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1.  Randomized Controlled Pilot Trial of Mindfulness Training for Stress Reduction during Pregnancy 
Psychology & health  2013;29(3):334-349.
This randomized controlled pilot trial tested a 6-week mindfulness-based intervention in a sample of pregnant women experiencing high levels of perceived stress and pregnancy anxiety. Forty-seven women enrolled between 10 and 25 weeks gestation were randomly assigned to either a series of weekly Mindful Awareness Practices (MAPS) classes (n = 24) with home practice or to a reading control condition (n = 23). Hierarchical linear models of between-group differences in change over time demonstrated that participants in the mindfulness intervention experienced larger decreases from pre-to post-intervention in pregnancy-specific anxiety and pregnancy-related anxiety than participants in the reading control condition. However, these effects were not sustained through follow-up at six weeks post-intervention. Participants in both groups experienced increased mindfulness, as well as decreased perceived stress and state anxiety over the course of the intervention and follow-up periods. This study is one of the first randomized controlled pilot trials of a mindfulness meditation intervention during pregnancy and provides some evidence that mindfulness training during pregnancy may effectively reduce pregnancy-related anxiety and worry. We discuss some of the dilemmas in pursuing this translational strategy and offer suggestions for researchers interested in conducting mind-body interventions during pregnancy.
PMCID: PMC4160533  PMID: 24180264
Pregnancy; Meditation; Mindfulness; Prenatal Stress; Pregnancy Anxiety
2.  Racial and Ethnic Disparities in Personal Capital During Pregnancy: Findings from the 2007 Los Angeles Mommy and Baby (LAMB) Study 
Maternal and child health journal  2014;18(1):10.1007/s10995-013-1256-3.
To determine if racial and ethnic differences in personal capital during pregnancy exist and to estimate the extent to which any identified racial and ethnic differences in personal capital are related to differences in maternal sociodemographic and acculturation characteristics.
Data are from the 2007 Los Angeles Mommy and Baby (LAMB) study (n=3,716). Personal capital comprised internal resources (self-esteem and mastery) and social resources (partner, social network, and neighborhood support) during pregnancy. The relationships between race/ethnicity and personal capital were assessed using multivariable generalized linear models, examining the impact of sociodemographic and acculturation factors on these relationships.
Significant racial and ethnic disparities in personal capital during pregnancy exist. However, socioeconomic status (i.e., income and education) and marital status completely explained Black-White disparities and Hispanic-White disparities in personal capital, whereas acculturation factors, especially nativity and language spoken at home, partially mediated the disparities in personal capital between Asian/Pacific Islander women and White women.
Findings suggest that the risks associated with low socioeconomic status, single motherhood, and low acculturation, rather than race or ethnicity, contribute to low personal capital for many pregnant women. As personal capital during pregnancy may influence subsequent maternal and child health outcomes, the development of interventions should consider addressing sociodemographic and acculturation factors in order to reduce racial and ethnic disparities in personal capital and ultimately in poor maternal and child health outcomes.
PMCID: PMC3748227  PMID: 23504131
Maternal and child health; personal capital; racial and ethnic disparities; pregnancy
3.  The 2007 Los Angeles Mommy and Baby Study: A Multilevel, Population-Based Study of Maternal and Infant Health in Los Angeles County 
Objectives. In order to comprehensively examine the risks and resources associated with racial-ethnic disparities in adverse obstetric outcomes, the Los Angeles County Department of Public Health and the University of California, Los Angeles, joined efforts to design and implement the 2007 Los Angeles Mommy and Baby (LAMB) study. This paper aims to present the conceptual frameworks underlying the study's development, highlight the successful collaboration between a research institution and local health department, describe the distinguishing characteristics of its methodology, and discuss the study's implications for research, programs, and policies. Methods. The LAMB study utilized a multilevel, multistage cluster design with a mixed-mode methodology for data collection. Two samples were ultimately produced: the multilevel sample (n = 4,518) and the augmented final sample (n = 6,264). Results. The LAMB study allowed us to collect multilevel data on the risks and resources associated with racial-ethnic disparities in adverse obstetric outcomes. Both samples were more likely to be Hispanic, aged 20–34 years, completed at least 12 years of schooling, and spoke English. Conclusions. The LAMB study represents the successful collaboration between an academic institution and local health department and is a theoretically based research database and surveillance system that informs effective programmatic and policy interventions to improve outcomes among LAC's varied demographic groups.
PMCID: PMC4279178  PMID: 25580305
4.  CD151-α3β1 integrin complexes suppress ovarian tumor growth by repressing slug-mediated EMT and canonical Wnt signaling 
Oncotarget  2014;5(23):12203-12217.
