 15 days, relative to the lowest transfusing NICU. The presence of arterial catheters increased the frequency of blood transfusions. The rates of intraventricular hemorrhage, necrotizing enterocolitis, and bronchopulmonary dysplasia were not higher in the 2 lowest transfusing NICUs, nor were there differences in 28-day weight gain or length of stay. CONCLUSIONS Major differences in transfusion practices for very low birth weight infants exist among NICUs. Because clinical outcomes were no different in lower transfuser NICUs, it is likely that transfusion and phlebotomy guidelines could result in fewer transfusions, fewer complications, and reduced cost.

Maternal and neonatal morbidity associated with in vitro fertilization

OBJECTIVE The purpose of this case-control study was to examine the maternal and neonatal morbidities associated with in vitro fertilization (IVF) in a single large teaching hospital. It was hypothesized that IVF mothers would have more perinatal complications and IVF infants would have higher mortality and morbidity rates than non-IVF control subjects. METHODS One hundred forty-three gestations resulting from 101 IVF pregnancies, which included singletons (n = 62), twins (n = 72), and triplets (n = 9), were compared with equal numbers of non-IVF control subjects. Each pregnancy was matched by maternal age, race, insurance type, neonatal gender, order of gestation, order in delivery, and date of delivery (+/- 6 months). Among the 143 matched gestations, six IVF and seven control infants died, leaving 137 IVF and 136 control neonates for comparison. RESULTS The IVF mothers had more pregnancy-induced hypertension (21% vs 4%), premature labor (44% vs 22%), labor induction (25% vs 1%), and preterm delivery (37% vs 21%). The IVF infant survivors had a lower mean (+/- SD) birth weight (2623 +/- 857 gm vs 3006 +/- 797 gm), more frequent occurrence of low birth weight (42% vs 27%), and shorter gestations (37 +/- 4 vs 38 +/- 3 weeks). The IVF infants had longer hospitalizations, more days of oxygen therapy, more days of continuous positive airway pressure, and increased prevalence of respiratory distress syndrome, patent ductus arteriosus, and sepsis. CONCLUSIONS Couples who undergo IVF appear to be at increased risk of having low birth weight and preterm infants, and multiple gestations account for most of the neonatal morbidities. Both the mothers who conceive multiple gestations by means of IVF and their neonates are at an increased risk of having multiple morbidities.

Effect of carotenoid supplementation on plasma carotenoids, inflammation and visual development in preterm infants

Objective:Dietary carotenoids (lutein, lycopene and β-carotene) may be important in preventing or ameliorating prematurity complications. Little is known about carotenoid status or effects of supplementation.Study Design:This randomized controlled multicenter trial compared plasma carotenoid levels among preterm infants (n=203, <33 weeks gestational age) fed diets with and without added lutein, lycopene and β-carotene with human milk (HM)-fed term infants. We assessed safety and health.Result:Plasma carotenoid levels were higher in the supplemented group at all time points (P<0.0001) and were similar to those of term HM-fed infants. Supplemented infants had lower plasma C-reactive protein (P<0.001). Plasma lutein levels correlated with the full field electroretinogram-saturated response amplitude in rod photoreceptors (r=0.361, P=0.05). The supplemented group also showed greater rod photoreceptor sensitivity (least squares means 6.1 vs 4.1; P<0.05).Conclusion:Carotenoid supplementation for preterm infants raises plasma concentrations to those observed in HM-fed term infants. Carotenoid supplementation may decrease inflammation. Our results point to protective effects of lutein on preterm retina health and maturation.

Perinatal risk and severity of illness in newborns at 6 neonatal intensive care units.

OBJECTIVES This multisite study sought to identify (1) any differences in admission risk (defined by gestational age and illness severity) among neonatal intensive care units (NICUs) and (2) obstetric antecedents of newborn illness severity. METHODS Data on 1476 babies born at a gestational age of less than 32 weeks in 6 perinatal centers were abstracted prospectively. Newborn illness severity was measured with the Score for Neonatal Acute Physiology. Regression models were constructed to predict scores as a function of perinatal risk factors. RESULTS The sites differed by several obstetric case-mix characteristics. Of these, only gestational age, small for gestational age. White race, and severe congenital anomalies were associated with higher scores. Antenatal corticosteroids, low Apgar scores, and neonatal hypothermia also affected illness severity. At 2 sites, higher mean severity could not be explained by case mix. CONCLUSIONS Obstetric events and perinatal practices affect newborn illness severity. These risk factors differ among perinatal centers and are associated with elevated illness severity at some sites. Outcomes of NICU care may be affected by antecedent events and perinatal practices.

