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1.  The Association of Obesity With Episodic and Chronic Migraine 
Headache  2012;52(4):663-671.
About 18% of adolescents and 33% of adults are obese in the United States. Recent studies demonstrating an association between migraine and obesity raise fascinating questions about the mechanism for this association and suggest new potential avenues of treatment for migraine.
doi:10.1111/j.1526-4610.2012.02114.x
PMCID: PMC3973149  PMID: 22404044
migraine; obesity; adipose tissue; headache; exercise; bariatric surgery
2.  Risk of Spontaneous Preterm Birth in Relation to Maternal Exposure to Intimate Partner Violence During Pregnancy in Peru 
Maternal and child health journal  2013;17(3):485-492.
Objective
Intimate partner violence (IPV) is increasingly recognized as an important cause of maternal and perinatal morbidity. We assessed the relation between IPV and risk of spontaneous preterm birth (PTB) among Peruvian women.
Methods
The study was conducted among 479 pregnant women who delivered a preterm singleton infant (<37 weeks gestation) and 480 controls (≥37 weeks gestation). Participants’ exposure to physical and emotional violence during pregnancy was collected during in-person interviews conducted after delivery and while patients were in hospital. Odds ratios (aOR) and 95% confidence intervals (CI) were estimated from logistic regression models.
Results
The prevalence of any IPV during pregnancy was 52.2% among cases and 34.6% among controls. Compared with those reporting no exposure to IPV during pregnancy, women reporting any exposure had a 2.1-fold increased risk of PTB (95% CI 1.59–2.68). The association was attenuated slightly after adjusting for maternal age, pre-pregnancy weight, and other covariates (OR=1.99; 95% CI: 1.52–2.61). Emotional abuse in the absence of physical violence was associated with a 1.6-fold (95% CI 1.21–2.15) increased risk of PTB. Emotional and physical abuse during pregnancy was associated with a 4.7-fold increased risk of PTB (95% CI 2.74–7.92). Associations of similar directions and magnitudes were observed when PTB were sub-categorized according to clinical presentation or severity.
Conclusion
IPV among pregnant women is common and is associated with an increased risk of PTB. Our findings and those of others support recent calls for coordinated global health efforts to prevent violence against women.
doi:10.1007/s10995-012-1012-0
PMCID: PMC3565008  PMID: 22527763
Preterm birth; intimate partner violence; pregnant women; Peru
3.  Physical Activity and Metabolic Syndrome among Ethiopian Adults 
American Journal of Hypertension  2013;26(4):535-540.
BACKGROUND
The global prevalence of chronic noncommunicable diseases (NCDs) is on the rise, with the majority of the growth occurring among populations in developing countries. Few studies have quantified the health benefits for physical activity among sub-Saharan African adults. We examined associations of physical activity with the prevalence of metabolic syndrome (MetS) and its components in Ethiopian men and women.
METHODS
This cross-sectional study of 1,843 individuals (1,117 men and 726 women) was conducted among working adults (public schools and bank employees) in Addis Ababa, Ethiopia. The study was conducted in accordance with the STEPwise approach of the World Health Organization. Physical activity was assessed using a previously validated Global Physical Activity Questionnaire. MetS was defined according to the International Diabetes Federation criteria. Multivariable logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CI).
RESULTS
The odds of MetS was inversely associated with physical activity in men (P trend = 0.02) but not women (P trend = 0.85). Among men, the OR of MetS comparing those with high vs. low levels of physical activity was 0.56 (95% CI = 0.33–0.97). For women, the corresponding OR was 1.07 (95% CI = 0.57–2.01). Physical activity was significantly and inversely associated with high waist circumference and hypertriglyceridemia among men, but no such associations were observed among women.
CONCLUSIONS
Higher levels of physical activity were inversely associated with MetS and several individual components among men. No similar trends were observed among women in this cohort, in part because of the small sample size.
doi:10.1093/ajh/hps079
PMCID: PMC3626042  PMID: 23422933
Africa; blood pressure; global health; hypertension; metabolic syndrome; noncommunicable disease; physical activity.
4.  Multispectral optical imaging device for in vivo detection of oral neoplasia 
Journal of biomedical optics  2008;13(2):024019.
A multispectral digital microscope (MDM) is designed and constructed as a tool to improve detection of oral neoplasia. The MDM acquires in vivo images of oral tissue in fluorescence, narrowband (NB) reflectance, and orthogonal polarized reflectance (OPR) modes, to enable evaluation of lesions that may not exhibit high contrast under standard white light illumination. The device rapidly captures image sequences so that the diagnostic value of each modality can be qualitatively and quantitatively evaluated alone and in combination. As part of a pilot clinical trial, images are acquired from normal volunteers and patients with precancerous and cancerous lesions. In normal subjects, the visibility of vasculature can be enhanced by tuning the reflectance illumination wavelength and polarization. In patients with histologically confirmed neoplasia, we observe decreased blue/green autofluorescence and increased red autofluorescence in lesions, and increased visibility of vasculature using NB and OPR imaging. The perceived lesion borders change with imaging modality, suggesting that multimodal imaging has the potential to provide additional diagnostic information not available using standard white light illumination or by using a single imaging mode alone.
