Nina Markovic

Uric Acid Is as Important as Proteinuria in Identifying Fetal Risk in Women With Gestational Hypertension

Gestational hypertension is differentiated into higher and lower risk by the presence or absence of proteinuria. We asked if hyperuricemia, a common finding in pregnancy hypertension, might also be an indicator of increased risk. We examined fetal outcome data from 972 pregnancies collected from 1997 to 2002 in a nested case-control study. Participants were nulliparous with no known medical complications. The frequency of preterm birth, the duration of pregnancy, frequency of small-for-gestational-age infants, and birth weight centile were determined for pregnancies assigned to 8 categories by the presence or absence of combinations of hypertension, hyperuricemia, and proteinuria. In women with gestational hypertension, hyperuricemia was associated with shorter gestations and smaller birth weight centiles and increased risk of preterm birth and small-for-gestational-age infants. Hyperuricemia increased the risk of these outcomes in the presence or absence of proteinuria. Risk was also increased in a small group of women with hyperuricemia and proteinuria without hypertension. Women with only hypertension and hyperuricemia have similar or greater risk as women with only hypertension and proteinuria. Those with hypertension, proteinuria, and hyperuricemia have greater risk than those with hypertension and proteinuria alone. The risk of these outcomes increased with increasing uric acid. Hyperuricemia is at least as effective as proteinuria at identifying gestational hypertensive pregnancies at increased risk. Uric acid should be reexamined for clinical and research utility.

Selective Overexpression of the Hypoxia-Inducible Transcription Factor, HIF-2α, in Placentas from Women with Preeclampsia

Abstract Transcription factors orchestrate the development of extraembryonic tissues. Because placental hypoxia likely plays an important role in both normal and abnormal placentation, we have been investigating the hypoxia-inducible transcription factors (HIFs) in the human placenta. In this report, we focus on the placentas from women with preeclampsia. Because the placenta is a large, heterogeneous organ, we employed a systematic and unbiased approach to placental sampling, and our results are based on the analyses of eight biopsy sites per placenta. We observed no significant differences in HIF-1α or -2α mRNA expression between normal term and preeclamptic placentas. Nor was HIF protein expression significantly different, with the notable exception of HIF-2α, which, on average, was increased by 1.7-fold in the preeclamptic placentas (P < 0.03 vs. normal term placentas). Considering all 48 paired placental biopsy sites (eight sites each for six normal term and six preeclamptic placentas), HIF-2α protein levels in the preeclamptic placentas exceeded those in the normal term placentas in 39, or 81%, of the paired sites (P < 0.0013). The HIF-2α immunoreactivity was mainly located in the nuclei of the syncytiotrophoblast and fetoplacental vascular endothelium in the preeclamptic villous placenta. To control for the earlier gestational age of the preeclamptic placentas, an additional group of placentas from preterm deliveries without preeclampsia were also evaluated. The HIF protein expression was comparable in these preterm specimens and the normal term placentas. We conclude that protein expression of HIF-2α, but not of HIF-1α or -1β, is selectively increased in the preeclamptic placenta. The molecular mechanism(s) of this abnormality as well as the genes affected downstream are currently under investigation. To our knowledge, this is the first report of abnormal HIF-2α expression in human disease other than cancer.

Agonistic angiotensin II type 1 receptor autoantibodies in postpartum women with a history of preeclampsia