Evidence for human placental synthesis of 24,25-dihydroxyvitamin D3 and 23,25-dihydroxyvitamin D3

ABSTRACT: The two principal dihydroxylated metabolites of the vitamin D prohormone 25-hydroxyvitamin D3 [25(OH)D3] are 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3, the active hormone] and 24R,25-dihydroxyvitamin D3 [24,25(OH)2D3, a putative regulator of developmental bone formation]. Although several studies have demonstrated placental synthesis of 1,25(OH)2D3 from 25(OH)D3, placental production of 24,25(OH)2D3 has not been thoroughly investigated. Therefore, we studied 25(OH)D3 metabolism in term human placenta using a villous explant model and cultures of isolated trophoblast and villous mesenchymal cells. We determined that both vitamin D-replete and vitamin D-deficient trophoblast metabolize 25(OH)D3 predominantly via 24-hydroxylation. Placental 24,25(OH)2D3 was identified by cochromatography with authentic standard on four different HPLC systems, scanning UV spectrophotometry profile of the metabolite, sensitivity to periodate cleavage, and mass spectrometry of the putative placental 24,25(OH)2D3 and its periodate cleavage product. We also identified for the first time placental synthesis of 23,25(OH)2D3 using cochromatography with authentic standard on two different HPLC systems, scanning UV spectrophotometry, resistance to periodate cleavage, and mass spectrometry. When trophoblast was incubated for up to 4 h with physiologic concentrations of [3H]25(OH)D3 (6 nM) significant amounts of [3H]24,25(OH)2D3 were produced, but ]3H]1,25(OH)2D3 could not be consistently detected. In contrast, when we incubated trophoblast with supraphysiologic concentrations of 25(OH)D3 (6–10 μM), both 24,25(OH)2D3 and 1,25(OH)2D3 were synthesized. These results provide unequivocal evidence for placental synthesis of both 24,25(OH)2D3 and 23,25(OH)2D3. These findings also suggest that supraphysiologic substrate concentrations saturate the placental 24-hydroxylase and may permit accumulation of placental 1,25(OH)2D3 by preventing its further metabolism. Consequently, the identification of this high basal 24-hydroxylase activity in trophoblast may explain inconsistencies among previous reports regarding placental 1,25(OH)2D3 production. We speculate that active placental 24-hydroxylation may serve important functions in perinatal vitamin D metabolism.

Role of macular xanthophylls in prevention of common neovascular retinopathies: Retinopathy of prematurity and diabetic retinopathy

Retinopathy of prematurity (ROP) and diabetic retinopathy (DR) are important causes of blindness among children and working-age adults, respectively. The development of both diseases involves retinal microvascular degeneration, vessel loss and consequent hypoxic and inflammatory pathologic retinal neovascularization. Mechanistic studies have shown that oxidative stress and subsequent derangement of cell signaling are important factors in disease progression. In eye and vision research, role of the dietary xanthophyll carotenoids, lutein and zeaxanthin, has been more extensively studied in adult onset macular degeneration than these other retinopathies. These carotenoids also may decrease severity of ROP in preterm infants and of DR in working-age adults. A randomized controlled clinical trial of carotenoid supplementation in preterm infants indicated that lutein has functional effects in the neonatal eye and is anti-inflammatory. Three multicenter clinical trials all showed a trend of decreased ROP severity in the lutein supplemented group. Prospective studies on patients with non-proliferative DR indicate serum levels of lutein and zeaxanthin are significantly lower in these patients compared to normal subjects. The present review describes recent advances in lutein and zeaxanthin modulation of oxidative stress and inflammation related to ROP and DR and discusses potential roles of lutein/zeaxanthin in preventing or lessening the risks of disease initiation or progression.