doi:10.1117/1.2904658
PMCID: PMC3970814  PMID: 18465982
oral cancer; diagnosis; noninvasive; optical imaging; fluorescence; decreased autofluorescence; reflectance; polarized; orthogonal; porphyrin; vasculature; monochromatic
5.  Effects of Social Injustice on Breast Health–Seeking Behaviors of Low-Income Women 
Purpose
The study uses qualitative research to gain a better understanding of what occurs after low-income women receive an abnormal breast screening and the factors that influence their decisions and behavior. A heuristic model is presented for understanding this complexity.
Design
Qualitative research methods used to elicited social and cultural themes related to breast cancer screening follow-up.
Setting
Individual telephone interviews were conducted with 16 women with confirmed breast anomaly.
Participants
Low-income women screened through a national breast cancer early detection program.
Method
Grounded theory using selective coding was employed to elicit factors that influenced the understanding and follow-up of an abnormal breast screening result. Interviews were digitally recorded, transcribed, and uploaded into NVivo 8, a qualitative management and analysis software package.
Results
For women (16, or 72% of case management referrals) below 250% of the poverty level, the impact of social and economic inequities creates a psychosocial context underlined by structural and cultural barriers to treatment that forecasts the mechanism that generates differences in health outcomes. The absence of insurance due to underemployment and unemployment and inadequate public infrastructure intensified emotional stress impacting participants’ health decisions.
Conclusion
The findings that emerged offer explanations of how consistent patterns of social injustice impact treatment decisions in a high-risk vulnerable population that have implications for health promotion research and systems-level program improvement and development.
doi:10.4278/ajhp.110505-QUAL-189
PMCID: PMC3971010  PMID: 23448411
Breast Cancer; African-American; Health Care–Seeking Behavior; Social Inequity; Prevention Research
7.  Risk of spontaneous preterm birth in relation to maternal experience of serious life events during pregnancy 
Background
The purpose of this study was to examine the risk of preterm birth (PTB) in relation to serious life events experienced during pregnancy in Peruvian women.
Methods
This case-control study included 479 PTB cases and 480 term controls. In-person interviews asked information regarding sociodemographics, medical and reproductive histories, and serious life events experienced during pregnancy. Multivariate logistic regression procedures were used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs).
Results
Compared with women who did not experience a serious life event during pregnancy, those who experienced the following life events had a more than two-fold increased odds of PTB: death of first-degree relative (adjusted OR 2.10; 95% CI 1.38–3.20), divorce or separation (adjusted OR 2.09; 95% CI 1.10–4.00), financial troubles (adjusted OR 2.70; 95% CI 1.85–3.94), or serious fight with partner (adjusted OR 2.40; 95% CI 1.78–3.17). Women who experienced any serious life events during pregnancy had higher odds (adjusted OR 2.29; 95% CI 1.65–3.18) of suffering spontaneous preterm labor and preterm premature rupture of membranes (adjusted OR 2.19; 95% CI 1.56–3.08), compared with women who did not experience any such events. Associations of similar directions and extent were observed for severity of PTB (ie, very, moderate, or late PTB). The magnitude of the associations increased as increased frequency of serious life events (Ptrend <0.001).
Conclusion
Experiencing serious life events during pregnancy was associated with increased odds of PTB among Peruvian women. Interventions aimed at assisting women experiencing serious life events may reduce the risk of PTB. Future studies should include objective measures of stress and stress response to understand better the biological underpinnings of these associations.
doi:10.2147/IJWH.S54269
PMCID: PMC3938466  PMID: 24591850
preterm birth; serious life events; Peru
8.  Platelets and Smooth Muscle Cells Affecting the Differentiation of Monocytes 
PLoS ONE  2014;9(2):e88172.
Background
Atherosclerosis is characterised by the formation of plaques. Monocytes play a pivotal role in plaque development as they differentiate into foam cells, a component of the lipid core whilst smooth muscle cells (SMC) are the principal cell identified in the cap. Recently, the ability of monocytes to differentiate into a myriad of other cell types has been reported. In lieu of these findings the ability of monocytes to differentiate into SMCs/smooth muscle (SM)-like cells was investigated.
Method and Results
Human monocytes were co-cultured with platelets or human coronary aortic SMCs and then analysed to assess their differentiation into SMCs/SM-like cells. The differentiated cells expressed a number of SMC markers and genes as determined by immunofluorescence staining and quantitative polymerase chain reaction (qPCR). CD array analysis identified marker expression profiles that discriminated them from monocytes, macrophages and foam cells as well as the expression of markers which overlapped with fibroblast and mesenchymal cells. Electron microscopy studies identified microfilaments and increased amounts of rough endoplasmic reticulum indicative of the SM- like cells, fibroblasts.