Human ovarian cancer is diagnosed in the late, metastatic stages but the underlying mechanisms remain poorly understood. We report a surprising functional link between CD151-α3β1 integrin complexes and the malignancy of serous-type ovarian cancer. Analyses of clinical specimens indicate that CD151 expression is significantly reduced or diminished in 90% of metastatic lesions, while it remains detectable in 58% of primary tumors. These observations suggest a putative tumor-suppressing role of CD151 in ovarian cancer. Indeed, our analyses show that knocking down CD151 or α3 integrin enhances tumor cell proliferation, growth and ascites production in nude mice. These changes are accompanied by impaired cell-cell contacts and aberrant expression of E-cadherin, Mucin 5AC and fibronectin, largely reminiscent of an epithelial to mesenchymal transition (EMT)-like change. Importantly, Slug, a master regulator of EMT, is markedly elevated. Knocking down Slug partially restores CD151-α3β1 integrin complex-dependent suppression of cell proliferation. Moreover, disruption of these adhesion protein complexes is accompanied by a concomitant activation of canonical Wnt signaling, including elevated levels of β-catenin and Axin-2 as well as resistance to the inhibition in β-catenin-dependent transcriptional complexes. Together, our study demonstrates that CD151-α3β1 integrin complexes regulate ovarian tumor growth by repressing Slug-mediated EMT and Wnt signaling.
PMCID: PMC4322965  PMID: 25356755
CD151; integrin; EMT; tumor growth; ovarian cancer
5.  Anterograde trafficking of neurotrophin-3 in the adult olfactory system in vivo 
Experimental neurology  2012;241:125-137.
The olfactory system continuously incorporates new neurons into functional circuits throughout life. Axons from olfactory sensory neurons (OSNs) in the nasal cavity synapse on mitral, tufted and periglomerular (PG) cells in the main olfactory bulb, and low levels of turnover within the OSN population results in ingrowth of new axons under normal physiological conditions. Subpopulations of bulb interneurons are continually eliminated by apoptosis, and are replaced by new neurons derived from progenitors in the adult forebrain subventricular zone. Integration of new neurons, including PG cells that are contacted by sensory axons, leads to ongoing reorganization of adult olfactory bulb circuits. The mechanisms regulating this adaptive structural plasticity are not all known, but the process is reminiscent of early nervous system development. Neurotrophic factors have well-established roles in controlling neuronal survival and connectivity during development, leading to speculation that trophic interactions between OSNs and their target bulb neurons may mediate some of these same processes in adults. A number of different trophic factors and their cognate receptors are expressed in the adult olfactory pathway. Neurotrophin-3 (NT3) is among these, as reflected by beta-galactosidase expression in transgenic reporter mice expressing lacZ under the NT3 promoter. Using a combination of approaches, including immunocytochemistry, real-time PCR of laser-captured RNA, and adenovirus-mediated gene transfer of NT3 fusion peptides in vivo, we demonstrate that OSNs express and anterogradely transport NT3 to the olfactory bulb. We additionally observe that in mice treated with adenovirus encoding NT3 tagged with hemagglutinin (HA), a subset of bulb neurons expressing the TrkC neurotrophin receptor are immunoreactive for HA, suggesting their acquisition of the fusion peptide from infected sensory neurons. Our results therefore provide evidence that OSNs may serve as an afferent source of trophic signals for the adult mouse olfactory bulb.
PMCID: PMC3570701  PMID: 23261763
6.  Use of Postpartum Care: Predictors and Barriers 
Journal of Pregnancy  2014;2014:530769.
This study aimed to identify actual and perceived barriers to postpartum care among a probability sample of women who gave birth in Los Angeles County, California in 2007. Survey data from the 2007 Los Angeles Mommy and Baby (LAMB) study (N = 4,075) were used to identify predictors and barriers to postpartum care use. The LAMB study was a cross-sectional, population-based study that examined maternal and child health outcomes during the preconception, prenatal, and postpartum periods. Multivariable analyses identified low income, being separated/divorced and never married, trying hard to get pregnant or trying to prevent pregnancy, Medi-Cal insurance holders, and lack of prenatal care to be risk factors of postpartum care nonuse, while Hispanic ethnicity was protective. The most commonly reported barriers to postpartum care use were feeling fine, being too busy with the baby, having other things going on, and a lack of need. Findings from this study can inform the development of interventions targeting subgroups at risk for not obtaining postpartum care. Community education and improved access to care can further increase the acceptability of postpartum visits and contribute to improvements in women's health. Postpartum care can serve as a gateway to engage underserved populations in the continuum of women's health care.
PMCID: PMC3945081  PMID: 24693433
7.  Na+/K+-ATPase Expression Changes in the Rabbit Lacrimal Glands During Pregnancy 
Current eye research  2012;38(1):18-26.