Maternal and pediatric health and disease: integrating biopsychosocial models and epigenetics

The concepts of allostasis (stability through adaptation) and accumulated life stress (McEwen’s allostatic load) aim to understand childhood and adult outcomes. Chronic malnutrition, changes in social condition, and adverse early-life experiences may program phenotypes and contribute to long-lasting disease risk. However, integration of life course approaches, social and economic contexts, and comparison among different biopsychosocial models has not generally been explored. This review critically examines the literature and evaluates recent insights into how environmental stress can alter lifelong hypothalamic–pituitary–adrenal axis and immune system responsiveness and induce metabolic and neurodevelopmental maladaptation. Models of biopsychosocial stress overlap but may consider different conditions. Concepts include allostasis, which incorporates hormonal responses to predictable environmental changes, and Geronimus’s “weathering,” which aims to explain how socially structured, repeated stress can accumulate and increase disease vulnerability. Weathering emphasizes roles of internalized/interpersonal racism in outcomes disparities. For Mexican immigrants and Mexican Americans, the “acculturation” framework has proven especially useful to explore disparities, including preterm birth and neuropsychiatric risks in childhood. Complexities of stress assessments and recent research into epigenetic mechanisms mediating effects of physical, nutritional, psychological, and social stress are reviewed.

Mitochondrial Beta-Carotene 9, 10 Oxygenase Modulates Prostate Cancer Growth via NF-kappaB Inhibition: a Lycopene-Independent Function

Despite numerous inquiries into protective roles of lycopene in prostate cancer prevention or therapy, little is known about mechanisms by which lycopene or its metabolites inhibit prostate cancer. The enzyme β-carotene 9′,10′-oxygenase (BCO2), which catalyzes asymmetric cleavage of several carotenoids, is the principal regulator of lycopene metabolism, but the range of BCO2 biological functions is incompletely understood. This study investigated expression and functional roles of BCO2 in human prostate cancer. Expression of the bco2 gene is dramatically decreased in prostate cancer tissue and in a range of prostate cancer cell lines as compared with nonneoplastic prostate tissue and normal prostatic epithelial cells, respectively. Inhibition of DNA methyltransferase activity restored bco2 expression in prostate cancer cell lines tested. Treatment with lycopene or its metabolite, apo-10-lycopenal, also increased bco2 expression and reduced cell proliferation in androgen-sensitive cell lines, but lycopene neither altered bco2 expression nor cell growth in androgen-resistant cells. Notably, restoring bco2 expression in prostate cancer cells inhibited cell proliferation and colony formation, irrespective of lycopene exposure. Exogenous expression of either wild-type BCO2 or a mutant (enzymatically inactive) BCO2 in prostate cancer cells reduced NF-κB activity and decreased NF-κB nuclear translocation and DNA binding. Together, these results indicate epigenetic loss of BCO2 expression is associated with prostate cancer progression. Moreover, these findings describe previously unanticipated functions of BCO2 that are independent of its enzymatic role in lycopene metabolism. Implications: This study identifies BCO2 as a tumor suppressor in prostate cancer. BCO2-mediated inhibition of NF-κB signaling implies BCO2 status is important in prostate cancer progression. Mol Cancer Res; 14(10); 966–75. ©2016 AACR.

Genome-Wide Methylome Analyses Reveal Novel Epigenetic Regulation Patterns in Schizophrenia and Bipolar Disorder

Schizophrenia (SZ) and bipolar disorder (BP) are complex genetic disorders. Their appearance is also likely informed by as yet only partially described epigenetic contributions. Using a sequencing-based method for genome-wide analysis, we quantitatively compared the blood DNA methylation landscapes in SZ and BP subjects to control, both in an understudied population, Hispanics along the US-Mexico border. Remarkably, we identified thousands of differentially methylated regions for SZ and BP preferentially located in promoters 3′-UTRs and 5′-UTRs of genes. Distinct patterns of aberrant methylation of promoter sequences were located surrounding transcription start sites. In these instances, aberrant methylation occurred in CpG islands (CGIs) as well as in flanking regions as well as in CGI sparse promoters. Pathway analysis of genes displaying these distinct aberrant promoter methylation patterns showed enhancement of epigenetic changes in numerous genes previously related to psychiatric disorders and neurodevelopment. Integration of gene expression data further suggests that in SZ aberrant promoter methylation is significantly associated with altered gene transcription. In particular, we found significant associations between (1) promoter CGIs hypermethylation with gene repression and (2) CGI 3′-shore hypomethylation with increased gene expression. Finally, we constructed a specific methylation analysis platform that facilitates viewing and comparing aberrant genome methylation in human neuropsychiatric disorders.