Conclusions
In the appropriate environmental conditions, monocytes can differentiate into SM-like cells potentially contributing to cap formation and plaque stability. Thus, monocytes may play a dual role in the development of plaque formation and ultimately atherosclerosis.
doi:10.1371/journal.pone.0088172
PMCID: PMC3925135  PMID: 24551082
9.  Modifiable Cardiovascular Disease Risk Factors among Indigenous Populations 
Objective. To identify modifiable cardio-metabolic and lifestyle risk factors among indigenous populations from Australia (Aboriginal Australians/Torres Strait Islanders), New Zealand (Māori), and the United States (American Indians and Alaska Natives) that contribute to cardiovascular disease (CVD). Methods. National health surveys were identified where available. Electronic databases identified sources for filling missing data. The most relevant data were identified, organized, and synthesized. Results. Compared to their non-indigenous counterparts, indigenous populations exhibit lower life expectancies and a greater prevalence of CVD. All indigenous populations have higher rates of obesity and diabetes, hypertension is greater for Māori and Aboriginal Australians, and high cholesterol is greater only among American Indians/Alaska Natives. In turn, all indigenous groups exhibit higher rates of smoking and dangerous alcohol behaviour as well as consuming less fruits and vegetables. Aboriginal Australians and American Indians/Alaska Natives also exhibit greater rates of sedentary behaviour. Conclusion. Indigenous groups from Australia, New Zealand, and the United States have a lower life expectancy then their respective non-indigenous counterparts. A higher prevalence of CVD is a major driving force behind this discrepancy. A cluster of modifiable cardio-metabolic risk factors precede CVD, which, in turn, is linked to modifiable lifestyle risk factors.
doi:10.1155/2014/547018
PMCID: PMC3933231  PMID: 24649368
10.  Migraine and Psychiatric Comorbidities among Sub-Saharan African Adults 
Headache  2012;53(2):310-321.
Background
Despite being a highly prevalent disorder and substantial cause of disability, migraine is understudied in Africa. Moreover, no previous study has investigated the effects of stress and unipolar psychiatric comorbidities on migraine in a sub-Saharan African cohort.
Objective
To evaluate the prevalence of migraine and its association with stress and unipolar psychiatric comorbidities among a cohort of African adults.
Methods
This was a cross-sectional epidemiologic study evaluating 2,151 employed adults in sub-Saharan Africa. A standardized questionnaire was used to identify socio-demographic, headache, and lifestyle characteristics of participants. Migraine classification was based on the International Classification of Headache Disorders (ICHD)-2 diagnostic criteria. Depressive, anxiety and stress symptoms were ascertained with the Patient Health Questionnaire (PHQ-9) and the Depression Anxiety Stress Scale (DASS-21) respectively. Multivariable logistic regression models were used to estimate adjusted odds ratio (OR) and 95% confidence intervals (CI).
Results
A total of 9.8% (n=212) of study participants fulfilled criteria for migraine (9.8%; 95%CI: 8.6, 11.1) with a higher frequency among women (14.3%; 95%CI: 11.9, 16.6) than men (6.9%; 95%CI: 5.5, 8.3). Similar to predominantly Caucasian migraine cohorts, sub-Saharan African migraineurs were more likely to be younger, have a lower education and more likely to report a poor health status than non-migraineurs. However, in contrast to historical reports in predominantly Caucasian migraine cohorts, sub-Saharan African migraineurs were less likely to report smoking than non-migraineurs. Participants with moderately severe depressive symptoms had over a 3-fold increased odds of migraine (OR=3.36; 95% CI 1.30,8.70), compared with those classified as having minimal or no depressive symptoms; and the odds of migraine increased with increasing severity of depressive symptoms (p-trend <0.001). Similarly those with mild, moderate and severe anxiety symptoms had increased odds of migraine (OR=2.28; 95%CI 1.24, 4.21; OR=1.77; 95%CI 0.93, 3.35, and OR=5.39; 95%CI 2.19, 13.24, respectively). Finally, those with severe stress had a 3.57-fold increased odds of migraine (OR=3.57; 95%CI 1.35, 9.46).
Conclusion
Although historically it has been reported that migraine prevalence is greater in Caucasians than African Americans, our study demonstrates a high migraine prevalence among urban dwelling Ethiopian adults (9.9%) that is comparable to what is typically reported in predominantly Caucasian cohorts. Further, among employed sub-Saharan African adults, and similar to predominantly Caucasian populations, migraine is strongly associated with stress and unipolar psychiatric symptoms. The high burden of migraine and its association with stress and unipolar psychiatric symptoms in our study of well-educated and urban dwelling African adults has important clinical and public health implications pending confirmation in other African populations.
doi:10.1111/j.1526-4610.2012.02259.x
PMCID: PMC3556345  PMID: 23095087
Migraine; Depression; Anxiety; Stress; Comorbidities; Sub-Saharan Africa
11.  Landscape of DNA Virus Associations across Human Malignant Cancers: Analysis of 3,775 Cases Using RNA-Seq 
Journal of Virology  2013;87(16):8916-8926.