To investigate the expressional changes of Na+/K+-ATPase subunits in the lacrimal glands (LG) of term pregnant rabbits.
LG were obtained from term pregnant rabbits and age-matched female control rabbits for laser capture microdissection (LCM), real time RT-PCR, western blot, and immunofluorescence. The mRNA and proteins of α1, α2, β1, β2, and β3 subunits of Na+/K+-ATPase were detected and quantified.
Although only the mRNA for β3 from whole LG of pregnant rabbits was significantly different from that of normal controls, many mRNA levels for α1, α2, β1, β2, and β3 from acini and epithelial cells from various duct segments that were collected by LCM were significantly different from those of normal control rabbits. Western blots demonstrated that the expressions of all three β subunits were significantly higher in pregnant rabbits, while both α subunits remained unchanged during pregnancy. Interestingly, immunofluorescence results showed that the distribution patterns of all Na+/K+-ATPase subunits during pregnancy were similar to those of the control rabbits.
Changes were found in mRNA and protein expressions of Na+/K+-ATPase subunits in LG from term pregnant rabbits and these changes suggest a role in the pregnancy-related LG secretion changes and dry eye symptoms observed in these animals.
PMCID: PMC3636992  PMID: 23009595
Dry eye; Lacrimal gland; Na+/K+-ATPase; Pregnancy
8.  Mental Health Outcomes in US Children and Adolescents Born Prematurely or with Low Birthweight 
We examined the effects of prematurity (<37 weeks of gestation) and low birthweight (<2500 g) on mental health outcomes among US children aged 2–17 years. The 2011-2012 National Survey of Children's Health (N = 95,677) was used to estimate prevalence of parent-reported mental health problems in children. Prevalence of mental disorders was 22.9% among children born prematurely, 28.7% among very-low-birth-weight (<1500 g) children, and 18.9% among moderately low-birth-weight (1500–2499 g) children, compared with 15.5% in the general child population. Compared to those born full term, children born prematurely had 61% higher adjusted odds of serious emotional/behavioral problems, 33% higher odds of depression, and 58% higher odds of anxiety. Children born prematurely had 2.3 times higher odds of autism/ASD, 2.9 times higher odds of development delay, and 2.7 times higher odds of intellectual disability than term children. Very-low-birth-weight children had 3.2 times higher odds of autism/ASD, 1.7 times higher odds of ADD/ADHD, 5.4 times higher odds of development delay, and 4.4 times higher odds of intellectual disability than normal-birth-weight children. Social factors were significant predictors of mental disorders in both premature/low-birth-weight and term/normal-birth-weight children. Neurodevelopmental conditions accounted for the relationship between prematurity and depression/anxiety/conduct problems. Prematurity and low birthweight are significant risk factors for mental health problems among children.
PMCID: PMC3845867  PMID: 24324882
9.  Direct Interaction between AR and PAK6 in Androgen-Stimulated PAK6 Activation 
PLoS ONE  2013;8(10):e77367.
A p21-activated kinase 6 (PAK6) was previously identified to be an androgen receptor (AR) interacting protein through a yeast two-hybrid screening. We used hormone responsive prostate cancer LAPC4 and LNCap cell lines as models to study the signaling events associated with androgen stimulation and PAK6. An androgen-stimulated PAK6 kinase activation was observed in LAPC4 cells expressing endogenous PAK6 and in LNCap cells ectopically expressing a wild type PAK6. This activation was likely mediated through a direct interaction between AR and PAK6 since siRNA knock-down of AR in LAPC4 cells downregulated androgen-stimulated PAK6 activation. In addition, LNCap cells expressing a non-AR-interacting PAK6 mutant exhibited dampened androgen-stimulated kinase activation. As a consequence of androgen-stimulated activation, PAK6 was phosphorylated at multiple serine/threonine residues including the AR-interacting domain of PAK6. Furthermore, androgen-stimulation promoted prostate cancer cell motility and invasion were demonstrated in LNCap cells ectopically expressing PAK6-WT. In contrast, LNCap expressing non-AR-interacting mutant PAK6 did not respond to androgen stimulation with increased cell motility and invasion. Our results demonstrate that androgen-stimulated PAK6 activation is mediated through a direct interaction between AR and PAK6 and PAK6 activation promotes prostate cancer cells motility and invasion.
PMCID: PMC3795072  PMID: 24130878
10.  One Hundred Intentional Acts of Kindness Toward a Pregnant Woman: Building Reproductive Social Capital in Los Angeles 
Ethnicity & disease  2010;20(1 0 2):S2-36-40.