Activating angiotensin II type 1 autoantibodies (AT1-AAs) develop in women with preeclampsia and may contribute to the disorder. Insulin resistance and serum concentrations of the antiangiogenic soluble fms-like tyrosine kinase 1 (sFlt-1) are also increased in women with preeclampsia compared with normal pregnancy. sFlt-1 and insulin resistance decrease substantially after delivery; however, significant group differences persist postpartum. Women who have had preeclampsia are at increased cardiovascular risk later in life. We measured AT1-AAs in groups of women with previous preeclampsia (n=29) and previous normal pregnancies (n=35) 18±9 months after the first completed pregnancy. These women had had sFlt-1, insulin resistance homeostasis model assessment score, and related cardiovascular risk factors measured. Activating antibodies were detected by the chronotropic response of cultured neonatal rat cardiomyocytes coupled with receptor-specific antagonists (losartan and prazosin). AT1-AAs were detected in 17.2% of women with previous preeclampsia versus 2.9% of women with previous uncomplicated pregnancies (P<0.05). In contrast, there was no difference in the prevalence of autoantibodies against the α1-adrenoceptor (10% of previous preeclamptic versus 14% of previous normal pregnant). Women with activating autoantibodies had significantly increased sFlt-1, reduced free vascular endothelial growth factor, and higher insulin resistance homeostasis model assessment values compared with autoantibody-negative women. These data suggest that, as with sFlt-1 and insulin resistance, the AT1-AA does not regress completely after delivery and, secondarily, that correlations exist among these variables. The impact of AT1-AA after preeclampsia, especially in the context of cardiovascular risk, remains to be determined.

Physical activity and cardiovascular risk factors in a developing population.

PURPOSE Noncommunicable diseases are emerging in developing countries. However, few studies have been conducted in those countries to evaluate the role of physical activity in the development of cardiovascular diseases. This study investigated physical activity and its relationship to risk factors for cardiovascular disease in a large population (N = 799) of civil servants from Benin City, Nigeria. METHODS Physical activity levels were estimated by an interviewer-administered questionnaire, which determined the average hours per week over the past year spent in occupational and leisure activities. Time spent walking or biking to work was assessed as well. Other major measures included body mass index (BMI), waist-hip ratio (WHR), blood pressures, plasma insulin level, lipid profiles, and diet. RESULTS More of the physical activity was attributed to occupational than to leisure activities. Compared with women, men had a higher activity level. No significant trend was observed across age groups. Male senior staff (a marker of higher socioeconomic status) had a lower physical activity level than male junior staff. Physical activity, especially time walking or biking to work, was inversely correlated with weight, BMI, WHR, blood pressures, insulin, total cholesterol, LDL and HDL cholesterol, and triglycerides in men, while such correlations were not consistent in women. In multivariate analysis in men, blood pressure and insulin were independently associated with BMI but not with walking, while an independent inverse association was seen between walking and BMI. CONCLUSION Lack of physical activity was associated with adverse risk profiles for cardiovascular disease in this developing population.

Preeclampsia Activates Circulating Immune Cells with Engagement of the NF‐κB Pathway

Compelling evidence implicates peripheral immune activation in the pathophysiology of preeclampsia. Polymorphonuclear neutrophils appear to be the cells most strongly affected, with changes in expression of surface markers and release of granule enzymes. Here, we investigated activation in additional leukocyte populations among women with preeclampsia.

Do men become infertile after having sexually transmitted urethritis? An epidemiologic examination

OBJECTIVE To critically assess the possibility that gonorrhea or chlamydia causes male infertility. DESIGN Comprehensive literature review structured to evaluate the epidemiologic tenets for causality, including biologic plausibility, strength of association, dose response, consistency, temporality, and treatment effect. RESULT(S) It is biologically plausible that gonorrhea and/or chlamydia could cause male infertility. There is clinical and pathologic evidence linking these pathogens to urethritis, linking urethritis to epididymo-orchitis, and linking epididymo-orchitis to infertility. Retrospective epidemiologic results also support an association between chlamydia serologies and male infertility, which in most of these small studies does not reach the level of statistical significance. However, there is no consistent epidemiologic evidence that these pathogens alter sperm characteristics. We discuss the methodologic limitations of previous epidemiologic studies and suggest strategies for future research. CONCLUSION(S) Whether gonorrhea and/or chlamydia cause male infertility is currently unclear. Sound methodologic research strategies must be applied to future studies.

Elevated asymmetric dimethylarginine concentrations precede clinical preeclampsia, but not pregnancies with small-for-gestational-age infants.