Elucidation of tumor-DNA virus associations in many cancer types has enhanced our knowledge of fundamental oncogenesis mechanisms and provided a basis for cancer prevention initiatives. RNA-Seq is a novel tool to comprehensively assess such associations. We interrogated RNA-Seq data from 3,775 malignant neoplasms in The Cancer Genome Atlas database for the presence of viral sequences. Viral integration sites were also detected in expressed transcripts using a novel approach. The detection capacity of RNA-Seq was compared to available clinical laboratory data. Human papillomavirus (HPV) transcripts were detected using RNA-Seq analysis in head-and-neck squamous cell carcinoma, uterine endometrioid carcinoma, and squamous cell carcinoma of the lung. Detection of HPV by RNA-Seq correlated with detection by in situ hybridization and immunohistochemistry in squamous cell carcinoma tumors of the head and neck. Hepatitis B virus and Epstein-Barr virus (EBV) were detected using RNA-Seq in hepatocellular carcinoma and gastric carcinoma tumors, respectively. Integration sites of viral genes and oncogenes were detected in cancers harboring HPV or hepatitis B virus but not in EBV-positive gastric carcinoma. Integration sites of expressed viral transcripts frequently involved known coding areas of the host genome. No DNA virus transcripts were detected in acute myeloid leukemia, cutaneous melanoma, low- and high-grade gliomas of the brain, and adenocarcinomas of the breast, colon and rectum, lung, prostate, ovary, kidney, and thyroid. In conclusion, this study provides a large-scale overview of the landscape of DNA viruses in human malignant cancers. While further validation is necessary for specific cancer types, our findings highlight the utility of RNA-Seq in detecting tumor-associated DNA viruses and identifying viral integration sites that may unravel novel mechanisms of cancer pathogenesis.
doi:10.1128/JVI.00340-13
PMCID: PMC3754044  PMID: 23740984
12.  Evaluation of Hyperpolarized [1-13C]-Pyruvate by Magnetic Resonance to Detect Ionizing Radiation Effects in Real Time 
PLoS ONE  2014;9(1):e87031.
Ionizing radiation (IR) cytotoxicity is primarily mediated through reactive oxygen species (ROS). Since tumor cells neutralize ROS by utilizing reducing equivalents, we hypothesized that measurements of reducing potential using real-time hyperpolarized (HP) magnetic resonance spectroscopy (MRS) and spectroscopic imaging (MRSI) can serve as a surrogate marker of IR induced ROS. This hypothesis was tested in a pre-clinical model of anaplastic thyroid carcinoma (ATC), an aggressive head and neck malignancy. Human ATC cell lines were utilized to test IR effects on ROS and reducing potential in vitro and [1-13C] pyruvate HP-MRS/MRSI imaging of ATC orthotopic xenografts was used to study in vivo effects of IR. IR increased ATC intra-cellular ROS levels resulting in a corresponding decrease in reducing equivalent levels. Exogenous manipulation of cellular ROS and reducing equivalent levels altered ATC radiosensitivity in a predictable manner. Irradiation of ATC xenografts resulted in an acute drop in reducing potential measured using HP-MRS, reflecting the shunting of reducing equivalents towards ROS neutralization. Residual tumor tissue post irradiation demonstrated heterogeneous viability. We have adapted HP-MRS/MRSI to non-invasively measure IR mediated changes in tumor reducing potential in real time. Continued development of this technology could facilitate the development of an adaptive clinical algorithm based on real-time adjustments in IR dose and dose mapping.
doi:10.1371/journal.pone.0087031
PMCID: PMC3903593  PMID: 24475215
13.  Sleep duration and plasma leptin concentrations in early pregnancy among lean and overweight/obese women: a cross sectional study 
BMC Research Notes  2014;7:20.
Background
Early-pregnancy short sleep duration is predictive of gestational diabetes and preeclampsia; mechanisms for these associations are unknown. Leptin, an adipocyte-derived peptide involved in regulating food intake and energy expenditure, may play a role in these observed associations. Given inconsistent reports linking short sleep duration with leptin, and absence of studies among pregnant women, we examined the association of maternal sleep duration with plasma leptin in early pregnancy.
Methods
This cross-sectional study included 830 pregnant women. Plasma leptin was measured in samples collected around 13 weeks gestation. Sleep duration was categorized as: ≤5, 6, 7–8 (reference), and ≥9 hours. Differences in leptin concentrations across categories were estimated using linear regression. Analyses were completed for lean and overweight/obese women.
Results
Overall, women with long sleep duration had elevated plasma leptin (p-value = 0.04). However, leptin concentrations were not statistically significantly elevated in women with a short sleep duration. There was no association of leptin with sleep duration among lean women. Among overweight/obese women, a U-shaped relation between leptin and sleep duration was observed: Mean leptin was elevated (β = 21.96 ng/ml, P < 0.001) among women reporting ≤5 hour of sleep compared with reference group; and women reporting ≥9 hours of sleep also had elevated leptin (β = 4.29 ng/ml, P = 0.09).