This article describes the development of an innovative community-based program, One Hundred Intentional Acts of Kindness toward a Pregnant Woman© (100 Acts), which seeks to increase reproductive social capital for pregnant women in south and central Los Angeles communities. Reproductive social capital includes features such as networks, norms, and social trust that facilitate optimal reproductive health within a community. 100 Acts was designed and developed by the Healthy African American Families project, using community participatory methods, to increase local community and social network support for pregnant women. Dialog groups with pregnant women identified specific actions that families, friends, and strangers might do to support pregnancies. Participants primarily wanted emotional and instrumental support from family and friends. From strangers, they wanted respect for personal space and common courtesy. Based on these results, the 100 Acts was created for use in the Los Angeles community. 100 Acts encourages and engages active participation from community members in promoting healthy pregnancies. By seeking to increase community-level reproductive social capital, 100 Acts shifts the provision of social support during pregnancy from a high-risk approach to a population approach. 100 Acts also establishes new social norms about how pregnant women are valued, treated and respected.
PMCID: PMC3787313  PMID: 20629245
11.  Lifecourse Health Development: Past, Present and Future 
Maternal and Child Health Journal  2013;18(2):344-365.
During the latter half of the twentieth century, an explosion of research elucidated a growing number of causes of disease and contributors to health. Biopsychosocial models that accounted for the wide range of factors influencing health began to replace outmoded and overly simplified biomedical models of disease causation. More recently, models of lifecourse health development (LCHD) have synthesized research from biological, behavioral and social science disciplines, defined health development as a dynamic process that begins before conception and continues throughout the lifespan, and paved the way for the creation of novel strategies aimed at optimization of individual and population health trajectories. As rapid advances in epigenetics and biological systems research continue to inform and refine LCHD models, our healthcare delivery system has struggled to keep pace, and the gulf between knowledge and practice has widened. This paper attempts to chart the evolution of the LCHD framework, and illustrate its potential to transform how the MCH system addresses social, psychological, biological, and genetic influences on health, eliminates health disparities, reduces chronic illness, and contains healthcare costs. The LCHD approach can serve to highlight the foundational importance of MCH, moving it from the margins of national debate to the forefront of healthcare reform efforts. The paper concludes with suggestions for innovations that could accelerate the translation of health development principles into MCH practice.
PMCID: PMC3890560  PMID: 23975451
Lifecourse health development; LCHD; Epigenetics; Systems biology; Genomics; Biopsychosocial; DOHaD; Complexity
12.  CFTR-Mediated Cl− Transport in the Acinar and Duct Cells of Rabbit Lacrimal Gland 
Current eye research  2012;37(8):671-677.
We investigated the role that the cystic fibrosis transmembrane conductance regulator (CFTR) may play in Cl− transport in the acinar and ductal epithelial cells of rabbit lacrimal gland (LG).
Primary cultured LG acinar cells were processed for whole-cell patch-clamp electrophysiological recording of Cl− currents by using perfusion media with high and low [Cl−], 10 μM forskolin and 100 μM 3-isobutyl-1-methylxanthine (IBMX), the non-specific Cl− channel blocker 4,4′-disothiocyanostilbene-2, 2′ sulphonic acid (DIDS; 100 μM) and CFTRinh-172 (10 μM), a specific blocker for CFTR. Ex vivo live cell imaging of [Cl−] changes in duct cells was performed on freshly dissected LG duct with a multiphoton confocal laser scanning microscope using a Cl− sensitive fluorescence dye, N-[ethoxycarbonylmethyl]-6-methoxy-quinolinium bromide.
Whole-cell patch-clamp studies demonstrated the presence of Cl− current in isolated acinar cells and revealed that this Cl− current was mediated by CFTR channel. Live cell imaging also showed the presence of CFTR-mediated Cl− transport across the plasma membrane of duct cells.
Our previous data showed the presence of CFTR in all acinar and duct cells within the rabbit LG, with expression most prominent in the apical membranes of duct cells. The present study demonstrates that CFTR is actively involved in Cl− transport in both acinar cells and epithelial cells from duct segments, suggesting that CFTR may play a significant role in LG secretion.
PMCID: PMC3625439  PMID: 22578307
CFTR; Chloride channel; Lacrimal gland; Dry eye
13.  Not All Lacrimal Epithelial Cells are Created Equal—Heterogeneity of the Rabbit Lacrimal Gland and Differential Secretion 
Current eye research  2011;36(11):971-978.
To test the hypotheses that some epithelial cells in the rabbit lacrimal gland (LG) are mucin-secreting cells that are also particularly rich in aquaporin 5 (AQP5) and sodium potassium ATPase β1 subunit (NKAβ1), LG-secreted mucins contribute to the total mucin pool in tear film, and that the rabbit LG is a heterogenic gland where proteins secreted in response to different agonists are varied.