OBJECTIVE The purpose of this study was to investigate maternal plasma concentrations of asymmetric dimethylarginine (ADMA) in mid pregnancy and at the time of disease in women who experience preeclampsia, compared with women with uncomplicated pregnancies and women with small-for-gestational-age infants. STUDY DESIGN Plasma samples were collected at mid-pregnancy and at the time of delivery from 31 women with uncomplicated pregnancies, from 12 women with small-for-gestational-age infants, and from 15 women with preeclampsia. ADMA and L-arginine concentrations were measured using high-pressure liquid chromatography. RESULTS Maternal ADMA concentrations were elevated at mid pregnancy and remained elevated at delivery in women who later experienced preeclampsia (0.45 +/- 0.09 micromol/L) compared with women with uncomplicated pregnancies (0.34 +/- 0.08 micromol/L; P < .01) and with women with small-for-gestational-age infants (0.33 +/- 0.06 micromol/L; P < .01). CONCLUSION Maternal ADMA concentrations are higher in mid pregnancy in women who experience preeclampsia, compared with women with uncomplicated pregnancies and small-for-gestational-age infants. Elevated ADMA concentration before clinical onset of preeclampsia suggests a role of this nitric oxide synthase inhibitor in the pathophysiologic condition of preeclampsia.

HIV Infection and Sexual Risk among Men Who Have Sex with Men and Women (MSMW): A Systematic Review and Meta-Analysis

Objectives To estimate the number of men who have sex with men and women who are HIV-positive in the United States, and to compare HIV prevalence rates between men who have sex with men and women, men who have sex with men only, and men who have sex with women exclusively. Methods Following PRISMA guidelines, we conducted a systematic review and meta-analysis of reports referencing HIV prevalence and men who have sex with men and women. We searched PubMed and Ovid PsycINFO for peer-reviewed, U.S.-based articles reporting on HIV prevalence among men who have sex with men and women. We conducted event rate, effect size, moderation and sensitivity analyses. Results We estimate that 1.0% of U.S. males are bisexually-behaving, and that 121,800 bisexually-behaving men are HIV-positive. Men who have sex with men and women are less than half as likely to be HIV-positive as men who have sex with men only (16.9% vs. 33.3%; OR = 0.41, 95% CI: 0.31, 0.54), but more than five times as likely to be HIV-positive as men who have sex with women exclusively (18.3% vs. 3.5%; OR = 5.71, 95% CI: 3.47, 9.39). They are less likely to engage in unprotected receptive anal intercourse than men who have sex with men only (15.9% vs. 35.0%; OR = 0.36, 95% CI: 0.28, 0.46). Men who have sex with men and women in samples with high racial/ethnic minority proportions had significantly higher HIV prevalence than their counterparts in low racial/ethnic minority samples. Conclusions This represents the first meta-analysis of HIV prevalence in the U.S. between men who have sex with men and women and men who have sex with men only. Data collection, research, and HIV prevention and care delivery specifically tailored to men who have sex with men and women are necessary to better quantify and ameliorate this population’s HIV burden.

Sexual Abuse, Sexual Orientation, and Obesity in Women

BACKGROUND Among adult women an association between childhood sexual abuse (CSA) and obesity has been observed. Research with lesbian women has consistently identified high rates of obesity as well as frequent reports of CSA, but associations between sexual abuse and obesity have not been fully explored. Our aim was to investigate the relationship between sexual abuse (SA) history and obesity among heterosexual (n = 392) and lesbian (n = 475) women (age 35-64) who participated in the Epidemiologic STudy of HEalth Risk in Women (ESTHER) Project in Pittsburgh, Pennsylvania. METHODS Obesity was defined as body mass index (BMI) > or =30. Covariates included self-reported SA, sexual orientation, demographic factors, and history of a depression or anxiety diagnosis. SA history was assessed by three factors: (1) SA experienced under the age of 18 by a family member or (2) by a nonfamily member and (3) forced, unwanted sexual experience(s) at age > or =18. Data were analyzed using chi-square tests and logistic regression models. RESULTS Multiple logistic regression analyses revealed that obesity was associated with African American race, lesbian sexual orientation, intrafamilial CSA, and history of mental health diagnosis. Protective factors were having a household income of at least

Increased Myeloperoxidase in the Placenta and Circulation of Women With Preeclampsia

75,000 and having a bachelors degree or higher. CONCLUSIONS Results suggest that lesbian women may be at greater risk of obesity than heterosexual women and that intrafamilial CSA--regardless of sexual orientation--may play a role in the development of obesity.