Conclusions
Short sleep duration, and to a lesser extent long sleep duration, were associated with elevated leptin among overweight/obese women. These data add some evidence to help understand mechanistic relationships of sleep duration with pregnancy complications.
doi:10.1186/1756-0500-7-20
PMCID: PMC3896691  PMID: 24405869
Leptin; Overweight; Obesity; Pregnancy; Sleep duration
14.  Idiopathic Inflammation of the Orbit and Contiguous Structures 
Ophthalmic plastic and reconstructive surgery  2012;28(4):10.1097/IOP.0b013e31822ddfb5.
doi:10.1097/IOP.0b013e31822ddfb5
PMCID: PMC3878054  PMID: 22082592
15.  Association of Retinol Binding Protein 4 with Risk of Gestational Diabetes 
Aim
We investigated association of maternal retinol binding protein 4 (RBP4) with risk of gestational diabetes (GDM).
Methods
GDM cases (N=173) and controls (N=187) were selected from among participants of a cohort study of risk factors of pregnancy complications. Early pregnancy (16 weeks on average) serum RBP4 concentration was measured using an ELISA-based immunoassay. Logistic regression was used to estimate unadjusted and adjusted odds ratios (ORs/aORs) and 95% confidence intervals (95%CI).
Results
Mean serum RBP4 was significantly higher among GDM cases compared with controls (47.1 vs. 41.1 μg/ml, respectively; p-value<0.05). Participants in the highest quartile for serum RBP4 had a 1.89-fold higher risk of GDM compared with participants in the lowest quartile (95%CI: 1.05-3.43). However, this relationship did not reach statistical significance after adjustment for confounders (aOR: 1.54; 95%CI: 0.82-2.90). Women who were ≥35 years old and who had high RBP4 (≥38.3 μg/ml, the median) had a 2.31-fold higher risk of GDM compared with women who were < 35 years old and had low RBP4 (<38.3 μg/ml) (aOR: 2.31; 95%CI: 1.26-4.23; p-value for interaction=0.021).
Conclusion
Overall, there is modest evidence of a positive association of early pregnancy elevated RBP4 concentration with increased GDM risk, particularly among women with advanced age.
doi:10.1016/j.diabres.2012.10.023
PMCID: PMC3544538  PMID: 23153527
Retinol binding protein 4; gestational diabetes; pregnancy; maternal age
16.  Risk of Spontaneous Preterm Birth in Relation to Maternal Depressive, Anxiety and Stress Symptoms 
Objective
To examine the risk of preterm birth (PTB) in relation to maternal psychiatric symptoms during pregnancy in Peruvian women.
Methods
This case control study included 479 PTB cases and 480 term controls. In-person interviews were conducted to assess women’s depressive, anxiety and stress symptoms using the Patient Health Questionnaire (PHQ-9) and the Depression Anxiety Stress Scales (DASS-21). Multivariable logistic regression procedures were used to estimate adjusted odds ratios (aOR) and 95% confidence intervals (CI).
Results
Compared with women reporting no or minimal depressive symptoms, the aOR (95% CI) for PTB associated with consecutive severity of depressive symptoms based on the PHQ-9 assessment method were as follows: mild 2.22 (95% CI 1.64–3.00) and moderate-severe 3.67 (95% CI 2.09–6.46). The corresponding aORs for mild, moderate, and moderate- severe depressive symptoms based on the DASS-21 assessment were, 1.00 (reference), 3.82 (95% CI 1.90–7.66) and 2.90 (95% CI 1.66–5.04), respectively. A positive gradient was observed for the odds of PTB with severity of anxiety (ptrend <0.001) and stress symptoms (ptrend <0.001).
Conclusions
The odds of PTB are increased in pregnant Peruvian women with psychiatric symptoms. Efforts to screen and treat affected women may modify risks of PTB and possibly other associated disorders.
PMCID: PMC3662498  PMID: 23447915
17.  Agreement of self-reported physician diagnosis of migraine with international classification of headache disorders-II migraine diagnostic criteria in a cross-sectional study of pregnant women 
BMC Women's Health  2013;13:50.
Background
Migraine, a common chronic-intermittent disorder among reproductive age women, has emerged as a novel risk factor for adverse perinatal outcomes. Diagnostic reliability of self-report of physician-diagnosed migraine has not been investigated in pregnancy cohort studies. We investigated agreement of self-report of physician-diagnosed migraine with the diagnostic criteria promoted by the International Classification of Headache Disorders, 2nd edition (ICHD-II).
Methods
The cross-sectional study was conducted among 500 women who provided information on a detailed migraine questionnaire that allowed us to apply all ICHD-II diagnostic criteria.
Results
Approximately 92% of women reporting a diagnosis of migraine had the diagnosis between the ages of 11 and 40 years (<10 years 6.8%; 11–20 years 38.8%; 21–30 years 42.7%; 31–40 years 10.7%; and >40 years 1.0%). We confirmed self-reported migraine in 81.6% of women when applying the ICHD-II criteria for definitive migraine (63.1%) and probable migraine (18.5%).