Materials and methods
LGs were obtained from adult female rabbits and processed for paraffin sections for hematoxylin and eosin (HE) staining, periodic acid-Schiff (PAS), mucicarmine, and Alcian blue (pH 0.4, 1.0, and 2.5) for the detection of mucins. Serial sections were used for immunohistochemistry (IHC) and PAS. LG lysates and fluids were assayed by dot blot for detection of mucins, and by SDS-PAGE to detect differences in protein profiles of LG fluids stimulated by different agonists.
HE staining demonstrated that the LG is a heterogeneous gland where most epithelial cells are serous, while all duct cells are mucous cells. Some acini and individual acinar cells within serous acini are also mucous or seromucous cells and these cells are particularly rich in AQP5 and NKAβ1. Dot blot assay showed the presence of mucins in the LG fluids. The protein profiles of LG fluids from pilocarpine, phenylephrine, and isoproterenol varied significantly, particularly in the mid range.
Our data indicated that the rabbit LG is a heterogeneous gland that is composed of both serous and mucin-secreting cells, and mucins produced by the LG contribute to the mucin pool in the tear film. The heterogeneity of the rabbit LG supports the notion of differential secretion, i.e. the volume and composition of the LG fluids vary depending on various circumstances in the ocular surface and the body’s needs.
PMCID: PMC3625438  PMID: 21999223
Lacrimal gland; Heterogeneity; Mucin; Dry eye; Differential secretion
14.  Changes of Chloride Channels in the Lacrimal Glands of a Rabbit Model of Sjögren’s syndrome 
Cornea  2012;31(3):273-279.
To test the hypothesis that expression of Na+-K+-2Cl− co-transporter-1 (NKCC1), cystic fibrosis transmembrane conductance regulator (CFTR), and chloride channel 2 γ subunit (ClC2γ) in the lacrimal glands (LG) of rabbits with induced autoimmune dacryoadenitis (IAD) are changed.
LGs were obtained from adult female rabbits with IAD, and age-matched female control rabbits. LGs were processed for laser capture microdissection, real time RT-PCR, western blot, and immunofluorescence.
In rabbits with IAD, mRNA abundances and protein expressions for NKCC1 and CFTR from whole LGs were significantly lower than in controls. mRNA abundances of NKCC1, CFTR, and ClC2γ from rabbits with IAD were significantly different from acini and ductal cells from controls. NKCC1 was localized to the basolateral membranes of all acinar and ductal cells, with weaker staining intensity in ductal cells, and the staining pattern from rabbits with IAD appeared similar to that from controls. CFTR was found as punctate aggregates in the apical cytoplasm of all acinar and ductal cells, with the intensity in ductal cells much stronger, and no significant difference between controls and rabbits with IAD. ClC2γ was also localized to the apical cytoplasm as punctate aggregates of all acinar cells, but not in ductal cells, and similar staining pattern was observed in rabbits with IAD to control rabbits.
Our data demonstrated significant changes of mRNA and protein expressions of NKCC1, CFTR, and ClC2γ in rabbits with IAD, suggesting that these changes may contribute to the altered lacrimal secretion, particularly Cl− transport, in rabbits with IAD.
PMCID: PMC3276741  PMID: 22157573
lacrimal gland; chloride channels; dry eye; Sjögren’s syndrome
15.  An Alternative Kaposi's Sarcoma-Associated Herpesvirus Replication Program Triggered by Host Cell Apoptosis 
Journal of Virology  2012;86(8):4404-4419.
Kaposi's sarcoma-associated herpesvirus (KSHV) is linked to several neoplastic diseases: Kaposi's sarcoma, primary effusion lymphoma (PEL), and multicentric Castleman's disease (MCD). KSHV replicates actively, via a controlled gene expression program, but can also remain latent. It had been thought that the transition from latent to lytic replication was controlled exclusively by the replication and transcription activator protein RTA (open reading frame 50 [ORF50] gene product). A dominant-negative (DN) ORF50 mutant, ORF50ΔSTAD, blocks gene expression and replication. We produced a PEL cell line derivative containing both latent KSHV genomes and an inducible ORF50ΔSTAD. We unexpectedly found that induction of apoptosis triggered high-level viral replication, even when DN ORF50ΔSTAD was present, suggesting that apoptosis triggers KSHV replication through a distinct RTA-independent pathway. We verified that apoptosis triggers KSHV replication independent of RTA using ORF50 small interfering RNA (siRNA) and also showed that caspase activity is required to trigger KSHV replication. We showed that when apoptosis triggers KSHV replication, the kinetics of late gene expression is accelerated by 12 to 24 h and that virus produced following apoptosis has reduced infectivity. KSHV therefore appears to replicate via two distinct pathways, a conventional pathway requiring RTA, with slower replication kinetics, producing virus with higher infectivity, and an alternative apoptosis-triggered pathway that does not require RTA, has faster replication kinetics, and produces virus with lower infectivity. The existence of a distinct apoptosis-triggered, accelerated replication pathway may have evolutionary advantages for the virus and clinical significance for the treatment of KSHV-associated neoplasms. It also provides further evidence that KSHV can sense and react to its environment.
PMCID: PMC3318647  PMID: 22345480
16.  The Contribution of Maternal Stress to Preterm Birth: Issues and Considerations 
Clinics in perinatology  2011;38(3):351-384.
Preterm birth represents the most significant problem in maternal-child health. The ongoing search to elucidate its underlying causes and pathophysiological mechanisms has identified maternal stress as a variable of interest. Based on emerging models of causation of complex common disorders, we suggest that the effects of maternal stress on risk of preterm birth may, for the most part, vary as a function of context. In this paper we focus on select key issues and questions that highlight the need to develop a better understanding of which particular subgroups of pregnant women, under what circumstances, and at which stage(s) of gestation, may be especially vulnerable to the potentially detrimental effects of maternal stress. Our discussion addresses issues related to the characterization and assessment of maternal stress and candidate biological (maternal-placental-fetal endocrine, immune, vascular and genetic) mechanisms. We propose the adoption of newer approaches (ecological momentary assessment) and a life-course perspective to further our understanding of the contribution of maternal stress to preterm birth.
PMCID: PMC3179976  PMID: 21890014
stress; preterm birth; psychosocial; maternal-placental-fetal endocrine; immune; vascular; genetic
17.  Pericyte-Derived MFG-E8 Regulates Pathologic Angiogenesis 
MFG-E8 (lactadherin, SED1) is a secreted glycoprotein that has been previously implicated in enhancement of VEGF-dependent angiogenesis. Major sources of MFG-E8 in vivo, and precise mechanisms of MFG-E8 action remain undetermined. The objective of this study was to identify important sources of MFG-E8 in vivo, and further elucidate the role(s) of MFG-E8 in the regulation of angiogenesis.
Methods and Results
We utilized knockout mice and anti-MFG-E8 antibodies to study MFG-E8 function in vivo. In melanomas and in retinas of mice with oxygen-induced retinopathy, MFG-E8 colocalized with pericytes rather than endothelial cells, and platelet-derived growth factor receptor β (PDGFRβ)+ pericytes/pericyte precursors purified from tumors contained large amounts of MFG-E8 mRNA. Tumor- and retinopathy-associated angiogenesis was diminished in MFG-E8 knockout mice and pericyte coverage of neovessels was reduced. Inhibition of MFG-E8 production by 10T1/2 cells (surrogate pericyte/pericyte precursors) using small interfering (si)RNAs and short hairpin (sh)RNAs, or inhibition of MFG-E8 action with some anti-MFG-E8 antibodies, selectively attenuated migration in vitro. Significantly, the anti-MFG-E8 antibodies that inhibited 10T1/2 cell migration in vitro also inhibited pathologic angiogenesis in vivo.
These studies strongly implicate MFG-E8 in pericytes/pericyte precursor function, and indicate that MFG-E8-directed therapeutics may merit further development.
PMCID: PMC3184509  PMID: 21737783
MFG-E8; pericyte; angiogenesis; oxygen-induced retinopathy; melanoma
18.  Na+/K+-ATPase in the lacrimal glands of rabbits and its changes during induced autoimmune dacryoadenitis 
Molecular Vision  2011;17:2368-2379.
To test the hypothesis that expression of Na+/K+-ATPase subunits in the lacrimal glands (LGs) of rabbits with induced autoimmune dacryoadenitis (IAD) changes.
LGs were obtained from adult female rabbits with IAD and age-matched female control rabbits. The LGs were processed for laser capture microdissection (LCM), real time RT–PCR, western blot, and immunofluorescence for the detection of mRNA and proteins of the α1, α2, β1, β2, and β3 subunits of Na+/K+-ATPase.
In the rabbits with IAD, mRNA levels of α1, β1, and β3 from whole LGs were significantly lower. In samples of acini and epithelial cells from various duct segments, collected by LCM, mRNA levels of α1, β1, β2, and β3 were significantly lower in the rabbits with IAD, although mRNA for α2 could not be detected. However, western blots demonstrated that all five subunits were significantly higher in the rabbits with IAD, although their distribution patterns were similar to those of the control rabbits, as demonstrated by immunofluorescence.