Conclusion
There is good agreement between self-reported migraine and ICHD-II-based migraine classification in this pregnancy cohort. We demonstrate the feasibility of using questionnaire-based migraine assessment according to full ICHD-II criteria in epidemiological studies of pregnant women.
doi:10.1186/1472-6874-13-50
PMCID: PMC3878724  PMID: 24330724
Migraine; Pregnancy; Diagnosis; ICHD-II; Self-report; Agreement
18.  Genome-wide and candidate gene association studies of placental abruption 
Placental abruption (PA), a pregnancy-related vascular disorder, is a leading cause of maternal and perinatal morbidity and mortality. The success of identifying genetic susceptibility loci for PA, a multi-factorial heritable disorder, has been limited. We conducted a genome-wide association study (GWAS) and candidate gene association study using 470 PA cases and 473 controls from Lima, Peru. Genotyping for common genetic variations (single nucleotide polymorphisms, SNPs) was conducted using the Illumina Cardio-Metabo Chip platform. Common variations in 35 genes that participate in mitochondrial biogenesis (MB) and oxidative phosphorylation (OS) were selected for the candidate gene study. Regression models were fit to examine associations of each SNP with risk of PA. In pathway analyses, we examined functions and functional relationships of genes represented by the top GWAS hits. Genetic risk scores (GRS), based on top hits of the GWAS and candidate gene analyses, respectively, were computed using the risk allele counting method. The top hit in the GWAS analyses was rs1238566 (empirical P-value=1.04e-4 and FDR-adjusted P-value=5.65E-04) in FLI-1 gene, a megakaryocyte-specific transcription factor. Networks of genes involved in lipid metabolism and cell signaling were significantly enriched by the 51 genes whose SNPs were among the top 200 GWAS hits (P-value <2.1e-3). SNPs known to regulate MB (e.g. CAMK2B, NR1H3, PPARG, PRKCA, and THRB) and OP (e.g., COX5A, and NDUF family of genes) were associated with PA risk (P-value <0.05). GRS was significantly associated with PA risk (trend P-value <0.001 and 0.01 for GWAS and candidate gene based GRS, respectively). Our study suggests that integrating multiple analytical strategies in genetic association studies can provide opportunities for identifying genetic risk factors and novel molecular mechanisms that underlie PA.
PMCID: PMC3773564  PMID: 24046805
Placental abruption; genome-wide association study; pathway analyses; candidate gene; genetic risk score
19.  ErbB3 downregulation enhances luminal breast tumor response to antiestrogens 
The Journal of Clinical Investigation  2013;123(10):4329-4343.
Aberrant regulation of the erythroblastosis oncogene B (ErbB) family of receptor tyrosine kinases (RTKs) and their ligands is common in human cancers. ErbB3 is required in luminal mammary epithelial cells (MECs) for growth and survival. Since breast cancer phenotypes may reflect biological traits of the MECs from which they originate, we tested the hypothesis that ErbB3 drives luminal breast cancer growth. We found higher ERBB3 expression and more frequent ERBB3 gene copy gains in luminal A/B breast cancers compared with other breast cancer subtypes. In cell culture, ErbB3 increased growth of luminal breast cancer cells. Targeted depletion of ErbB3 with an anti-ErbB3 antibody decreased 3D colony growth, increased apoptosis, and decreased tumor growth in vivo. Treatment of clinical breast tumors with the antiendocrine drug fulvestrant resulted in increased ErbB3 expression and PI3K/mTOR signaling. Depletion of ErbB3 in fulvestrant-treated tumor cells reduced PI3K/mTOR signaling, thus decreasing tumor cell survival and tumor growth. Fulvestrant treatment increased phosphorylation of all ErbB family RTKs; however, phospho-RTK upregulation was not seen in tumors treated with both fulvestrant and anti-ErbB3. These data indicate that upregulation of ErbB3 in luminal breast cancer cells promotes growth, survival, and resistance to fulvestrant, thus suggesting ErbB3 as a target for breast cancer treatment.
doi:10.1172/JCI66764
PMCID: PMC3784526  PMID: 23999432
20.  Intestinal Parasitic Infection and Nutritional Status among School Children in Angolela, Ethiopia 
Introduction
To estimate the prevalence of parasitic infection and nutritional status, and to evaluate the extent to which the two are associated among schoolchildren in rural Ethiopia.
Methods
This is a cross sectional study of 664 students aged from 6 to 19 years old from Angolela, Ethiopia. Socio-demographic information was collected using a structured questionnaire. Anthropometric measurements were taken at the time of interview. Examinations of fecal samples for helminthic and protozoan parasitic infections were performed. Logistic regression procedures were employed to evaluate the association between stunting, underweightedness, and wasting with parasitic infections.