The data presented herein demonstrated significant changes in mRNA and protein expressions of Na+/K+-ATPase subunits in rabbits with IAD, suggesting that these changes may play a role in the pathogenesis of Sjögren’s syndrome and altered LG secretion, as observed in these animals.
PMCID: PMC3171493  PMID: 21921989
19.  Changes of the ocular surface and aquaporins in the lacrimal glands of rabbits during pregnancy 
Molecular Vision  2011;17:2847-2855.
To test the hypotheses that pregnancy represents a physiologic condition that is associated with dry eye symptoms, and the expression of aquaporin 4 (AQP4) and AQP5 are altered in the lacrimal gland (LG) from term pregnant rabbits.
Schirmer’s test, tear break-up time (BUT), and Rose Bengal staining were used to evaluate ocular surface health. LG were obtained from term pregnant rabbits and age-matched female control rabbits and then processed for laser capture microdissection (LCM), real time RT–PCR, western blot, and immunofluorescence for the detection and quantification of mRNA and proteins of AQP4 and AQP5.
Pregnant rabbits demonstrated typical clinical symptoms of dry eye, including decreased Schirmer score and BUT as well as increased Rose Bengal staining of cornea. In term pregnant rabbits, mRNA for AQP5 from whole LG was significantly lower than that of control rabbits, while mRNA for AQP4 was not. Levels of mRNA for AQP4 and AQP5 underwent significant changes in acini and epithelial cells from specific duct segments during pregnancy. Western blot from whole LG lysates demonstrated that expression of AQP4 was 24% more abundant in term pregnant rabbits while AQP5 was 22% less when compared to control rabbits respectively. At term pregnancy, AQP4 immunoreactivity (AQP4-IR) was increased in acini while its intensity remained the same in ducts. AQP5-IR was present in both apical and basolateral membranes of acinar cells in normal control and pregnant rabbits, while ductal cells in pregnant rabbits also showed significant amount of AQP5-IR.
The data presented here demonstrated significant dry eye symptoms in pregnant rabbits. Our data also showed altered expressions of AQP4 and AQP5 during pregnancy and suggested that these changes may contribute to the altered LG secretion and dry eye symptoms during pregnancy.
PMCID: PMC3224838  PMID: 22128232
20.  Early Life Disease Programming during the Preconception and Prenatal Period: Making the Link between Stressful Life Events and Type-1 Diabetes 
PLoS ONE  2010;5(7):e11523.
To assess the risk of developing Type-1 diabetes among children who were exposed to maternal bereavement during the prenatal or 1-year preconception period.
We identified N = 1,548,746 singleton births born in Denmark between January 1st 1979 through December 31st 2004, and their next of kin. Altogether, 39,857 children were exposed to bereavement during their prenatal life. The main outcome of interest was hospitalization for type-1 diabetes (ICD 8: 249; ICD 10: E10).
We found the strongest association for type-1 diabetes among children exposed to traumatic father or sibling deaths (aIRR: 2.03, 1.22–3.38); the association was mainly seen for girls (aIRR: 2.91, 1.61–5.26).
We found evidence to suggest that female fetuses exposed to severe prenatal stress are at increased risk for developing type-1 diabetes.
PMCID: PMC2901388  PMID: 20634978
21.  Trans allele methylation and paramutation-like effects in mice 
Nature genetics  2003;34(2):199-202.
In mammals, imprinted genes have parent-of-origin–specific patterns of DNA methylation that cause allele-specific expression. At Rasgrf1 (encoding RAS protein-specific guanine nucleotide-releasing factor 1), a repeated DNA element is needed to establish methylation and expression of the active paternal allele1. At Igf2r (encoding insulin-like growth factor 2 receptor), a sequence called region 2 is needed for methylation of the active maternal allele2,3. Here we show that replacing the Rasgrf1 repeats on the paternal allele with region 2 allows both methylation and expression of the paternal copy of Rasgrf1, indicating that sequences that control methylation can function ectopically. Paternal transmission of the mutated allele also induced methylation and expression in trans of the normally unmethylated and silent wild-type maternal allele. Once activated, the wild-type maternal Rasgrf1 allele maintained its activated state in the next generation independently of the paternal allele. These results recapitulate in mice several features in common with paramutation described in plants4.
PMCID: PMC2744043  PMID: 12740578
22.  Reformatted 4-Chamber and Short Axis Views of the Heart Using Thin Section (≤2mm) MDCT Images 
Academic radiology  2007;14(9):1108-1112.
In cardiovascular CT, thin collimation results in a large number of images per examination. Moreover, interpretation relies on multiplanar reformatted images. While many strategies for approaching cardiac reformations have been described, as CT utilization increases, so does the importance of simple and reproducible post-processing algorithms. The clinical importance of reformations has recently extended beyond the left ventricle to include the right ventricular in patients with pulmonary embolism (PE). This work illustrates an algorithm to reformat two of the most important views in cardiovascular CT: the 4-chamber and short axis views. The illustration is performed in the context of two cardiovascular examinations: cardiac CT and CT pulmonary angiography (CTPA).