Results
One-third of the participants were found to have a protozoan infection, while 7.1% were found to have a helminthic infection. Approximately 11% of the students were stunted, 19.6% were wasted, and 20.8% were underweight. Severely underweight boys were 3.88-times more likely than boys of adequate weight (OR=3.88, 95%CI: 1.12–13.52) to be diagnosed with protozoan infections. Among girls, those who were severely stunted were approximately 12 times (OR=11.84, 95%CI: 1.72–81.62) as likely to be infected with a helminthic parasite, than those who were not. Overall, there was a deficit in normal growth patterns as indicated by lower than average anthropometric measures.
Discussion and conclusion
There is a high prevalence of intestinal parasitic infections. Stunting, wasting, and underweightedness were also prevalent, and showed patterns of associations with intestinal parasitic infections. Efforts should be made to strengthen and expand school and community-based programs that promote inexpensive, though effective, practices to prevent the spread of parasitic diseases. Initiatives aimed at improving the nutritional status of school children are also needed.
PMCID: PMC3587130  PMID: 23362622
intestinal parasitic infection; helminth infection; schoolchildren; nutrition; anthropometric measures
21.  Risk of Preterm Delivery and Hypertensive Disorders of Pregnancy in Relation to Maternal Comorbid Mood and Migraine Disorders during Pregnancy 
Summary
We evaluated risks of preterm delivery and hypertensive disorders of pregnancy among pregnant women with mood and migraine disorders. We used data from a cohort study of 3,432 pregnant women. Maternal pre-gestational or early pregnancy (before 20 weeks gestational) mood disorder and pre-gestational migraine diagnoses were ascertained from in-person interview and medical record review. We fitted generalized linear models to derive risk ratios (RR) and 95% confidence intervals (CI) of preterm delivery and hypertensive disorders of pregnancy for women with isolated mood, isolated migraine, and comorbid mood-migraine disorders, respectively. Reported RRs were adjusted for maternal age, race/ethnicity, marital status, parity, smoking status, chronic hypertension or pre-existing diabetes mellitus, and pre-pregnancy body mass index. Women without mood or migraine disorders were defined as the reference group. The risks for preterm delivery and hypertensive disorders of pregnancy were more consistently elevated among women with comorbid mood-migraine disorders than among women with isolated mood or migraine disorder. Women with comorbid disorders were almost twice as likely to deliver preterm (adjusted RR=1.87, 95% CI 1.05–3.34) compared with the referent group. There was no clear evidence of increased risks of preterm delivery and its subtypes with isolated migraine disorder. Women with mood disorder had elevated risks of preeclampsia (adjusted RR=3.57, 95% CI 1.83–6.99). Our results suggest an association between isolated migraine disorder and pregnancy-induced hypertension (adjusted RR=1.42, 95% CI 1.00–2.01). This is the first study examining perinatal outcomes in women with comorbid mood-migraine disorders. Pregnant women with a history of migraine may benefit from depression screening during prenatal care, and vigilant monitoring, especially for women with comorbid mood-migraine disorders.
doi:10.1111/j.1365-3016.2010.01182.x
PMCID: PMC3756187  PMID: 21281324
Mood disorders; Migraine; Pregnant women; Preterm Delivery; Preeclampsia
22.  Preterm Delivery Risk in Relation to Maternal Occupational and Leisure Time Physical Activity Among Thai Women 
Background
Little is known about the relationship between maternal occupational physical exertion and leisure time physical activity (LTPA) with preterm delivery (PTD) among Thai women, a population that differs in many respects from women in Western countries.
Objectives
To evaluate associations of maternal occupational physical exertion and LTPA with PTD in aggregate and in subgroups (i.e., spontaneous preterm labor, preterm premature rupture of membrane, medically indicated preterm delivery, moderate preterm delivery [gestational age 32–36 weeks], and very preterm delivery [<32 weeks]) among Thai women.
Methods
This case-control study included 467 PTD cases and 467 term controls. Maternal occupational exertion during pregnancy, as well as habitual engagement in LTPA before and during pregnancy was assessed using a structured questionnaire administered after delivery. Logistic regression procedures were used to examine relationships between both occupational and leisure time physical activity and PTD.
Results
After controlling for potential confounders, women who reported heavy physical occupational exertion during pregnancy, compared with other women, had a 2.42-fold increased risk of PTD overall [OR=2.42, 95% CI: 1.15, 5.09]. Very PTD [OR=4.57, 95% CI: 1.65, 12.64] and medically indicated PTD [OR=3.79, 95% CI: 1.54, 9.32] were particularly strongly associated with heavy occupational exertion. Maternal participation in LTPA before pregnancy was associated with a 24% reduction in PTD risk overall [OR=0.76, 95% CI: 0.57, 1.00], though no similar pattern in risk reduction was observed for LTPA performed during the first 6 months of pregnancy [OR=0.96, 95% CI: 0.68, 1.36].
Conclusion
Consistent with some previous reports, we noted that heavy occupational physical exertion is associated with at least a doubling in PTD risk. Patterns of associations of PTD risk with LTPA were less well delineated in this Thai population.
PMCID: PMC3756907  PMID: 23997840
Exercise; Occupational Activity; Physical Activity; Pregnancy; Preterm Delivery
23.  Tumor grafts derived from patients with head and neck squamous carcinoma authentically maintain the molecular and histologic characteristics of human cancers 
Background
The patient-derived xenograft (PDX) model is likely to reflect human tumor biology more accurately than cultured cell lines because human tumors are implanted directly into animals; maintained in an in vivo, three-dimensional environment; and never cultured on plastic. PDX models of head and neck squamous cell carcinoma (HNSCC) have been developed previously but were not well characterized at the molecular level. HNSCC is a deadly and disfiguring disease for which better systemic therapy is desperately needed. The development of new therapies and the understanding of HNSCC biology both depend upon clinically relevant animal models. We developed and characterized the patient-derived xenograft (PDX) model because it is likely to recapitulate human tumor biology.
Methods
We transplanted 30 primary tumors directly into mice. The histology and stromal components were analyzed by immunohistochemistry. Gene expression analysis was conducted on patient tumors and on PDXs and cell lines derived from one PDX and from independent, human tumors.
Results
Five of 30 (17%) transplanted tumors could be serially passaged. Engraftment was more frequent among HNSCC with poor differentiation and nodal disease. The tumors maintained the histologic characteristics of the parent tumor, although human stromal components were lost upon engraftment. The degree of difference in gene expression between the PDX and its parent tumor varied widely but was stable up to the tenth generation in one PDX. For genes whose expression differed between parent tumors and cell lines in culture, the PDX expression pattern was very similar to that of the parent tumor. There were also significant expression differences between the human tumors that subsequently grew in mice and those that did not, suggesting that this model enriches for cancers with distinct biological features. The PDX model was used successfully to test targeted drugs in vivo.
Conclusion
The PDX model for HNSCC is feasible, recapitulates the histology of the original tumor, and generates stable gene expression patterns. Gene expression patterns and histology suggested that the PDX more closely recapitulated the parental tumor than did cells in culture. Thus, the PDX is a robust model in which to evaluate tumor biology and novel therapeutics.
doi:10.1186/1479-5876-11-198
PMCID: PMC3844397  PMID: 23981300
Patient-derived xenograft; Translational animal models; Gene expression; Head and neck cancer
24.  Intimate Partner Violence (IPV) During Pregnancy: A Pilot Intervention Program in Lima, Peru 
Journal of interpersonal violence  2010;25(11):2054-2076.
This pilot study examined the effectiveness of standard care and an empowerment intervention for abused pregnant women. Severe psychological abuse was most prevalent (42.2%) among this sample of women. Compared with women in the standard care group at the post-intervention survey, women in the empowerment group were more likely to hide money (44.6% vs. 34.3%), establish a code with family or friends (19.6% vs. 16.2%), ask neighbors to call police if violence began (6.9% vs. 1.0%), had available bank account numbers (17.1% vs. 3.1%), had valuable jewelry (8.4% vs. 3.8%), and had available a hidden bag with extra clothing (9.0% vs. 3.1%). However, there was no statistically significant difference in health-related quality of life, adoption of safety behaviors, and use of community resources between women in the two groups. Simply asking pregnant women about abuse and offering referral could potentially interrupt and prevent further abuse.
doi:10.1177/0886260509354517
PMCID: PMC3741342  PMID: 20145196
Intimate partner violence; Pregnant women; Intervention; Peru
25.  Maternal blood mitochondrial DNA copy number and placental abruption risk: results from a preliminary study 
Oxidative stress and impaired placental function – pathways implicated in the pathogenesis of placental abruption – have their origins extending to mitochondrial dysfunction. To the best of our knowledge, there are no published reports of associations of placental abruption with circulating mitochondrial DNA (mtDNA) copy number – a novel biomarker of systemic mitochondrial dysfunction. This pilot case-control study was comprised of 233 placental abruption cases and 238 non-abruption controls. Real-time quantitative polymerase chain reaction (PCR) was used to assess the relative copy number of mtDNA in maternal whole blood samples collected at delivery. Logistic regression procedures were used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI). There was some evidence of an increased odds of placental abruption with the highest quartile of mtDNA copy number (P for trend = 0.09) after controlling for confounders. The odds of placental abruption was elevated among women with higher mtDNA copy number (≥336.9) as compared with those with lower values (<336.9) (adjusted OR = 1.60; 95% CI 1.04-2.46). Women diagnosed with preeclampsia and with elevated mtDNA copy number had a dramatically increased odds of placental abruption as compared with normotensive women without elevated mtDNA copy number (adjusted OR = 6.66; 95% CI 2.58-17.16). Maternal mitochondrial dysfunction appears to be associated with placental abruption in the presence of preeclampsia. Replication in other studies, particularly prospective cohort studies and those that allow for tissue specific assessment of mitochondrial dysfunction (e.g., the placenta) are needed to further understand cellular and genomic biomarkers of normal and abnormal placental function.
PMCID: PMC3709116  PMID: 23875065
Placental abruption; mitochondrion; mitochondrial DNA; pregnancy; biomarkers

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