PMCID: PMC2706116  PMID: 17707319
Image Processing; Computed Tomography Angiography; Cardiovascular; Pulmonary Embolism
23.  Preconception Care Between Pregnancies: The Content of Internatal Care 
Maternal and Child Health Journal  2006;10(Suppl 1):107-122.
For more than two decades, prenatal care has been a cornerstone of our nation’s strategy for improving pregnancy outcomes. In recent years, however, a growing recognition of the limits of prenatal care and the importance of maternal health before pregnancy has drawn increasing attention to preconception and internatal care. Internatal care refers to a package of healthcare and ancillary services provided to a woman and her family from the birth of one child to the birth of her next child. For healthy mothers, internatal care offers an opportunity for wellness promotion between pregnancies. For high-risk mothers, internatal care provides strategies for risk reduction before their next pregnancy. In this paper we begin to define the contents of internatal care. The core components of internatal care consist of risk assessment, health promotion, clinical and psychosocial interventions. We identified several priority areas, such as FINDS (family violence, infections, nutrition, depression, and stress) for risk assessment or BBEEFF (breastfeeding, back-to-sleep, exercise, exposures, family planning and folate) for health promotion. Women with chronic health conditions such as hypertension, diabetes, or weight problems should receive on-going care per clinical guidelines for their evaluation, treatment, and follow-up during the internatal period. For women with prior adverse outcomes such as preterm delivery, we propose an internatal care model based on known etiologic pathways, with the goal of preventing recurrence by addressing these biobehavioral pathways prior to the next pregnancy. We suggest enhancing service integration for women and families, including possibly care coordination and home visitation for selected high-risk women. The primary aim of this paper is to start a dialogue on the content of internatal care.
PMCID: PMC1592148  PMID: 16817001
Preconception care; Internatal care; Content; Preterm birth; Interpregnancy
24.  Dissection of the Kaposi's Sarcoma-Associated Herpesvirus Gene Expression Program by Using the Viral DNA Replication Inhibitor Cidofovir 
Journal of Virology  2004;78(24):13637-13652.
Treatment of primary effusion lymphoma cells latently infected by Kaposi's sarcoma-associated herpesvirus (KSHV; human herpesvirus-8 [HHV-8]) with agents such as 12-O-tetradecanoylphorbol-13-acetate (TPA) induces a lytic viral replication cycle, with an ordered gene expression program. Initial studies of the KSHV expression program following TPA induction using viral microarrays yielded useful information concerning the viral expression program, but precise kinetic assignments for some genes remained unclear. Classically, late herpesvirus genes require viral DNA replication for maximal expression. We used cidofovir (CDV), a nucleotide-analogue KSHV DNA polymerase inhibitor, to dissect KSHV expression into two components: genes expressed without viral DNA replication and those requiring it. The expression of known immediate-early or early genes (e.g., open reading frames [ORFs] 50, K8 bZIP, and 57) serving lytic regulatory roles was relatively unaffected by the presence of CDV, while known late capsid and tegument structural genes (e.g., ORFs 25, 26, 64, and 67) were CDV sensitive. Latency-associated transcript ORF 73 was unaffected by the presence of TPA or CDV, suggesting that it was constitutively expressed. Expression of several viral cellular gene homologs, including K2 (vIL-6), ORF 72 (vCyclin), ORF 74 (vGPCR), and K9 (vIRF-1), was unaffected by the presence of CDV, while that of others, such as K4.1 (vMIP-III), K11.1 (vIRF-2), and K10.5 (LANA2, vIRF-3), was inhibited. The results distinguish KSHV genes whose full expression required viral DNA replication from those that did not require it, providing additional insights into KSHV replication and pathogenesis strategies and helping to show which viral cell homologs are expressed at particular times during the lytic process.
PMCID: PMC533899  PMID: 15564474
25.  In Vitro Killing of Community-Associated Methicillin-Resistant Staphylococcus aureus with Drug Combinations 
Antimicrobial Agents and Chemotherapy  2004;48(10):4016-4019.
This study employs time-kill techniques to examine the most common drug combinations used in the therapy of methicillin-resistant Staphylococcus aureus (MRSA) infections, vancomycin plus either gentamicin or rifampin. Community-associated MRSA were more likely to be synergistically inhibited by combinations of vancomycin and gentamicin versus vancomycin alone compared to inhibition associated with hospital-acquired strains.
PMCID: PMC521878  PMID: 15388469

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